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The aetiology of C.L.P. is multifaceted and involves genetic and environmental factors that impact the shape and position of the nasal cartilage, resulting in an asymmetrical appearance of the nose. Growth factors are crucial in regulating cartilage synthesis and repair. Exosomes have emerged as a promising cell-free drug delivery system that facilitates intercellular communication and maintains tissue homeostasis. This study identifies and quantifies the growth factors present in exosomes derived from lactating maternal blood of cleft and non-cleft infants and compares them to evaluate the differences. The study aims to assess the potential of these exosomes as a therapeutic approach for C.L.P. management. Methods Blood samples were collected from lactating mothers at Sharad Pawar Dental College and isolating plasma using centrifugation. Exosome and total protein isolation will be conducted in the laboratory, and immunoblotting will evaluate growth factors. Quantitative and comparative protein and growth factor analysis will be conducted separately for maternal blood samples. Results The growth factors responsible for cartilage growth and development will be present in maternal exosomes, potentially leading to novel therapies for C.L.P. management. The study aims to demonstrate the therapeutic potential of exosomes, as carriers of intra-cellular factors, in transporting growth factors to the required site for managing C.L.P. Conclusions Overall, by understanding the roles played by growth factors, intercellular communication, and genetic and environmental factors in the aetiology of C.L.P., this research can contribute to creating effective treatment strategies for C.L.P. management. Finding growth factors in exosomes made from the blood of nursing mothers could be a cutting-edge therapeutic strategy for treating C.L.P. \" } { \"@context\": \"http://schema.org\", \"@type\": \"BreadcrumbList\", \"itemListElement\": [ { \"@type\": \"ListItem\", \"position\": \"1\", \"item\": { \"@id\": \"https://f1000research.com/\", \"name\": \"Home\" } }, { \"@type\": \"ListItem\", \"position\": \"2\", \"item\": { \"@id\": \"https://f1000research.com/browse/articles\", \"name\": \"Browse\" } }, { \"@type\": \"ListItem\", \"position\": \"3\", \"item\": { \"@id\": \"https://f1000research.com/articles/12-531\", \"name\": \"Comparison of growth factors isolated from exosomes present in maternal...\" } } ] } Home Browse Comparison of growth factors isolated from exosomes present in maternal... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Soni N, Niranjane P, Daigavane P and Shinde M. Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.12688/f1000research.134062.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Study Protocol Revised Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] Nikita Soni https://orcid.org/0000-0002-4068-3358 1 , Priyanka Niranjane 2 , Pallavi Daigavane 3 , Mrudula Shinde https://orcid.org/0000-0001-7916-7943 5 Nikita Soni https://orcid.org/0000-0002-4068-3358 1 , Priyanka Niranjane 2 , Pallavi Daigavane 3 , Mrudula Shinde https://orcid.org/0000-0001-7916-7943 5 PUBLISHED 18 Jan 2024 Author details Author details 1 Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, Maharastra, 442001, India 2 Associate Professor, Department of Orthodontics and Dentofacial Orthopedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharashtra, 442001, India 3 Associate Professor, Department of Orthodontics and Dentofacial Orthopedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharashtra, 442001, India 4 central research laboratory, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharashtra, 442001, India 5 Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharastra, 442001, India Nikita Soni Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Priyanka Niranjane Roles: Supervision Pallavi Daigavane Roles: Conceptualization, Supervision Mrudula Shinde Roles: Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Datta Meghe Institute of Higher Education and Research collection. Abstract Background Cleft lip and palate (C.L.P.) is a common congenital condition which affects the orofacial region. The aetiology of C.L.P. is multifaceted and involves genetic and environmental factors that impact the shape and position of the nasal cartilage, resulting in an asymmetrical appearance of the nose. Growth factors are crucial in regulating cartilage synthesis and repair. Exosomes have emerged as a promising cell-free drug delivery system that facilitates intercellular communication and maintains tissue homeostasis. This study identifies and quantifies the growth factors present in exosomes derived from lactating maternal blood of cleft and non-cleft infants and compares them to evaluate the differences. The study aims to assess the potential of these exosomes as a therapeutic approach for