Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer

Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Help Center Sign In Submit a Preprint Cite Share Download PDF Primary research Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer Chen Peng, Yansong Yang, Li Ji, Panpan Yang, Xiaoqing Yang, Yuquan Zhang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-20434/v3 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jul, 2020 Read the published version in Cancer Cell International → Version 3 posted 9 You are reading this latest preprint version Show more versions Abstract Background: Cell cycle dysregulation plays a key role in the pathogenesis of malignant tumors. As a part of the CDK-activating kinase (CAK) trimeric complex, cyclin H is necessary to regulate the cell cycle and proliferation. This investigation aims to characterize the clinical significance and the biological functions of cyclin H in ovarian cancer. Methods: Immunohistochemical staining was performed on 60 ovarian cancer cases, and a correlation between cyclin H expression and the clinical characteristics of ovarian cancer was analyzed. The function of cyclin H in ovarian cancer was further explored using HO8910 cells and a subcutaneous xenograft model of nude mice. Result: Cyclin H was slightly expressed in grade 1 ovarian cancer but highly expressed in grade 2 and grade 3 cancerous tissues. The Spearman’s rank correlation analysis showed that the expression of cyclin H is positively correlated with the tumor grade, the FIGO stage, histological grade, and the peritoneal metastasis of ovarian cancer and is also positively correlated with the Ki67 and p-CDK2 in ovarian cancer. Additionally, we found that the five-year survival rate was higher in patients expressing low cyclin H than those expressing high cyclin H . Further, knockdown of cyclin H was achieved using an shRNA in HO8910 ovarian cancer cell line. Silencing cyclin H resulted in a G1/S cell cycle arrest in ovarian cancer cells suppressing its growth. The Ki67 expression was also decreased in cyclin H silenced ovarian cancer. Conclusion: These results suggest that high expression of cyclin H predicts the poor prognosis and promotes the growth of ovarian cancer by regulating the cell cycle. Cancer Biology Cyclin H CDK2 ovarian cancer cell cycle Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Ovarian cancer is the seventh most common tumor in women and also the most lethal gynecological malignancy with a high recurrence and mortality rate[1–3]. A five-year survival rate of an ovarian cancer patient is less than 35% [4]. Most ovarian cancer patients do not get diagnosed until the advanced stages because they do not show symptoms in the early stages [3, 5, 6]. Therefore, investigating the pathogenesis of ovarian cancer and finding new target proteins that are closely related to the occurrence, development, and prognosis of ovarian cancer may increase the early diagnosis rate and provide new ideas in treating the disease. Deregulation of cell cycle and abnormal signaling pathways caused by various reasons are general features of the tumor cells [7]. Excessive cell proliferation, blocked differentiation, and impaired apoptosis play a key role in the occurrence and development of tumors. Clarifying the molecular mechanism of cell cycle regulation in tumor cells may provide the basis for developing tumor treatment strategies [8, 9]. The three main types of molecules involved in cell cycle regulation are as follows: cyclin, cyclin-dependent kinase (CDK), and cyclin-dependent kinase inhibitor (CDKI). The expression of cell cycle regulators is linked to tumor development, prognosis, and treatment response [10]. Cyclin H, a member of the cyclin family, together with CDK7 and MAT1 forms the CDK-activating kinase (CAK) trimeric complex, which is necessary for the regulation of cell cycle and proliferation. Abnormal expression of cyclin H is reported in a variety of tumors such as breast cancer[11], esophageal cancer[12], endometrial cancer[13], and gastrointestinal stromal tumors[14]. However, the clinical significance and the biological function of cyclin H in ovarian cancer remains unclear. Immunohistochemical staining was used in this study to evaluate the expression of cyclin H in 60 pathological specimens of ovarian cancer with different grades. The correlation of cyclin H with the clinical characteristics, prognosis, and the proliferation parameters of tumor patients were analyzed. Additionally, we down-regulated the expression of cyclin H in ovarian cancer cells using shRNA and explored its effect on cell cycle and tumor growth. This study revealed that cyclin H is highly expressed in high-grade ovarian cancers and promotes the growth of ovarian cancer by regulating the cell cycle. Methods Pathological Samples Paraffin embedded ovarian cancer specimens were obtained from 60 patients who underwent surgery in the Department of Obstetrics and Gynecology at Affiliated Hospital of Nantong University from June 2009 to April 2013. All the tumors were from newly diagnosed ovarian cancer patients and also from the patients who did not receive any treatment before surgery. Among these, four patients’ survival information was missing. All the investigations in this study were performed after obtaining informed consent. The study was approved by the Research Ethics Committee of the Affiliated Hospital of Nantong University. Immunohistochemistry (IHC) and quantification Formalin-fixed and paraffin-embedded sections were prepared for all the tissues and reviewed by three pathologists. The protein expression of cyclin H, Ki67, and p-CDK2 in ovarian cancer was determined by IHC. In short, ovarian cancer tissue sections were first dewaxed in xylene, then rehydrated through gradient ethanol, and heated in Tris-EDTA buffer (pH 8.0) for 15 min in a microwave oven to retrieve the antigen. After cooling it at room temperature and rinsing with phosphate-buffered saline, slides were incubated with 3% hydrogen peroxide for 10 min to block endogenous peroxidase activity. Next, it was incubated with 2% bovine serum albumin (Beyotime Biotechnology, Shanghai, China) for 2 h at room temperature to block nonspecific reactions. Tissue sections were then incubated with cyclin H monoclonal antibody (1:50, MA5–32331, Thermo Fisher Scientific, Waltham, MA, USA), Ki67 monoclonal antibody (1:300, ab92742, Abcam, Cambridge, MA, USA) or p-CDK2 polyclonal antibody (1:100, PA5–38128, Thermo Fisher Scientific) at 4 °C overnight. All the slides were finally visualized using the Envision kit (Dako, Glostrup, Denmark) as per the instructions and then counterstained with hematoxylin, dehydrated, and sealed with coverslips. The sections were imaged under an optical microscope and evaluated in a blinded manner. More than 500 cells in each slide were counted to determine the mean positive percentage and the expression range was scored as follows: 0 (75% points). For the frozen sections of tumors from nude mice, dewaxing steps were omitted. Cell culture and transfection Human ovarian carcinoma HO8910 cell line was used in this study, which was obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). The HO8910 cell line was cultured in RPMI 1640 (Gibco, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS, Gibco ), 2 mM L-glutamine, 0.11g/L Sodium Pyruvate, 100 U/mL penicillin-streptomycin mixture (Gibco) at 37 °C in 5% CO 2 incubator. Cyclin H shRNA(sequence: 5’-CCG GCG ACC TGG TAG AAT CTC TCT ACT CGA GTA GAG AGA TTC TAC CAG GTC GTT TTT G-3’) was synthesized by Sangon Biotech (Shanghai, China), cloned into a pLenti-CMV-puro vector and then transfected to HO8910 cells using FuGENE transfection reagent (Promega, Madison, WI, USA ). The stable transfected cell lines were obtained after screening the cells with 1 µg/mL of puromycin. Empty plasmids were transfected into HO8910 cells and used as a control. Cell viability assay Cells were seeded in a 96 well plate (3000 cells per well) and cultured in complete RPMI 1640 medium (with 10% fetal bovine serum). Cell viability was measured at time points 0, 12, 24, 48, and 72 h after seeding by cell counting kit-8 (C0038, Beyotime, Shanghai, China) according to the manufacturer’s instructions. Five wells were used for each time point, and their cell viability was measured and compared to the initial cell viability. Western blot HO8910 cells were harvested by trypsin, washed with PBS, and collected after centrifugation. Cell pellets were resuspended with cell lysate buffer and incubated on ice for 20 min. For tumor samples, 1 mL of cell lysate buffer was added to 0.1 g of tissue followed by homogenization and centrifugation. Prepared samples were run on SDS-PAGE gel and transferred to polyvinylidene fluoride membranes (0.2 µm, Millipore, USA). After blocking with 5% non-fat milk, the membranes were incubated with cyclin H antibody (1:1500, MA5–32331, Thermo Fisher Scientific), MAT1 antibody (1:1000, ab129176, Abcam), CDK7 antibody (1:1000, 2916, Cell Signaling Technology, Danvers, MA, USA), p-CDK2 antibody (1:100, PA5–38128, Thermo Fisher Scientific) or CDK2 antibody (1:1000, 2546, Cell Signaling Technology) and then incubated with HRP goat anti-rabbit or mouse IgG (ABclonal, Wuhan, China). Membranes were finally visualized using an enhanced chemiluminescence reagent (34095, Thermo Pierce) and GAPDH (1:2000, Abcam) was used as a control. Quantitative PCR Total RNA of HO8910 cells was isolated using Trizol (Invitrogen) and reverse transcription was done using a commercial kit (RR047B, TaKaRa, Tokyo, Japan) that contained gDNA Eraser to eliminate genomic DNA contamination. The relative mRNA level of cyclin H was determined by real-time quantitative PCR (RR420L, TaKaRa), where β-actin was used as a control. The following primers were used in the reaction: cyclin H forward, 5’-TGT TCG GTG TTT AAG CCA GCA-3’; cyclin H reverse, 5’-TCC TGG GGT GAT ATT CCA TTA CT-3’; β-actin forward, 5’-TCG AGC ACG GCA TCG TCA CCA-3’; β-actin reverse, 5’-ATA GCA ACG TAC ATG GCT-3’. Cell cycle