C.L.P. management. Methods Blood samples were collected from lactating mothers at Sharad Pawar Dental College and isolating plasma using centrifugation. Exosome and total protein isolation will be conducted in the laboratory, and immunoblotting will evaluate growth factors. Quantitative and comparative protein and growth factor analysis will be conducted separately for maternal blood samples. Results The growth factors responsible for cartilage growth and development will be present in maternal exosomes, potentially leading to novel therapies for C.L.P. management. The study aims to demonstrate the therapeutic potential of exosomes, as carriers of intra-cellular factors, in transporting growth factors to the required site for managing C.L.P. Conclusions Overall, by understanding the roles played by growth factors, intercellular communication, and genetic and environmental factors in the aetiology of C.L.P., this research can contribute to creating effective treatment strategies for C.L.P. management. Finding growth factors in exosomes made from the blood of nursing mothers could be a cutting-edge therapeutic strategy for treating C.L.P. READ ALL READ LESS Keywords cleft lip and palate, congenital anomalies, nasal cartilage, growth factors, exosomes, lactating maternal blood, intercellular communication, cartilage synthesis. Corresponding Author(s) Nikita Soni ( [email protected] ) Close Corresponding author: Nikita Soni Competing interests: No competing interests were disclosed. Grant information: The author(s) declared that no grants were involved in supporting this work. Copyright: © 2024 Soni N et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Soni N, Niranjane P, Daigavane P and Shinde M. Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.12688/f1000research.134062.2 ) First published: 23 May 2023, 12 :531 ( https://doi.org/10.12688/f1000research.134062.1 ) Latest published: 18 Jan 2024, 12 :531 ( https://doi.org/10.12688/f1000research.134062.2 ) Revised Amendments from Version 1 In response to the reviewers' feedback, the paper has been updated with references added to sentences, extensive proofreading, and my grammatical errors are fixed. Discussed my methodology and the potential outcomes of my research in more detail. In response to the reviewers' feedback, the paper has been updated with references added to sentences, extensive proofreading, and my grammatical errors are fixed. Discussed my methodology and the potential outcomes of my research in more detail. See the authors' detailed response to the review by Junichi Iwata See the authors' detailed response to the review by Mohsen Sheykhhasan READ REVIEWER RESPONSES Introduction Background and rationale Cleft lip and palate (C.L.P.) constitutes one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child. This condition can be present in numerous variations and combinations. 1 The prevalence of C.L.P. is very high in the Asian and American populations compared to the African population. 1 According to a study in 2009, India, with an estimated 1.1 billion population, yields 24.5 million births per year, with a birth prevalence of around 27,000-33,000 clefts per year. The incidence of C.L.P. is higher in males than in females. 1 This congenital disability creates medical, psychological, and social problems affecting individuals and their families. Genetic and environmental variables play a role in the complex multifactorial aetiology of C.L.P. 1 The genes responsible for non-syndromic C.L.P. are FGFR2, IRF6, FGF8, and BMP4 2 and shared environmental factors are maternal smoking, alcohol consumption, consanguineous marriage consumption of certain medications such as topiramate, valproic acid during the first trimester, nutritional deficiency like folic acid deficiency, vitamin A deficiency, chemical exposure like cosmetics, pesticides and psychological factors such as stress and depression. 1 The anatomy of C.L.P. includes the abnormal shape and position of the nasal septum and nasal tip cartilage, which creates an uneven appearance of the nostril, nasal tip, and nasal dome/contour. The deviated nasal cartilage is moulded and corrected with the help of various P.S.I.O. appliances to mould the nasal cartilage pre-surgically. 3 The nasal cartilage is a structure within the nose that provides form and support to the nasal cavity and is made of hyaline cartilage. 4 As the cartilage is avascular connective tissue with no direct blood supply, it receives its nutrition by diffusion from the surrounding enviroment, and this increases when there is an increase in compressive forces acting on it. The structure and organisation of cartilage’s extra-cellular matrix are crucial for the proper functioning of cartilage because cartilage contains particular, differentiated cells whose main job is to maintain the stability of matrix elements. When wounded, its capacity for self-repair is constrained. 5 The growth and development of cartilages are regulated by various growth factors that signal the extracellular matrix and other components. 6 Even after a prosperous cleft palate and lip surgery in a C.L.P. child, there are chances for relapse, possibly due to something lacking on a cellular level. Intercellular communication is an essential function for maintaining homeostasis, or direct cell-to-cell interaction. Since the previous decade, extra-cellular vesicles, particularly exosomes, have drawn more attention for their potential applications. 6 Recent research has shown that exosomes can serve as a portal for cell-free drug delivery systems that retain their original characteristics from the parent cell. Extra-cellular vesicles, or exosomes, are found in nearly all cells, tissues, and bodily secretions. 7 They support intercellular communication and preserve tissue homeostasis in pathological physiology. Nine thousand seven hundred sixty-nine proteins, 2838 miRNAs, 3408 mRNAs, and 1116 lipids are found in exosomes. These exosomes can act as a drug delivery tool as their characteristics are derived from the parent cell. Almost all the cells, blood, tissue, saliva, tear, breast milk, urine, and G.I.T. secretion secrete exosomes. Exosomes can cross the blood-brain barrier and the lipid bilayer guards against immune cells and enzymes. They can regenerate new blood vessels and cellular proliferation. 8 Exosomes are secreted as extra-cellular vesicles and contain growth factors, amongst many other essential cellular components. These exosomes contain signalling growth factors that may have therapeutic potential in the growth and development of nasal cartilage in C.L.P. infants. 9 There is a need to access various factors, illustrated in Table 1 (genes, D.N.A., R.N.A., protein, enzyme, growth factor), responsible for the growth and development of cartilage. It was thought that accessing the quality and quantity of growth factors in the exosomes would play a role in the cartilage’s growth and development. Table 1. Various factors responsible for the growth and development of cartilage. Growth factor present in cartilage Functions Present in blood Normal range • TGF superfamily (β1, β2, β3) 9 • As IL-1 activates matrix-degrading enzymes, suppresses matrix synthesis, and inhibits chondrocyte proliferation, it increases the synthesis of E.C.M. and lowers the catabolic activity of M.M.Ps and IL-1. • Promotes cartilage synthesis, chondrocyte growth, and cartilage repair as it shows high collagen type II activity. ✓ 2-12 ng/ml <0.2 ng/ml <0.1 ng/ml • BMP-7 9 • It promotes the production of E.C.M. • Decreases IL and MMP activity and expression, lessening cartilage breakdown. ✓ 64.6 pg/ml • FGF-2 9 • FGF-18 • Increases chondrocyte proliferation and stimulates the ECM. • Function in post-natal maintenance of cartilage stimulates cartilage development and regeneration of hyaline cartilage. ✓ <10.8 ng/l The following study is one of a kind. The growth factors present in the mother are genetically transferred to the child to produce a type of cartilage with specific characteristics. They thought to assess the quality and quantity of growth factors in the mother of a child with C.L.P. and a child with non-cleft. The current conventional treatment regime for C.L.P. management does not address the cellular aspect, especially the cellular signalling for cartilage moulding. This rate-limiting factor for C.L.P. management may be overcome by providing cartilage growth and development-triggering growth factors. The following study is designed with the hypothesis that there may be a difference in the quality and quantity of growth factors in the blood of lactating mothers of cleft and non-cleft infants. The study presents a challenging scenario in managing cleft lip and palate (C.L.P.) due to the complex process of nasoalveolar cartilage moulding. The importance of time in the initial 2-3 months of a child’s life for cartilage moulding is emphasised, but C.L.P. infants are deprived of essential nutrients in the mother’s milk. While some developed countries provide fortified milk for C.L.P. infants, developing countries like India rely heavily on animal-derived milk, which has limited nutrients. This lack of essential nutrients can lead to a decline in the crucial 2–3-month period to less than one month, failing mechanical appliances like nasal stunts. Objective To identify growth factors present in the exosomes of lactating maternal blood of cleft and non-cleft infants. To quantify the identified growth factors in the exosomes of lactating maternal blood of cleft and non-cleft infants. To compare the identified growth factors present in the exosomes of lactating maternal blood of cleft and non-cleft infants. Study design Analytical observational study. Study setting The following study will be conducted in the Department of Orthodontics and Dentofacial Orthopaedics at Sharad Pawar