detection HO8910 cells were synchronized by deprivation of serum 4q 72 h. The serum-free medium was then replaced by complete medium, and cells were cultured for another 48 h before collection. Cells were harvested using trypsinization, and a single-cell suspension was prepared before fixing and staining them. Propidium staining was done using a detection kit (C1052, Beyotime) and was detected by BD FACSCanto II (San Diego, CA, USA). The data was analyzed using Modfit software, and the percentage of cells in each phase were counted. Tumor model Female BALBC/c nude mice (5–6 weeks old, 14–16 g) were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China) and maintained in specific pathogen-free conditions. HO8910 cells (5 × 10 5 /mouse) in 100 µL of PBS were inoculated subcutaneously to the nude mice, in the flank. Tumor diameters were measured with digital calipers every other day, and the tumor volume was calculated by the following formula: Volume = (width) 2 × length/2. All animal experiments were performed according to the Guidelines for the Care and Use of Laboratory Animals (No. 55 issued by Ministry of Health, China on January 25, 1998) and were approved by the Ethics Committee for Laboratory Animals of Nantong University. Statistical Analysis IBM SPSS was used for all statistical analyses. Chi-square test was used for clinicopathological categorical variables, and the overall survival was analyzed by the Kaplan-Meier method. T-test was used for studying the difference between the two groups. Spearman’s rank correlation analysis was used to measure the association between the expression of cyclin H, Ki67, and p-CDK2. Differences were considered statistically significant at p <0.05. Results High expression of cyclin H in ovarian cancer. To investigate the expression and the potential role of cyclin H in ovarian cancer, immunohistochemical staining was performed on 60 cases of ovarian cancer, and cyclin H expression was scored subsequently. Representative results of immunohistochemistry are shown in Figure 1. In the ovarian cancer tissues, cyclin H is localized in the nucleus and the cytoplasm. The mean percentage of cyclin H positive cells was 33.16% (ranged from 3.10% to 77.48%). Cyclin H was slightly expressed in grade 1 ovarian cancer while highly expressed in high grade 2 and grade 3 samples (Fig. 1 A-C). High cyclin H expression was significantly correlated with the increased tumor grade (Fig. 1 D and Table1). Correlation between cyclin H expression and Clinicopathological Variables of ovarian cancer. Further, to explore the potential physiological or the pathological role of cyclin H in ovarian cancer, the correlation between cyclin H and the clinicopathological parameters was analyzed and summarized in Table 1. The result of spearman Spearman’s rank correlation analysis showed that cyclin H in ovarian cancer was not associated with age, histological subtype, residual tumor size, and chemotherapy. Interestingly, Cyclin H positively correlated with the FIGO (International Federation of Gynecology and Obstetrics) stage (P = 0.002), histologic grade (P = 0.0017), and the peritoneal metastasis. Compared to the patients with no peritoneal metastasis, cyclin H expression was significantly increased in patients with malignant tumor cells in peritoneal fluid (P = 0.016). These data suggest that the abnormal expression of cyclin H is closely related to the pathological characteristics of ovarian cancer. Cyclin H positively correlates with Ki67 and p-CDK2 in ovarian cancer Cyclin H is a well-known component of CDK-activating kinase, which contributes to the cell cycle by mediating CDK activation [15]. Therefore, the expression of cell cycle-related molecules, Ki67, and p-CDK2 were determined by immunohistochemical staining. As expected, Ki67 was highly expressed in grade 2 and grade 3 ovarian cancer when compared to the grade 1 specimens (Fig. 2 A-C). The expression trend of p-CDK2 (Fig. 2 D-F) was similar to that of Ki67 and cyclin H. Additionally, the results showed that Cyclin H was positively correlated to Ki-67 (r = 0.907; P <0.001) (Fig. 2 G) and p-CDK2 (r = 0.788; P <0.001) (Fig. 2 H) expression in 60 ovarian cancer tissues, demonstrating the involvement of cyclin H in cell cycle regulation of ovarian cancer. Cyclin H expression is associated with poor patient outcome in ovarian cancer. To determine whether the expression of cyclin H predicts the survival of ovarian cancer patients or not, we analyzed the relationship of cyclin H protein and the mRNA expression with the survival of ovarian cancer patients. Carcinoma specimens were divided into cyclin H low expressers (score ≤ 2, n = 40) and cyclin H high expressers (score > 2, n = 16) according to the immunohistochemical staining results. Moreover, according to Kaplan-Meier analysis, the five-year survival rate of patients was significantly higher in the cyclin H low-expression group compared to that in the cyclin H high-expression group (P = 0.0014) (Fig. 3 A). Additionally, the relationship between cyclin H mRNA expression level and the survival of ovarian cancer patients was analyzed using publicly available datasets (n = 1656, http://www.kmplot.com ) according to the instructions. Patients with low mRNA expression of cyclin H showed a significant improvement in survival time (Fig. 1A). These data demonstrate that high expression of cyclin H correlates with the poor prognosis of ovarian cancer. The knockdown of cyclin H results in the G1/S cell cycle arrest of ovarian cancer cells. To clarify the role of cyclin H in the proliferation and cell cycle of ovarian cancer cells, HO8910 cells were used because of its high level of cyclin H (Supplementary Fig1). The expression of cyclin H was knocked down by shRNA in HO8910 cells, and its efficiency was determined by quantitative PCR (Fig. 4 A) and western blot (Fig. 4B). The cyclin H level was greatly reduced in cyclin H shRNA transfected cells compared to the control group. Cell viability and cell cycle of HO8910 cells were measured by CCK8 and flow cytometry, respectively. Cyclin H silenced HO8910 cells showed weaker proliferative capacity, which was indicated by lower cell viability than that of the control group cells (Fig. 4 C), while the migration and invasion were not affected (Supplementary Fig. 2). G1/S cell cycle arrest was observed in cyclin H interfered cells, where the percentage of cells in the G1 phase increased while the percentage of cells in S phase decreased compared to those in the control group (Fig. 4 D-F). The expression of cyclin H, MAT1, CDK7, and p-CDK2 in HO8910 cells gradually increased after serum stimulation (Fig. 4 G, H). These results suggest that cyclin H is a positive regulator of ovarian cancer cell proliferation. Cyclin H regulates the growth of ovarian cancer. We confirmed the role of cyclin H in ovarian cancer in vivo using a subcutaneous nude mouse tumor model. Cyclin H shRNA or the control shRNA transfected HO8910 cells were implanted subcutaneously to the mice, and the development of tumors was monitored every other day. Tumors were observed on day 8, and their volume was determined. Mice were sacrificed, the tumor was removed and weighed on day 20. Tumor’s weight and size in the cyclin H shRNA group was much lighter and smaller, respectively than those in the control group, indicating that cyclin H knockdown significantly reduced ovarian cancer growth (Fig. 5 A-C). Though, no obvious change in body weight and daily behavior was observed between the two groups. IHC staining shows that Ki67 decreased in cyclin H silenced tumors (Fig. 5 D). Similarly, the expression of cyclin H, MAT1, CDK7, and p-CDK2 also decreased in cyclin H silenced ovarian cancer. Discussion In the past decade, the incidence and the mortality rate of ovarian cancer in China have increased rapidly[16, 17]. Currently, the clinical treatment for ovarian cancer is surgery combined with chemotherapy drugs (cisplatin, carboplatin, etc.) [5, 18]. However, ovarian cancer is susceptible to chemotherapy resistance and prone to recurrence and metastasis after surgery [19, 20]. Ovarian cancer is a great challenge to gynecological oncologists, and it is urgent to identify new prognostic factors and develop new strategies in improving the outcome of ovarian cancer patients. In this study, we demonstrate the high expression of cyclin H in ovarian cancer and the association of cyclin H with the unfavorable clinicopathologic variables of patients. The destruction of the cell cycle regulatory mechanism leads to uncontrolled cell growth. The cell cycle is a complicated and delicate process that is strictly regulated by the activation and inactivation of cyclin, CDK, and CDKIs. Cyclin and CDK are regulatory and catalytic subunits that play key roles in regulating cell cycle initiation and phase transition. Each of the Cyclins and the CDKs are expressed in a specific phase of the cell cycle where they control the progress of that phase and then switch onto the next phase. Cyclin H is a polypeptide consisting of 323 amino acids, forming CAK with CDK7 and MAT1 [21]. CAK forms the core part of TFIIH, which phosphorylates the CTD subunit of RNA polymerase II (RNAPII) and then participates in the transcription [22, 23]. CAK also phosphorylates CDK2 and promotes the cell cycle from G1 to S phase [24]. Emerging evidence has indicated that abnormal expression or genetic polymorphism of cyclin H is associated with tumor progression and chemosensitivity[13, 25, 26]. Here, we observed that cyclin H was positively correlated with the increased tumor grade of ovarian cancer and the expression of the proliferation markers Ki-67 and p-CDK2. Similar results are reported by diffuse large B-cell lymphoma[27], esophageal squamous cell carcinoma[12], and breast cancer[11]. Prashant Bavi et al.’s study concluded that a reduced or an absent cyclin H expression was significantly associated with the poor overall survival of patients with diffuse large B-cell lymphoma [27]. Hetal Patel and colleagues also described that