Dental College in collaboration with the Central Research Laboratory (Centre of Translation Sciences), Sawangi, Wardha. Study participants The lactating mothers visiting the Department of Orthodontics and Dentofacial Orthopaedics, Department of Gynaecology and Obstetrics, and the Department of Paediatrics and fulfilling the inclusion criteria will be included in the study. Inclusion criteria Lactating mothers of non-syndromic isolated cleft lip and palate infants less than six months of age. Age of mothers: <35 years. No systemic conditions such as diabetes and hypertension. Exclusion criteria Age of mother: >35 years (due to hormonal changes). Lactating mother with systemic disease. Lactating mother with developmental and congenital disease. Lactating mother of an infant of more than six months of age. Non-lactating mothers Protocol Control Group: Mothers of healthy infants (non-cleft infants). Study Group: Mothers of an infant with a cleft lip and palate. Methodology Each lactating mother included in the sample will explain the need for the study and the entire procedure in their language of understanding, and informed consent will be obtained from them. The blood sample collection will be done in the Department of Oral Pathology/Oral Surgery, Sharad Pawar Dental College, in collaboration with the Department of Gynecology. 2 ml of the blood sample will be collected in EDTA collection tubes. Once sample collection is done, it will be taken to the laboratory in the R&D house (D.M.I.H.E.R.) for evaluation. First, the plasma will be separated through a centrifugation process and stored at -80 degrees Celsius until further experimentation. The isolation of exosomes from the plasma and the subsequent isolation of total proteins from the exosome will be done following standard protocol, and followed by an analysis of growth factors from the isolated total proteins (from both the exosomes) through immunoblotting. Once the analysis is done, the quality and quantity of growth factors responsible for cartilage growth and development will be compared for both groups. Immunoblotting is a technique in which host antibodies identify a target protein via an antigen-antibody reaction as it identifies the target protein among the number of unrelated proteins. Proteins are electrophoretically separated and then moved to nitrocellulose membranes. This method makes use of the following three components: (1) Size division. (2) Transfer to firm support. (3) Using a primary and secondary antibody to identify a target protein visually. Examples of equipment used for each component mentioned above are listed here: • Electrophoresis apparatus: Bio-Rad Mini-PROTEAN system, Invitrogen XCell SureLock Mini-Cell system, etc. • Transfer apparatus: Bio-Rad Trans-Blot system, Invitrogen iBlot system, GE Healthcare Amersham Biosciences Hybond Transfer System. • Blocking buffer: BSA and non-fat dry milk. • Primary antibodies: Santa Cruz Biotechnology, Cell Signaling Technology, Thermo Fisher Scientific. • Secondary antibodies: anti-mouse and anti-rabbit IgG conjugated to horseradish peroxidase (HRP) or alkaline phosphatase (AP). • Chemiluminescence substrate: SuperSignal West Pico, SuperSignal West Femto from Thermo Fisher Scientific, etc. • Imaging systems: Bio-Rad ChemiDoc MP Imaging System, Thermo Fisher Scientific iBright CL750 Imaging System, etc. • After immunoblotting, proteins and growth factors will be analyzed separately for the maternal blood of C.L.P. and non-CLP infants, and quantification and comparison for both groups will be made. Variables and data measurements OUTCOME : Following are the outcomes with their descriptions for the measurements mentioned below: The purpose of the study is to assess the growth factors, such as TGF-β and B.M.P., found in the exosomes of lactating mothers' blood. These exosomes can be used to identify, quantify, and compare growth factors that have been isolated from the maternal blood of mothers of infants with and without clefts. This means that separated mother exosomes should have a good number of growth factors that are important for cartilage growth and development. These growth factors can be used as a therapy in addition to common CLP management procedures. BIAS: Bias will be minimised as patients are random and will be selected from the O.P.D. of the Department of Orthodontics and Dentofacial Orthopaedics of Sharad Pawar Dental College and Hospital, Wardha. Study sample The sample size was calculated by using Daniel’s formula for sample size: n = Z ∝ 22 ∗ P 1 − P d2 Where, Z∝2 = is the level of significance at 5%, i.e., 95% confidence interval = 1.96 P = Prevalence of cleft lip and palate = 1% = 0.01 d = Desired error of margin = 6% = 0.06 n = 1.962 × 0.01 × 1 − 0.01 0.062 = 10.56 n is the population size Total sample size = 30 Statistical analysis All the demographic and outcome data will be presented using descriptive statistics for continuous variables, which can be categorized using mean, standard deviation, and median for discrete variables and frequency and proportion for continuous variables. Descriptive statistics for continuous variables will be used to offer data interpretations tested for normality using the KALMOGOROV-SMIRNOV TEST for continuous data to test the outcome variable. The R software version of SPSS software 3.2 will be used to analyse the results. Growth factors are categorised according to the range that will be distributed for analyzing the data into the normal range and not in the normal range. The chi-square test can be used to find the result of an association of growth factors with the blood of mothers of cleft and non-cleft infants. An odd ratio will be used to find the risk involved multiple times. An independent t-test will be used to find the results in two groups for outcome variables if the data falls under the normal distribution. A non-parametric test will find a significant difference if the data does not come under a normal distribution. Dissemination This study aims to evaluate the growth factors present in the exosomes of lactating maternal blood for their potential use in cleft lip and palate (C.L.P.) management. The study hypothesises that growth factors enhance cartilage growth and development, crucial during the first 2-3 months of a child’s life. However, C.L.P. infants are often deprived of essential nutrients in the mother’s milk, leading to a decline in the duration of cartilage moulding. Exosomes in lactating maternal blood can carry essential growth factors, hormones, and estrogen, which can be transported to the required site for therapeutic potential in C.L.P. management. Study status The study has yet to start. Discussion The study suggests that exosomes found in lactating maternal blood could be a promising therapeutic option for managing cleft lip and palate (C.L.P.). These exosomes can carry various growth factors, estrogen, or hormones to the site of injury, facilitating the growth and development of cartilage in C.L.P. infants. The study emphasises the need for innovative approaches to address the challenges of managing C.L.P., particularly in developing countries with limited resources. Numerous studies have demonstrated the potential of exosomes to carry growth factors. For instance, exosomes produced by stem cells have been studied as a treatment for osteoarthritis (O.A.) due to their potential to protect against chondroprotection, as emphasized by the research by Kwang Ho Yoo et al. (2022). 10 Additionally, exosomes derived from mesenchymal cells contain various growth factors like TGFβ1, VEGF, H.G.F., cytokines, and proteins, as demonstrated by Kan Yin et al . in 2019. 11 Studies have also shown the significance of genes like BMP7 and TGF-BETA2 in promoting the production of cartilage matrix, regulating the endochondral ossification process, and maintaining homeostasis in both healthy and unhealthy states of cartilage, as indicated by Yoo et al. (2022) 10 and Mengmeng Duaner et al . (2021), 12 respectively. Overall, these studies highlight the immense therapeutic potential of exosomes and genes like BMP7 and TGF-BETA2 in promoting cartilage growth and development. The findings emphasize the need for further research and innovative approaches to managing conditions like C.L.P. and O.A., particularly in developing countries with limited resources. Ethical considerations: Ethical approval received by Datta Meghe Institute of Higher Education and Research, Sawangi, Wardha IEC ref no.- DMIHER (DU)/IEC/2023/572 Written informed participant consent will be obtain prior to the study taking place. Data availability No data are associated with this article. Extended data Repository name: Zenodo Title of Project: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. File Name: STROBE cross-sectional Checklist DOI: 10.5281/zenodo.7780107 Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgements We thank the Institute and its colleagues for their support. References 1. Oner DA, Tastan H: Cleft lip and palate: Epidemiology and etiology. Otorhinolaryngol-Head Neck Surg. 2020 [cited 2023 Jan 24]; 5 (4). Publisher Full Text Reference Source 2. Leslie EJ, Marazita ML: Genetics of Cleft Lip and Cleft Palate. Am. J. Med. Genet. C Semin. Med. Genet. 2013 Nov; 163 (4): 246–258. PubMed Abstract | Publisher Full Text | Free Full Text 3. Attiguppe PR, Karuna YM, Yavagal C, et al. : Presurgical nasoalveolar molding: A boon to facilitate the surgical repair in infants with cleft lip and palate. Contemp. Clin. Dent. 2016; 7 (4): 569–573. PubMed Abstract | Publisher Full Text | Free Full Text 4. Baddam P, Bayona-Rodriguez F, Campbell SM, et al. : Properties of the Nasal Cartilage, from Development to Adulthood: A Scoping Review. Cartilage. 