Cyclin H expression was associated with a better patient outcome in breast cancer [11]. However, with our protein and mRNA data, we arrived at an opposite conclusion in the case of ovarian cancer, where the five-year survival rate in cyclin H low patients was significantly higher than in the cyclin H high patients. Consistent with our research, cyclin H positivity was significantly associated with the reduced disease-specific survival in patients with gastrointestinal stromal tumors [14]. These findings suggest that cyclin H may play different roles in different types of tumors. The transition of G1 to S phase is a key step in the cell cycle process and plays an important role in developing most of the tumors. Suppressing G1/S transition may provide an attractive therapeutic target to stop cancer cells from proliferating [28]. Previously, a study reported that the down-regulation of cyclin H-CDK7 was implicated in the arrest of liver cancer cells in the G1 phase [29]. To further investigate the role of cyclin H in ovarian cancer cells, cyclin H in HO8910 cells was knocked down, and the cell cycle was detected after synchronizing the cell cycle by serum starvation and then serum release. We found that cyclin H shRNA resulted in G1/S cell cycle arrest and inhibited the proliferation of HO8910 cells. The expression of cyclin H, along with the associated cofactors CDK7 and MAT1, gradually increased after serum stimulation. The phosphorylation of CDK2 also showed a similar trend with CAK components, suggesting that cyclin H may promote G1/S transition by enhancing the phosphorylation of CDK2. Animal experiments confirmed that cyclin H has a positive regulatory role in ovarian cancer, and the knockdown of cyclin H suppresses the growth of tumors in nude mice. The expression of CDK7 and MAT1 along with the phosphorylation of CDK2 was decreased in cyclin H silenced xenografts. Conclusions These findings indicate that high expression of cyclin H in ovarian cancer is associated with the poor prognosis of patients and promotes tumor growth through cell cycle regulation. In the past decades, tremendous efforts were put into developing inhibitors of CDKs, and many inhibitors were described as well, but most of them failed rigorous clinical testing[30]. To minimize the impact on normal proliferating cells, therapies that target cell cycle progression are always used in combination[31]. This study reveals a candidate that helps in early diagnosis or predicts prognosis of ovarian cancer and also provides evidence to support the therapeutic value of cyclin H in ovarian cancer, which may help in improving the diagnosis and the prognostic classification of ovarian cancers. Considering the reports of the controversial role of cyclin H in different kinds of tumors, more in-depth, systematic studies are needed to confirm the therapeutic value of cyclin H in ovarian cancer. Abbreviations CAK: CDK-activating kinase; CDK: Cyclin-dependent kinase; CDKI: Cyclin-dependent kinase inhibitor; MAT1: for ménage à trois 1; RNAPII: RNA polymerase I; FBS: fetal bovine serum Declarations Ethics approval and consent to participate. Study protocol of ovarian cancer tissue section was approved by the Research Ethics Committee of Affiliated Hospital of Nantong University (approval No. 20080516-003). All animal procedures were carried out under the approval of the Ethics Committee for Laboratory Animals of Nantong University (approval No. 20150418). Consent for publication. Not applicable. Availability of data and materials Not applicable. Competing interests The authors have declared that no competing interest exists. Funding Not applicable. Authors' contributions Chen Peng and Yuquan Zhang; Data curation, Yansong Yang; Formal analysis, Yansong Yang; Investigation, Chen Peng and Yuquan Zhang; Methodology, Chen Peng, Yansong Yang, Li Ji and Panpan Yang; Project administration, Xiaoqing Yang and Yuquan Zhang; Resources, Li Ji, Xiaoqing Yang and Yuquan Zhang; Software, Panpan Yang; Supervision, Xiaoqing Yang and Yuquan Zhang; Validation, Li Ji; Writing – original draft, Chen Peng; Writing – review & editing, Yansong Yang, Panpan Yang and Yuquan Zhang. Acknowledgements Not applicable. References Herzog TJ, Pothuri B. Ovarian cancer: a focus on management of recurrent disease. 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Clinicopathological characteristic No. Cases Cyclin H Expression R P 0 1 2 3 Age (years) <Mean 27 1 8 10 8 -0.012 0.925 ≥Mean 33 3 6 16 8 FIGO stage, n (%) I 15 3 5 6 1 0.389 0.002 * II 6 0 3 1 2 III 31 1 5 16 9 IV 8 0 1 3 4 Histologic subtype, n (%) Serous papillary adenocarcinoma 42 2 9 17 14 -0.228 0.079 Endometrioid adenocarcinoma 7 1 2 2 2 Clear cell carcinoma 3 0 1 2 0 Mucinous carcinoma 8 1 2 5 0 Histologic grade, n (%) G1 20 4 7 7 2 0.466 0.0017 *** G2 16 0 3 11 2 G3 24 0 4 8 12 Residual tumor (cm), n (%) ≤1 45 3 12 20 10 0.166 0.194 >1 15 1 2 6 6 Chemotherapy, n (%) Platinum only 1 0 1 0 0 0.146 0.263 Other/platinum 40 2 7 20 11 None 10 2 6 6 5 Malignant tumor cells in peritoneal fluid Present 31 3 10 13 5 0.308 0.016* Absent or rare 29 1 4 13 11 Statistical analyses were performed by Pearson χ2 test. *, P < 0.05, **, P < 0.01 Supplementary Data Supplementary Figure 1. Expression of cyclin H in different ovarian cancer cell lines. The protein levels of cyclin H in HO8910, SK-OV-3, and NIH: OVCAR-3 cells were detected by western blot. Cyclin H was highly expressed in HO8910 cells. Supplementary Figure 2. Effect of cyclin H in migration and invasion of ovarian cancer cells. (A) Cell scratch test was used to evaluate the migration ability of HO8910 cells. HO8910 cells were seeded in a six-well plate at a density of 5×10 5 /well, and a straight scratch was made using a (yellow) pipette tip when the cultures are confluent. Twelve hours later, the distance of the wound was analyzed and the healing percentage was calculated. Bar = 200 µm. (B) Invasion of HO8910 cells was measured by transwell invasion assay. Upper chamber of 24-well transwell was blocked with Matrigel, and HO8910 cells were placed. After incubation for 20 h, the non-invaded cells on the top of the transwell were removed with a cotton swab and the invaded cells were counted under a light microscope. Bar = 20 µm. Supplementary Figure 3. Body weight of nude mice after tumor inoculation. The body weight of mice was compared with that observed on day 0, and no significant change was found between the cyclin H shRNA group and the control group. Supplementary Files revisesupple1.tif revisesup2.tif supfigure3.tif Cite Share Download PDF Status: Published Journal Publication published 16 Jul, 2020 Read the published version in Cancer Cell International → Version 3 posted Editorial decision: Accept 06 Jul, 2020 Review # 2 received at journal 05 Jul, 2020 Review # 1 received at journal 04 Jul, 2020 Reviewers invited by journal 01 Jul, 2020 Reviewer # 1 agreed at journal 01 Jul, 2020 Reviewer # 2 agreed at journal 01 Jul, 2020 Editor assigned by journal 25 Jun, 2020 Submission checks completed at journal 24 Jun, 2020 Editor invited by journal 24 Jun, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-20434","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Primary research","associatedPublications":[],"authors":[{"id":724803,"identity":"d6841af2-baf0-41f2-8fba-3f16b42e7a07","order_by":0,"name":"Chen Peng","email":"","orcid":"","institution":"Affiliated Hospital of Nantong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Peng","suffix":""},{"id":724804,"identity":"f691598d-871f-4214-a506-74fde13303d2","order_by":1,"name":"Yansong Yang","email":"","orcid":"","institution":"Affiliated Hospital of Nantong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yansong","middleName":"","lastName":"Yang","suffix":""},{"id":724805,"identity":"361270ea-298b-49bf-a7cb-8ee8844d2d1a","order_by":2,"name":"Li Ji","email":"","orcid":"","institution":"Nantong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Ji","suffix":""},{"id":724806,"identity":"21d8349e-b895-484d-a11e-3364f6432a52","order_by":3,"name":"Panpan Yang","email":"","orcid":"","institution":"Affiliated Hospital of Nantong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Panpan","middleName":"","lastName":"Yang","suffix":""},{"id":724807,"identity":"cd320ae5-313e-4d9e-afe3-1260d42a6f2d","order_by":4,"name":"Xiaoqing Yang","email":"","orcid":"","institution":"Affiliated Hospital of Nantong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiaoqing","middleName":"","lastName":"Yang","suffix":""},{"id":724808,"identity":"2bfa1048-c7e7-4c18-8321-d3958099a30e","order_by":5,"name":"Yuquan Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYBCDBBhDjo29/QApWhIYjPl4ziTgU4mpJXGehIMBXqUGN5K3SfzcUZfHP7v9AnPhj8PpbRJAjT8qtuHRklYm2XuGrVjizpkC5hkJh3PbpBsPMPacuY1HS46ZBG8bT2LDjZwEZh6QFpkDCcyMbfi1SP5tk0icD9WSziaRYEBQizRvm0HihhvpB0BaEghqkTzzrNhati0hceONHAZmnrR0wzZgIB/E5xe+48kbb75tq0ucdyP9ATOPjbW8fHv7wQc/KnBrUTjAAIsFHvMfMNEDONUDgXwDXAv7A3wKR8EoGAWjYAQDADpSWZxSDqNtAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-8337-3416","institution":"Affiliated Hospital of Nantong University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Yuquan","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2020-03-31 11:03:54","currentVersionCode":3,"declarations":"","doi":"10.21203/rs.3.rs-20434/v3","doiUrl":"https://doi.org/10.21203/rs.3.rs-20434/v3","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12935-020-01406-5","type":"published","date":"2020-07-16T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":1447898,"identity":"93e695e5-576c-49ea-85c8-074444f465f6","added_by":"auto","created_at":"2020-06-29 17:52:32","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1325373,"visible":true,"origin":"","legend":"Immunohistochemistry staining of Cyclin H in ovarian cancer tissues. The expression of Cyclin H in ovarian cancer of grade 1 (A), grade 2 (B), and grade 3 (C) was measured by immunohistochemistry staining, and representative images are displayed. Scale bar, 20 µm. (D) Quantification of Cyclin H expression in ovarian cancer (P \u003c 0.001). ","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/1.png"},{"id":1447899,"identity":"6a0ed678-dc46-4533-b51c-ab3897d11c2a","added_by":"auto","created_at":"2020-06-29 17:52:32","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":2389900,"visible":true,"origin":"","legend":"Cyclin H correlates with Ki67 and p-CDK2 in ovarian cancer. (A-C) Immunohistochemistry staining of ki67 in ovarian cancer of grade 1 (A), grade 2 (B), and grade 3 (C). (D-F) Immunohistochemistry staining of p-CDK2 in ovarian cancer. Scale bar, 20 µm. (G) Correlation between the expression of Ki67 and Cyclin H in ovarian cancer. (H) Cyclin H was positively correlated with p-CDK2 in ovarian cancer.