2022 Mar 28; 13 (1): 19476035221087696. PubMed Abstract | Publisher Full Text 5. Tuan RS, Chen AF, Klatt BA: Cartilage Regeneration. J. Am. Acad. Orthop. Surg. 2013 May; 21 (5): 303–311. PubMed Abstract | Publisher Full Text | Free Full Text 6. Chang LR, Marston G, Martin A: Anatomy, Cartilage. StatPearls. Treasure Island (FL): StatPearls Publishing; 2022 [cited 2023 Jan 25]. Reference Source 7. Yu W, Serrano M, Miguel SS, et al. : Cleft lip and palate genetics and application in early embryological development. Indian J. Plast. Surg. Off. Publ. Assoc. Plast. Surg. India. 2009 Oct; 42 (Suppl): 35. Publisher Full Text 8. Liu Y, Ma Y, Zhang J, et al. : Exosomes: A Novel Therapeutic Agent for Cartilage and Bone Tissue Regeneration. Dose-Response. 2019 Dec 13; 17 (4): 1559325819892702. PubMed Abstract | Publisher Full Text 9. Exosomes: biogenesis, biologic function and clinical potential|Cell & Bioscience: 2023 [cited 2023 Jan 25]. Publisher Full Text 10. Yoo KH, Thapa N, Chwae YJ, et al. : Transforming growth factor-β family and stem cell-derived exosome therapeutic treatment in osteoarthritis (Review). Int. J. Mol. Med. 2022 May; 49 (5): 62. PubMed Abstract | Publisher Full Text | Free Full Text 11. Fortier LA, Barker JU, Strauss EJ, et al. : The role of growth factors in cartilage repair. Clin. Orthop. 2011 Oct; 469 (10): 2706–2715. PubMed Abstract | Publisher Full Text | Free Full Text 12. Yin K, Wang S, Zhao RC: Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomark. Res. 2019 Apr 4; 7 : 8. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 23 May 2023 ADD YOUR COMMENT Comment Author details Author details 1 Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, Maharastra, 442001, India 2 Associate Professor, Department of Orthodontics and Dentofacial Orthopedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharashtra, 442001, India 3 Associate Professor, Department of Orthodontics and Dentofacial Orthopedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharashtra, 442001, India 4 central research laboratory, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharashtra, 442001, India 5 Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, wardha, maharastra, 442001, India Nikita Soni Roles: Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Priyanka Niranjane Roles: Supervision Pallavi Daigavane Roles: Conceptualization, Supervision Mrudula Shinde Roles: Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information The author(s) declared that no grants were involved in supporting this work. Article Versions (2) version 2 Revised Published: 18 Jan 2024, 12:531 https://doi.org/10.12688/f1000research.134062.2 version 1 Published: 23 May 2023, 12:531 https://doi.org/10.12688/f1000research.134062.1 Copyright © 2024 Soni N et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Soni N, Niranjane P, Daigavane P and Shinde M. Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.12688/f1000research.134062.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 18 Jan 2024 Revised Views 0 Cite How to cite this report: Pan Y. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.161273.r359461 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v2#referee-response-359461 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 04 Feb 2025 Yongchu Pan , Department of Orthodontics, Nanjing Medical University (NMU), Nanjing, China Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.161273.r359461 The study aims to demonstrate the therapeutic potential of exosomes, as carriers of intra-cellular factors, in transporting growth factors to the required site for managing C.L.P. Generally, It is clearly written and straightforward. It has a clear aim, and reasonable ... Continue reading READ ALL The study aims to demonstrate the therapeutic potential of exosomes, as carriers of intra-cellular factors, in transporting growth factors to the required site for managing C.L.P. Generally, It is clearly written and straightforward. It has a clear aim, and reasonable sample size. They need to present more information on the treatment of cleft with exosomes detailed and method should be more detailed. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: genetics of orofacial cleft I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Pan Y. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.161273.r359461 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v2#referee-response-359461 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Pilmane M. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.161273.r352739 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v2#referee-response-352739 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 31 Dec 2024 Māra Pilmane , Riga Stradiņš University, Riga, Latvia Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.161273.r352739 Despite the research topic might be of interests, the presentation and design is under the high criticism. So, Introduction: doesn't reveal the topicality of the research question. It seems rather a compilation of data about CLP without strict development ... Continue reading READ ALL Despite the research topic might be of interests, the presentation and design is under the high criticism. So, Introduction: doesn't reveal the topicality of the research question. It seems rather a compilation of data about CLP without strict development of necessity information. Also it is not clear how the authors plan to link the content of exosomes in mother milk with CLP; why different genes are mentioned, especially for non-syndromic CLP and what could be link of them with exosomes; how in all this CLP picture the affected cartilage is involved and how does it quality correlate to the mother milk exosomes content!? Material and Methods: Rise the question what is done by authors themselves if the material was sent to the company!? references for the methods are absent, like the careful description of the patient and controls... The main objection is that there is no any possibility to repeat the research by following the authors description! Results: This part is almost lacked, it just contains some mathematical formula and unclear example for the research; please, move it for the M+M part together with statistics; Discussion: Unclear, as there are no clarified points for the possible results! References.: Not acceptable as there is numerous of sources about the research questions not described by authors. Commonly, the research proposal requests normal english grammar, step-by-step Introduction and careful description of repeatable methodology along with all References for the protocols. Is the rationale for, and objectives of, the study clearly described? No Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: cleft lip palate, morphology of tissue and body fluids I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Pilmane M. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.161273.r352739 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v2#referee-response-352739 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 23 May 2023 Views 0 Cite How to cite this report: Sheykhhasan M. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.147088.r174820 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v1#referee-response-174820 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 01 Aug 2023 Mohsen Sheykhhasan , Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.147088.r174820 The study protocol entitled “Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage\" appears to be interesting, but ... Continue reading READ ALL The study protocol entitled “Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage\" appears to be interesting, but there are many flaws and concerns on it. Study can be greatly improved if following suggestions were incorporated: Title: the title is not appropriate. I suggesting making up it. Paper is replete with grammatical mistakes. Needs rewriting and thorough evaluation. Some references missing. For example, “Cleft lip and palate (C.L.P.) constitute one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child.” And etc. Protocol section requires more information: To confirm the success of exosome isolation, in addition to the NTA and transmission electron microscopy, it is necessary to confirm using the Western blot analysis and DLS. As a result, it is better to include the results of the NTA, transmission electron microscopy, the Western blot analysis and DLS in the Protocol section of the present paper. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: stem cell biology, extracellular vesicle, exosome, cancer, immunotherapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sheykhhasan M. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.147088.r174820 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v1#referee-response-174820 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 18 Jan 2024 nikita soni , Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 18 Jan 2024 Author Response REVIEWER’S QUESTIONS RESPONSE 1. Title: the title is not appropriate. I suggesting making up it. The title of article gives a much clearer summary of my research. It ... Continue reading REVIEWER’S QUESTIONS RESPONSE 1. Title: the title is not appropriate. I suggesting making up it. The title of article gives a much clearer summary of my research. It answers questions like: What I’m doing In whom am I doing this study? Reason for choosing and doing this study. 2.Paper is replete with grammatical mistakes. Needs rewriting and thorough evaluation The article has been proofread several times, and software was used to check for grammatical errors. 3.Some references missing. For example, “Cleft lip and palate (C.L.P.) constitute one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child.” And etc The words you specified are fully cited under reference (1) and similarly. 