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/2.png"},{"id":1447900,"identity":"433c18a6-b91c-4494-82cb-22c90839d432","added_by":"auto","created_at":"2020-06-29 17:52:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":258073,"visible":true,"origin":"","legend":"Survival analysis in ovarian cancer patients. (A) Analysis of patients showing a low level of cyclin H (score ≤ 2, n = 40) and those with high expression of cyclin H (score \u003e 2, n = 16). (B) Analysis of 1656 ovarian cancer patients showed that high expression of cyclin H predicted poor prognosis. The Kaplan-Meier plots were generated by Kaplan-Meier Plotter (http://www.kmplot.com). ","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/3.png"},{"id":1447901,"identity":"cc9fff03-800a-43b1-abf4-92b120f4a9bd","added_by":"auto","created_at":"2020-06-29 17:52:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":103102,"visible":true,"origin":"","legend":"Cyclin H regulates the proliferation and cell cycle of ovarian cancer cells. (A) mRNA level of cyclin H in vector and cyclin H shRNA transfected ovarian cancer HO8910 cells. (B) The protein expression of cyclin H was detected by Western blot. (C) Proliferation difference between control and cyclin H silencing HO8910 cells. PI staining was performed to measure the percentage of cells in each cell cycle phase using Modfit software (D and E). (F) Quantification of the percentage cells in each cell cycle phase after transfection with cyclin H shRNA. (G) Expression of cyclin H, CDK7, MAT1, p-CDK2, and CDK2 in HO8910 cells after serum deprivation and refeeding. Serum-starved HO8910 cells were cultured in serum-containing medium for 4, 8, 12, 24, and 48 h, and cell lysates were analyzed by western blot. (H) Relative level of p-CDK2 was normalized to the total level of CDK2 at each time point. * P\u003c0.05, **P\u003c0.01, ***P\u003c0.001. ","description":"","filename":"4.PNG","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/4.PNG"},{"id":1447902,"identity":"c5b5f21c-ed44-4bd3-b801-08b9129e6207","added_by":"auto","created_at":"2020-06-29 17:52:32","extension":"tif","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1781507,"visible":true,"origin":"","legend":"Cyclin H promotes the growth of ovarian cancer. Nude mice were implanted with cyclin H silenced HO8910 cells or control cells, and tumor volume was monitored regularly (A). (B) Tumor weight was measured at day 20 after mice were sacrificed. (C) Tumors from control or cyclin H shRNA group. Data are means ±SEM. Representative results of one of three independent experiments. **P\u003c0.01. (D) Immunohistochemical staining immunohistochemical staining of Ki67 in tumors from nude mice. Tumor tissues were isolated and fixed for the frozen section, and the thickness was 30 µm. Bar = 20 µm. (E) Expression of cyclin H, CDK7, MAT1, p-CDK2, and CDK2 in xenografts. ","description":"","filename":"reviseFigure52.tif","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/reviseFigure52.tif"},{"id":13547601,"identity":"3a426d10-69c0-4234-87cd-7f7ce754ca6e","added_by":"auto","created_at":"2021-09-17 02:14:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5065021,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/57da8f88-c38f-42f0-812c-dde46f28da04.pdf"},{"id":1447904,"identity":"2529ca57-464e-495a-b877-ac154448cdfa","added_by":"auto","created_at":"2020-06-29 17:52:33","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2929160,"visible":true,"origin":"","legend":"","description":"","filename":"revisesupple1.tif","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/revisesupple1.tif"},{"id":1447905,"identity":"f0f1de5d-7531-4a1c-8fd4-4794b5a1b0a7","added_by":"auto","created_at":"2020-06-29 17:52:33","extension":"tif","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":6176428,"visible":true,"origin":"","legend":"","description":"","filename":"revisesup2.tif","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/revisesup2.tif"},{"id":1447906,"identity":"22bf9a46-666e-49c2-938a-4832cc67fe1d","added_by":"auto","created_at":"2020-06-29 17:52:34","extension":"tif","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":3169632,"visible":true,"origin":"","legend":"","description":"","filename":"supfigure3.tif","url":"https://assets-eu.researchsquare.com/files/rs-20434/v3/supfigure3.tif"}],"financialInterests":"","formattedTitle":"Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer","fulltext":[{"header":"Background","content":"\u003cp\u003eOvarian cancer is the seventh most common tumor in women and also the most lethal gynecological malignancy with a high recurrence and mortality rate[1\u0026ndash;3]. A five-year survival rate of an ovarian cancer patient is less than 35% [4]. Most ovarian cancer patients do not get diagnosed until the advanced stages because they do not show symptoms in the early stages [3, 5, 6]. Therefore, investigating the pathogenesis of ovarian cancer and finding new target proteins that are closely related to the occurrence, development, and prognosis of ovarian cancer may increase the early diagnosis rate and provide new ideas in treating the disease.\u003c/p\u003e\n\u003cp\u003eDeregulation of cell cycle and abnormal signaling pathways caused by various reasons are general features of the tumor cells [7]. Excessive cell proliferation, blocked differentiation, and impaired apoptosis play a key role in the occurrence and development of tumors. Clarifying the molecular mechanism of cell cycle regulation in tumor cells may provide the basis for developing tumor treatment strategies [8, 9]. \u0026nbsp;The three main types of molecules involved in cell cycle regulation are as follows: cyclin, cyclin-dependent kinase (CDK), and cyclin-dependent kinase inhibitor (CDKI). The expression of cell cycle regulators is linked to tumor development, prognosis, and treatment response [10]. Cyclin H, a member of the cyclin family, together with CDK7 and MAT1 forms the CDK-activating kinase (CAK) trimeric complex, which is necessary for the regulation of cell cycle and proliferation. Abnormal expression of cyclin H is reported in a variety of tumors such as breast cancer[11], esophageal cancer[12], endometrial cancer[13], and gastrointestinal stromal tumors[14]. However, the clinical significance and the biological function of cyclin H in ovarian cancer remains unclear.\u003c/p\u003e\n\u003cp\u003eImmunohistochemical staining was used in this study to evaluate the expression of cyclin H in 60 pathological specimens of ovarian cancer with different grades. The correlation of cyclin H with the clinical characteristics, prognosis, and the proliferation parameters of tumor patients were analyzed. Additionally, we down-regulated the expression of cyclin H in ovarian cancer cells using shRNA and explored its effect on cell cycle and tumor growth. This study revealed that cyclin H is highly expressed in high-grade ovarian cancers and promotes the growth of ovarian cancer by regulating the cell cycle.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003ePathological Samples \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eParaffin embedded ovarian cancer specimens were obtained from 60 patients who underwent surgery in the Department of Obstetrics and Gynecology at Affiliated Hospital of Nantong University from June 2009 to April 2013. All the tumors were from newly diagnosed ovarian cancer patients and also from the patients who did not receive any treatment before surgery. Among these, four patients\u0026rsquo; survival information was missing. All the investigations in this study were performed after obtaining informed consent. The study was approved by the Research Ethics Committee of the Affiliated Hospital of Nantong University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmunohistochemistry (IHC) and quantification\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFormalin-fixed and paraffin-embedded sections were prepared for all the tissues and reviewed by three pathologists. The protein expression of cyclin H, Ki67, and p-CDK2 in ovarian cancer was determined by IHC. In short, ovarian cancer tissue sections were first dewaxed in xylene, then rehydrated through gradient ethanol, and heated in Tris-EDTA buffer (pH 8.0) for 15 min in a microwave oven to retrieve the antigen. After cooling it at room temperature and rinsing with phosphate-buffered saline, slides were incubated with 3% hydrogen peroxide for 10 min to block endogenous peroxidase activity. Next, it was incubated with 2% bovine serum albumin (Beyotime Biotechnology, Shanghai, China) for 2 h at room temperature to block nonspecific reactions. Tissue sections were then incubated with cyclin H monoclonal antibody (1:50, MA5\u0026ndash;32331, Thermo Fisher Scientific, Waltham, MA, USA), Ki67 monoclonal antibody (1:300, ab92742, Abcam, Cambridge, MA, USA) or p-CDK2 polyclonal antibody (1:100, PA5\u0026ndash;38128, Thermo Fisher Scientific) at 4 \u0026deg;C overnight. All the slides were finally visualized using the Envision kit (Dako, Glostrup, Denmark) as per the instructions and then counterstained with hematoxylin, dehydrated, and sealed with coverslips. The sections were imaged under an optical microscope and evaluated in a blinded manner. More than 500 cells in each slide were counted to determine the mean positive percentage and the expression range was scored as follows: 0 (\u0026lt;20%), 1 (20% to 50%), 2 (51% to 75%) and 3 (\u0026gt;75% points). For the frozen sections of tumors from nude mice, dewaxing steps were omitted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCell culture and transfection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuman ovarian carcinoma HO8910 cell line was used in this study, which was obtained from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). The HO8910 cell line was cultured in RPMI 1640 (Gibco, Grand Island, NY) supplemented with 10% fetal bovine serum (FBS, \u003cu\u003eGibco\u003c/u\u003e), 2 mM L-glutamine, 0.11g/L Sodium Pyruvate, 100 U/mL penicillin-streptomycin mixture (Gibco) at 37 \u0026deg;C in 5% CO\u003csub\u003e2\u003c/sub\u003e incubator. Cyclin H shRNA(sequence: 5\u0026rsquo;-CCG GCG ACC TGG TAG AAT CTC TCT ACT CGA GTA GAG AGA TTC TAC CAG GTC GTT TTT G-3\u0026rsquo;) was synthesized by Sangon Biotech (Shanghai, China), cloned into a pLenti-CMV-puro vector and then transfected to HO8910 cells using FuGENE transfection reagent (Promega, Madison, WI, USA ). The stable transfected cell lines were obtained after screening the cells with 1 \u0026micro;g/mL of puromycin. Empty plasmids were transfected into HO8910 cells and used as a control.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCell viability assay\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCells were seeded in a 96 well plate (3000 cells per well) and cultured in complete RPMI 1640 medium (with 10% fetal bovine serum). Cell viability was measured at time points 0, 12, 24, 48, and 72 h after seeding by cell counting kit-8 (C0038, Beyotime, Shanghai, China) according to the manufacturer\u0026rsquo;s instructions. Five wells were used for each time point, and their cell viability was measured and compared to the initial cell viability.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWestern blot\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHO8910 cells were harvested by trypsin, washed with PBS, and collected after centrifugation. Cell pellets were resuspended with cell lysate buffer and incubated on ice for 20 min. For tumor samples, 1 mL of cell lysate buffer was added to 0.1 g of tissue followed by homogenization and centrifugation. Prepared samples were run on SDS-PAGE gel and transferred to polyvinylidene fluoride membranes (0.2 \u0026micro;m, Millipore, USA). After blocking with 5% non-fat milk, the membranes were incubated with cyclin H antibody (1:1500, MA5\u0026ndash;32331, Thermo Fisher Scientific), MAT1 antibody (1:1000, ab129176, Abcam), CDK7 antibody (1:1000, 2916, Cell Signaling Technology, Danvers, MA, USA), p-CDK2 antibody (1:100, PA5\u0026ndash;38128, Thermo Fisher Scientific) or CDK2 antibody (1:1000, 2546, Cell Signaling Technology) and then incubated with HRP goat anti-rabbit or mouse IgG (ABclonal, Wuhan, China). Membranes were finally visualized using an enhanced chemiluminescence reagent (34095, Thermo Pierce) and GAPDH (1:2000, Abcam) was used as a control.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eQuantitative PCR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTotal RNA of HO8910 cells was isolated using Trizol (Invitrogen) and reverse transcription was done using a commercial kit (RR047B, TaKaRa, Tokyo, Japan) that contained gDNA Eraser to eliminate genomic DNA contamination. The relative mRNA level of cyclin H was determined by real-time quantitative PCR (RR420L, TaKaRa), where \u0026beta;-actin was used as a control. The following primers were used in the reaction: cyclin H forward, 5\u0026rsquo;-TGT TCG GTG TTT AAG CCA GCA-3\u0026rsquo;; cyclin H reverse, 5\u0026rsquo;-TCC TGG GGT GAT ATT CCA TTA CT-3\u0026rsquo;; \u0026beta;-actin forward, 5\u0026rsquo;-TCG AGC ACG GCA TCG TCA CCA-3\u0026rsquo;; \u0026beta;-actin reverse, 5\u0026rsquo;-ATA GCA ACG TAC ATG GCT-3\u0026rsquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCell cycle detection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHO8910 cells were synchronized by deprivation of serum 4q 72 h. The serum-free medium was then replaced by complete medium, and cells were cultured for another 48 h before collection. Cells were harvested using trypsinization, and a single-cell suspension was prepared before fixing and staining them. Propidium staining was done using a detection kit (C1052, Beyotime) and was detected by BD FACSCanto II (San Diego, CA, USA). The data was analyzed using Modfit software, and the percentage of cells in each phase were counted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTumor model\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFemale BALBC/c nude mice (5\u0026ndash;6 weeks old, 14\u0026ndash;16 g) were purchased from Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China) and maintained in specific pathogen-free conditions. HO8910 cells (5 \u0026times; 10\u003csup\u003e5\u003c/sup\u003e/mouse) in 100 \u0026micro;L of PBS were inoculated subcutaneously to the nude mice, in the flank. Tumor diameters were measured with digital calipers every other day, and the tumor volume was calculated by the following formula: Volume = (width)\u003csup\u003e2\u003c/sup\u003e \u0026times; length/2. All animal experiments were performed according to the Guidelines for the Care and Use of Laboratory Animals (No. 55 issued by Ministry of Health, China on January 25, 1998) and were approved by the Ethics Committee for Laboratory Animals of Nantong University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIBM SPSS was used for all statistical analyses. Chi-square test was used for clinicopathological categorical variables, and the overall survival was analyzed by the Kaplan-Meier method. T-test was used for studying the difference between the two groups. Spearman\u0026rsquo;s rank correlation analysis was used to measure the association between the expression of cyclin H, Ki67, and p-CDK2. Differences were considered statistically significant at \u003cem\u003ep\u003c/em\u003e\u0026lt;0.05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eHigh expression of cyclin H in ovarian cancer. \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the expression and the potential role of cyclin H in ovarian cancer, immunohistochemical staining was performed on 60 cases of ovarian cancer, and cyclin H expression was scored subsequently. Representative results of immunohistochemistry are shown in Figure 1. In the ovarian cancer tissues, cyclin H is localized in the nucleus and the cytoplasm. The mean percentage of cyclin H positive cells was 33.16% (ranged from 3.10% to 77.48%). Cyclin H was slightly expressed in grade 1 ovarian cancer while highly expressed in high grade 2 and grade 3 samples (Fig. 1 A-C). High cyclin H expression was significantly correlated with the increased tumor grade (Fig.\u0026nbsp;1 D and Table1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation between cyclin H expression and Clinicopathological Variables of ovarian cancer. \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFurther, to explore the potential physiological or the pathological role of cyclin H in ovarian cancer, the correlation between cyclin H and the clinicopathological parameters was analyzed and summarized in Table 1. The result of spearman Spearman\u0026rsquo;s rank correlation analysis showed that cyclin H in ovarian cancer was not associated with age, histological subtype, residual tumor size, and chemotherapy. Interestingly, Cyclin H positively correlated with the FIGO (International Federation of Gynecology and Obstetrics) stage (P\u0026nbsp;=\u0026nbsp;0.002), histologic grade (P\u0026nbsp;=\u0026nbsp;0.0017), and the peritoneal metastasis. Compared to the patients with no peritoneal metastasis, cyclin H expression was significantly increased in patients with malignant tumor cells in peritoneal fluid (P\u0026nbsp;=\u0026nbsp;0.016). These data suggest that the abnormal expression of cyclin H is closely related to the pathological characteristics of ovarian cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCyclin H positively correlates with Ki67 and p-CDK2 in ovarian cancer\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCyclin H is a well-known component of CDK-activating kinase, which contributes to the cell cycle by mediating CDK activation [15]. Therefore, the expression of cell cycle-related molecules, Ki67, and p-CDK2 were determined by immunohistochemical staining. As expected, Ki67 was highly expressed in grade 2 and grade 3 ovarian cancer when compared to the grade 1 specimens (Fig. 2 A-C). The expression trend of p-CDK2 (Fig. 2 D-F) was similar to that of Ki67 and cyclin H. Additionally, the results showed that Cyclin H was positively correlated to Ki-67 (r = 0.907; P \u0026lt;0.001) (Fig. 2 G) and p-CDK2 (r = 0.788; P \u0026lt;0.001) (Fig. 2 H) expression in 60 ovarian cancer tissues, demonstrating the involvement of cyclin H in cell cycle regulation of ovarian cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCyclin H expression is associated with poor patient outcome in ovarian cancer. \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo determine whether the expression of cyclin H predicts the survival of ovarian cancer patients or not, we analyzed the relationship of cyclin H protein and the mRNA expression with the survival of ovarian cancer patients. Carcinoma specimens were divided into cyclin H low expressers (score \u0026le; 2, n = 40) and cyclin H high expressers (score \u0026gt; 2, n = 16) according to the immunohistochemical staining results. Moreover, according to Kaplan-Meier analysis, the five-year survival rate of patients was significantly higher in the cyclin H low-expression group compared to that in the cyclin H high-expression group (P = 0.0014) (Fig.\u0026nbsp;3 A). Additionally, the relationship between cyclin H mRNA expression level and the survival of ovarian cancer patients was analyzed using publicly available datasets (n\u0026nbsp;=\u0026nbsp;1656, \u003ca href=\"http://www.kmplot.com\"\u003ehttp://www.kmplot.com\u003c/a\u003e) according to the instructions. Patients with low mRNA expression of cyclin H showed a significant improvement in survival time (Fig. 1A). These data demonstrate that high expression of cyclin H correlates with the poor prognosis of ovarian cancer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe knockdown of cyclin H results in the G1/S cell cycle arrest of ovarian cancer cells. \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo clarify the role of cyclin H in the proliferation and cell cycle of ovarian cancer cells, HO8910 cells were used because of its high level of cyclin H (Supplementary Fig1). The expression of cyclin H was knocked down by shRNA in HO8910 cells, and its efficiency was determined by quantitative PCR (Fig. 4 A) and western blot (Fig. 4B). The cyclin H level was greatly reduced in cyclin H shRNA transfected cells compared to the control group. Cell viability and cell cycle of HO8910 cells were measured by CCK8 and flow cytometry, respectively. Cyclin H silenced HO8910 cells showed weaker proliferative capacity, which was indicated by lower cell viability than that of the control group cells (Fig. 4 C), while the migration and invasion were not affected (Supplementary Fig. 2). G1/S cell cycle arrest was observed in cyclin H interfered cells, where the percentage of cells in the G1 phase increased while the percentage of cells in S phase decreased compared to those in the control group (Fig. 4 D-F). The expression of cyclin H, MAT1, CDK7, and p-CDK2 in HO8910 cells gradually increased after serum stimulation (Fig. 4 G, H). These results suggest that cyclin H is a positive regulator of ovarian cancer cell proliferation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCyclin H regulates the growth of ovarian cancer. \u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe confirmed the role of cyclin H in ovarian cancer \u003cem\u003ein vivo\u003c/em\u003e using a subcutaneous nude mouse tumor model. Cyclin H shRNA or the control shRNA transfected HO8910 cells were implanted subcutaneously to the mice, and the development of tumors was monitored every other day. Tumors were observed on day 8, and their volume was determined. Mice were sacrificed, the tumor was removed and weighed on day 20. Tumor\u0026rsquo;s weight and size in the cyclin H shRNA group was much lighter and smaller, respectively than those in the control group, indicating that cyclin H knockdown significantly reduced ovarian cancer growth (Fig. 5 A-C). Though, no obvious change in body weight and daily behavior was observed between the two groups. IHC staining shows that Ki67 decreased in cyclin H silenced tumors (Fig.\u0026nbsp;5 D). Similarly, the expression of cyclin H, MAT1, CDK7, and p-CDK2 also decreased in cyclin H silenced ovarian cancer.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the past decade, the incidence and the mortality rate of ovarian cancer in China have increased rapidly[16, 17]. Currently, the clinical treatment for ovarian cancer is surgery combined with chemotherapy drugs (cisplatin, carboplatin, etc.) [5, 18]. However, ovarian cancer is susceptible to chemotherapy resistance and prone to recurrence and metastasis after surgery [19, 20]. Ovarian cancer is a great challenge to gynecological oncologists, and it is urgent to identify new prognostic factors and develop new strategies in improving the outcome of ovarian cancer patients. In this study, we demonstrate the high expression of cyclin H in ovarian cancer and the association of cyclin H with the unfavorable clinicopathologic variables of patients.\u003c/p\u003e\n\u003cp\u003eThe destruction of the cell cycle regulatory mechanism leads to uncontrolled cell growth. The cell cycle is a complicated and delicate process that is strictly regulated by the activation and inactivation of cyclin, CDK, and CDKIs. Cyclin and CDK are regulatory and catalytic subunits that play key roles in regulating cell cycle initiation and phase transition. Each of the Cyclins and the CDKs are expressed in a specific phase of the cell cycle where they control the progress of that phase and then switch onto the next phase. Cyclin H is a polypeptide consisting of 323 amino acids, forming CAK with CDK7 and MAT1 [21]. CAK forms the core part of TFIIH, which phosphorylates the CTD subunit of RNA polymerase II (RNAPII) and then participates in the transcription [22, 23]. CAK also phosphorylates CDK2 and promotes the cell cycle from G1 to S phase [24].\u003c/p\u003e\n\u003cp\u003eEmerging evidence has indicated that abnormal expression or genetic polymorphism of cyclin H is associated with tumor progression and chemosensitivity[13, 25, 26]. Here, we observed that cyclin H was positively correlated with the increased tumor grade of ovarian cancer and the expression of the proliferation markers Ki-67 and p-CDK2. Similar results are reported by diffuse large B-cell lymphoma[27], esophageal squamous cell carcinoma[12], and breast cancer[11]. Prashant Bavi et al.\u0026rsquo;s study concluded that a reduced or an absent cyclin H expression was significantly associated with the poor overall survival of patients with diffuse large B-cell lymphoma [27]. Hetal\u0026nbsp;Patel and colleagues also described that Cyclin H expression was associated with a better patient outcome in breast cancer [11]. However, with our protein and mRNA data, we arrived at an opposite conclusion in the case of ovarian cancer, where the five-year survival rate in cyclin H \u003csup\u003elow\u003c/sup\u003e patients was significantly higher than in the cyclin H \u003csup\u003ehigh\u003c/sup\u003e patients. Consistent with our research, cyclin H positivity was significantly associated with the reduced disease-specific survival in patients with gastrointestinal stromal tumors [14]. These findings suggest that cyclin H may play different roles in different types of tumors.\u003c/p\u003e\n\u003cp\u003eThe transition of G1 to S phase is a key step in the cell cycle process and plays an important role in developing most of the tumors. Suppressing G1/S transition may provide an attractive therapeutic target to stop cancer cells from proliferating [28]. Previously, a study reported that the down-regulation of cyclin H-CDK7 was implicated in the arrest of liver cancer cells in the G1 phase [29]. To further investigate the role of cyclin H in ovarian cancer cells, cyclin H in HO8910 cells was knocked down, and the cell cycle was detected after synchronizing the cell cycle by serum starvation and then serum release. We found that cyclin H shRNA resulted in G1/S cell cycle arrest and inhibited the proliferation of HO8910 cells. The expression of cyclin H, along with the associated cofactors CDK7 and MAT1, gradually increased after serum stimulation. The phosphorylation of CDK2 also showed a similar trend with CAK components, suggesting that cyclin H may promote G1/S transition by enhancing the phosphorylation of CDK2. Animal experiments confirmed that cyclin H has a positive regulatory role in ovarian cancer, and the knockdown of cyclin H suppresses the growth of tumors in nude mice. The expression of CDK7 and MAT1 along with the phosphorylation of CDK2 was decreased in cyclin H silenced xenografts.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThese findings indicate that high expression of cyclin H in ovarian cancer is associated with the poor prognosis of patients and promotes tumor growth through cell cycle regulation. In the past decades, tremendous efforts were put into developing inhibitors of CDKs, and many inhibitors were described as well, but most of them failed rigorous clinical testing[30]. To minimize the impact on normal proliferating cells, therapies that target cell cycle progression are always used in combination[31]. This study reveals a candidate that helps in early diagnosis or predicts prognosis of ovarian cancer and also provides evidence to support the therapeutic value of cyclin H in ovarian cancer, which may help in improving the diagnosis and the prognostic classification of ovarian cancers. Considering the reports of the controversial role of cyclin H in different kinds of tumors, more in-depth, systematic studies are needed to confirm the therapeutic value of cyclin H in ovarian cancer.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCAK: CDK-activating kinase; CDK: Cyclin-dependent kinase; CDKI: Cyclin-dependent kinase inhibitor;\u0026nbsp; MAT1: for m\u0026eacute;nage \u0026agrave; trois 1; RNAPII: RNA polymerase I; FBS: fetal bovine serum\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate. \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy protocol of ovarian cancer tissue section was approved by the Research Ethics Committee of Affiliated Hospital of Nantong University (approval No. 20080516-003). All animal procedures were carried out under the approval of the Ethics Committee for Laboratory Animals of Nantong University (approval No. 20150418).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication. \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have declared that no competing interest exists.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChen Peng and Yuquan Zhang; Data curation, Yansong Yang; Formal analysis, Yansong Yang; Investigation, Chen Peng and Yuquan Zhang; Methodology, Chen Peng, Yansong Yang, Li Ji and Panpan Yang; Project administration, Xiaoqing Yang and Yuquan Zhang; Resources, Li Ji, Xiaoqing Yang and Yuquan Zhang; Software, Panpan Yang; Supervision, Xiaoqing Yang and Yuquan Zhang; Validation, Li Ji; Writing \u0026ndash; original draft, Chen Peng; Writing \u0026ndash; review \u0026amp; editing, Yansong Yang, Panpan Yang and Yuquan Zhang.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp; \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHerzog TJ, Pothuri B. 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Clin Cancer Res. 2016; 22(23):5929-5938.\u003c/li\u003e\n\u003cli\u003eZhang J, Yang X, Wang Y, Shi H, Guan C, Yao L, Huang X, Ding Z, Huang Y, Wang H\u003cem\u003e et al\u003c/em\u003e. Low expression of cyclinH and cyclin-dependent kinase 7 can decrease the proliferation of human esophageal squamous cell carcinoma. Dig Dis Sci. 2013; 58(7):2028-2037.\u003c/li\u003e\n\u003cli\u003eKayaselcuk F, Erkanli S, Bolat F, Seydaoglu G, Kuscu E, Demirhan B. Expression of cyclin H in normal and cancerous endometrium, its correlation with other cyclins, and association with clinicopathologic parameters. Int J Gynecol Cancer. 2006; 16(1):402-408.\u003c/li\u003e\n\u003cli\u003eDorn J, Spatz H, Schmieder M, Barth TF, Blatz A, Henne-Bruns D, Knippschild U, Kramer K. Cyclin H expression is increased in GIST with very-high risk of malignancy. BMC Cancer. 2010; 10:350.\u003c/li\u003e\n\u003cli\u003eSchneider E, Kartarius S, Schuster N, Montenarh M. 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Mol Cell Biol. 1995; 15(1):345-350.\u003c/li\u003e\n\u003cli\u003ePalugulla S, Devaraju P, Kayal S, Narayan SK, Mathaiyan J. Genetic polymorphisms in cyclin H gene are associated with oxaliplatin-induced acute peripheral neuropathy in South Indian digestive tract cancer patients. Cancer Chemother Pharmacol. 2018; 82(3):421-428.\u003c/li\u003e\n\u003cli\u003eMurali A, Nalinakumari KR, Thomas S, Kannan S. Association of single nucleotide polymorphisms in cell cycle regulatory genes with oral cancer susceptibility. Br J Oral Maxillofac Surg. 2014; 52(7):652-658.\u003c/li\u003e\n\u003cli\u003eBavi P, Abubaker J, Hussain A, Sultana M, Al-Dayel F, Uddin S, Al-Kuraya KS. Reduced or absent cyclin H expression is an independent prognostic marker for poor outcome in diffuse large B-cell lymphoma. Hum Pathol. 2008; 39(6):885-894.\u003c/li\u003e\n\u003cli\u003eLiu M, Liu H, Chen J. Mechanisms of the CDK4/6 inhibitor palbociclib (PD 0332991) and its future application in cancer treatment (Review). Oncol Rep. 2018; 39(3):901-911.\u003c/li\u003e\n\u003cli\u003eDai QS, Liu W, Wang XB, Lu N, Gong DD, Kong LY, Guo QL. NCPMF-60 induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Anticancer Drugs. 2011; 22(1):46-57.\u003c/li\u003e\n\u003cli\u003eSanchez-Martinez C, Lallena MJ, Sanfeliciano SG, de Dios A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015-2019). Bioorg Med Chem Lett. 2019; 29(20):126637.\u003c/li\u003e\n\u003cli\u003eDiaz-Moralli S, Tarrado-Castellarnau M, Miranda A, Cascante M. Targeting cell cycle regulation in cancer therapy. Pharmacol Ther. 2013; 138(2):255-271.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style=\"margin: 0in 0in 12pt;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif; font-size: 10px; color: rgb(0, 0, 0);\"\u003eTable 1. Relationship between clinicopathological characteristics and Cyclin H protein expression in ovarian cancer.\u003c/span\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellpadding=\"0\" cellspacing=\"0\" style=\"width: 435.3pt;border-collapse: collapse;border: none;\" width=\"580\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 171pt;border-width: 1.5pt 1pt;border-color: black rgb(191, 191, 191);border-style: solid;padding: 0in 5.4pt;height: 14.05pt;\" width=\"39.310344827586206%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eClinicopathological characteristic\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 44.85pt;border-top-width: 1.5pt;border-style: solid solid solid none;border-top-color: black;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.344827586206897%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eNo. Cases\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 131.6pt;border-top-width: 1.5pt;border-style: solid solid solid none;border-top-color: black;border-bottom-width: 1pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"30.17241379310345%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eCyclin H Expression\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 42.9pt;border-top-width: 1.5pt;border-style: solid solid solid none;border-top-color: black;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.827586206896552%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eR\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 44.95pt;border-top-width: 1.5pt;border-style: solid solid solid none;border-top-color: black;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.344827586206897%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eP\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"25%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"25.568181818181817%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"26.136363636363637%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"23.295454545454547%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eAge (years)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; \u0026lt;Mean\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e27\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e10\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e-0.012\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 12.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.925\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; \u0026ge;Mean\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e33\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e16\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n 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191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 8.35pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 8.35pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 8.35pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 8.35pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 8.35pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 8.35pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 8.35pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; I\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e15\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.389\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.002\u003csup\u003e*\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 15.5pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; II\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 15.5pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 15.5pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 15.5pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n 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15.5pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; III\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e31\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e16\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; IV\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eHistologic subtype, n (%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n 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5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Serous papillary adenocarcinoma\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e42\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e17\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e14\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e-0.228\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.079\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Endometrioid adenocarcinoma\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Clear cell carcinoma\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Mucinous carcinoma\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eHistologic grade, n (%)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; G1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e20\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.466\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"3\" style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.0017\u003csup\u003e***\u003c/sup\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; G2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e16\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e11\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; G3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e24\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e12\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eResidual tumor (cm), n (%)\u2028\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; \u0026le;1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e45\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e12\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e20\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e10\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.166\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.194\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n 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191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e15\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n 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rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eChemotherapy, n (%)\u2028\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 42.9pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Platinum only\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.573149741824441%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.74526678141136%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.917383820998279%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"7.056798623063683%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n 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width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.263\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Other/platinum\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e40\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e7\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e20\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e11\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; None\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e10\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e6\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width: 435.3pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 16.15pt;vertical-align: top;\" valign=\"top\" width=\"100%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003eMalignant tumor cells in peritoneal fluid\u2028\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-right-width: 1pt;border-bottom-width: 1pt;border-left-width: 1pt;border-style: none solid solid;border-right-color: rgb(191, 191, 191);border-bottom-color: rgb(191, 191, 191);border-left-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 17.65pt;vertical-align: top;\" valign=\"top\" width=\"39.24268502581756%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Present\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 17.65pt;vertical-align: top;\" valign=\"top\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e31\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1pt;border-bottom-color: rgb(191, 191, 191);border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 17.65pt;vertical-align: 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none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 17.65pt;\" width=\"9.81067125645439%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.308\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 44.95pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 17.65pt;\" width=\"10.327022375215146%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e0.016*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 171pt;border-style: none solid solid;border-left-width: 1pt;border-left-color: rgb(191, 191, 191);border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"49.13793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026nbsp; Absent or rare\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 44.85pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"12.931034482758621%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e29\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 32.7pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.482758620689655%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 33.8pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.698275862068966%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.6pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"9.913793103448276%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e13\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 30.5pt;border-style: none solid solid none;border-bottom-width: 1.5pt;border-bottom-color: black;border-right-width: 1pt;border-right-color: rgb(191, 191, 191);padding: 0in 5.4pt;height: 14.05pt;vertical-align: top;\" valign=\"top\" width=\"8.836206896551724%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: SimSun;text-align: center;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e11\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style=\"margin: 0in 0in 0.0001pt;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eStatistical analyses were performed by Pearson\u0026nbsp;\u003cspan style=\"line-height: 16.100000381469727px;\"\u003e\u0026chi;2\u0026nbsp;\u003c/span\u003etest.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"margin: 0in 0in 0.0001pt;font-family: SimSun;line-height: 18.399999618530273px;\"\u003e\u003cspan style=\"font-family: Verdana, Geneva, sans-serif; font-size: 10px; color: rgb(0, 0, 0);\"\u003e*, P \u0026lt; 0.05, **, P \u0026lt; 0.01\u003c/span\u003e\u003c/p\u003e"},{"header":"Supplementary Data","content":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1. Expression of cyclin H in different \u003c/strong\u003e\u003cstrong\u003eovarian cancer cell lines. \u003c/strong\u003eThe protein levels of cyclin H in HO8910, SK-OV-3, and NIH: OVCAR-3 cells were detected by western blot. Cyclin H was highly expressed in HO8910 cells.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Figure 2. Effect of cyclin H in migration and invasion of \u003c/strong\u003e\u003cstrong\u003eovarian cancer cells. (A) \u003c/strong\u003eCell\u0026nbsp;scratch\u0026nbsp;test was used to evaluate the migration ability of HO8910 cells. HO8910 cells were seeded in a six-well plate at a density of 5\u0026times;10\u003csup\u003e5\u003c/sup\u003e/well, and a straight\u0026nbsp;scratch was made using a (yellow) pipette tip when the cultures are confluent. Twelve hours later, the distance of the wound was analyzed and the healing percentage was calculated. Bar = 200 \u0026micro;m. (B) Invasion of HO8910 cells was measured by transwell invasion assay. Upper chamber of 24-well transwell was blocked with Matrigel, and HO8910 cells were placed. After incubation for 20 h, the non-invaded cells on the top of the transwell were removed with a cotton swab and the invaded cells were counted under a light microscope. Bar = 20 \u0026micro;m.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Figure 3. Body weight of nude mice after tumor inoculation. \u003c/strong\u003eThe body weight of mice was compared with that observed on day 0, and no significant change was found between the cyclin H shRNA group and the control group.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"cancer-cell-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccin","sideBox":"Learn more about [Cancer Cell International](http://cancerci.biomedcentral.com/)","snPcode":"12935","submissionUrl":"https://submission.nature.com/new-submission/12935/3","title":"Cancer Cell International","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cyclin H, CDK2, ovarian cancer, cell cycle","lastPublishedDoi":"10.21203/rs.3.rs-20434/v3","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-20434/v3","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Cell cycle dysregulation plays a key role in the pathogenesis of malignant tumors. As a part of the CDK-activating kinase (CAK) trimeric complex, cyclin H is necessary to regulate the cell cycle and proliferation. This investigation aims to characterize the clinical significance and the biological functions of cyclin H in ovarian cancer. \u003c/p\u003e\u003cp\u003eMethods: Immunohistochemical staining was performed on 60 ovarian cancer cases, and a correlation between cyclin H expression and the clinical characteristics of ovarian cancer was analyzed. The function of cyclin H in ovarian cancer was further explored using HO8910 cells and a subcutaneous xenograft model of nude mice. \u003c/p\u003e\u003cp\u003eResult: Cyclin H was slightly expressed in grade 1 ovarian cancer but highly expressed in grade 2 and grade 3 cancerous tissues. The Spearman’s rank correlation analysis showed that the expression of cyclin H is positively correlated with the tumor grade, the FIGO stage, histological grade, and the peritoneal metastasis of ovarian cancer and is also positively correlated with the Ki67 and p-CDK2 in ovarian cancer. Additionally, we found that the five-year survival rate was higher in patients expressing low cyclin H than those expressing high cyclin H . Further, knockdown of cyclin H was achieved using an shRNA in HO8910 ovarian cancer cell line. Silencing cyclin H resulted in a G1/S cell cycle arrest in ovarian cancer cells suppressing its growth. The Ki67 expression was also decreased in cyclin H silenced ovarian cancer. \u003c/p\u003e\u003cp\u003eConclusion: These results suggest that high expression of cyclin H predicts the poor prognosis and promotes the growth of ovarian cancer by regulating the cell cycle. \u003c/p\u003e","manuscriptTitle":"Cyclin H predicts the poor prognosis and promotes the proliferation of ovarian cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":3,"date":"2020-06-29 17:52:30","doi":"10.21203/rs.3.rs-20434/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-07-06T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-07-05T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2020-07-04T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewersInvited","content":"","date":"2020-07-01T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-07-01T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-07-01T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-06-25T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-06-24T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-06-24T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-cell-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccin","sideBox":"Learn more about [Cancer Cell International](http://cancerci.biomedcentral.com/)","snPcode":"12935","submissionUrl":"https://submission.nature.com/new-submission/12935/3","title":"Cancer Cell International","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2020-06-10 13:43:59","doi":"10.21203/rs.3.rs-20434/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-06-10T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-06-09T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"editorInvitedReview","content":"","date":"2020-06-07T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's policy.\n"},{"type":"reviewerAgreed","content":"","date":"2020-06-04T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-06-03T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-06-01T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-06-01T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-05-31T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-05-31T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"cancer-cell-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ccin","sideBox":"Learn more about [Cancer Cell International](http://cancerci.biomedcentral.com/)","snPcode":"12935","submissionUrl":"https://submission.nature.com/new-submission/12935/3","title":"Cancer Cell International","twitterHandle":"@OncoBioMed","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-04-02 14:57:21","doi":"10.21203/rs.3.rs-20434/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-05-04T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-05-03T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable due to the journal's 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