4. Protocol section requires more information: To confirm the success of exosome isolation, in addition to the NTA and transmission electron microscopy, it is necessary to confirm using the Western blot analysis and DLS. As a result, it is better to include the results of the NTA, transmission electron microscopy, the Western blot analysis and DLS in the Protocol section of the present paper Even though NTA and TEM yield better results, they will be chosen for subsequent research. REVIEWER’S QUESTIONS RESPONSE 1. Title: the title is not appropriate. I suggesting making up it. The title of article gives a much clearer summary of my research. It answers questions like: What I’m doing In whom am I doing this study? Reason for choosing and doing this study. 2.Paper is replete with grammatical mistakes. Needs rewriting and thorough evaluation The article has been proofread several times, and software was used to check for grammatical errors. 3.Some references missing. For example, “Cleft lip and palate (C.L.P.) constitute one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child.” And etc The words you specified are fully cited under reference (1) and similarly. 4. Protocol section requires more information: To confirm the success of exosome isolation, in addition to the NTA and transmission electron microscopy, it is necessary to confirm using the Western blot analysis and DLS. As a result, it is better to include the results of the NTA, transmission electron microscopy, the Western blot analysis and DLS in the Protocol section of the present paper Even though NTA and TEM yield better results, they will be chosen for subsequent research. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 18 Jan 2024 nikita soni , Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 18 Jan 2024 Author Response REVIEWER’S QUESTIONS RESPONSE 1. Title: the title is not appropriate. I suggesting making up it. The title of article gives a much clearer summary of my research. It ... Continue reading REVIEWER’S QUESTIONS RESPONSE 1. Title: the title is not appropriate. I suggesting making up it. The title of article gives a much clearer summary of my research. It answers questions like: What I’m doing In whom am I doing this study? Reason for choosing and doing this study. 2.Paper is replete with grammatical mistakes. Needs rewriting and thorough evaluation The article has been proofread several times, and software was used to check for grammatical errors. 3.Some references missing. For example, “Cleft lip and palate (C.L.P.) constitute one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child.” And etc The words you specified are fully cited under reference (1) and similarly. 4. Protocol section requires more information: To confirm the success of exosome isolation, in addition to the NTA and transmission electron microscopy, it is necessary to confirm using the Western blot analysis and DLS. As a result, it is better to include the results of the NTA, transmission electron microscopy, the Western blot analysis and DLS in the Protocol section of the present paper Even though NTA and TEM yield better results, they will be chosen for subsequent research. REVIEWER’S QUESTIONS RESPONSE 1. Title: the title is not appropriate. I suggesting making up it. The title of article gives a much clearer summary of my research. It answers questions like: What I’m doing In whom am I doing this study? Reason for choosing and doing this study. 2.Paper is replete with grammatical mistakes. Needs rewriting and thorough evaluation The article has been proofread several times, and software was used to check for grammatical errors. 3.Some references missing. For example, “Cleft lip and palate (C.L.P.) constitute one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child.” And etc The words you specified are fully cited under reference (1) and similarly. 4. Protocol section requires more information: To confirm the success of exosome isolation, in addition to the NTA and transmission electron microscopy, it is necessary to confirm using the Western blot analysis and DLS. As a result, it is better to include the results of the NTA, transmission electron microscopy, the Western blot analysis and DLS in the Protocol section of the present paper Even though NTA and TEM yield better results, they will be chosen for subsequent research. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Iwata J. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.147088.r190178 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v1#referee-response-190178 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 01 Aug 2023 Junichi Iwata , Department of Diagnostic & Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, Texas, USA Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.147088.r190178 This manuscript aims to propose a study protocol to analyze exosomes present in blood from mothers with cleft- and non-cleft infants to identify and quantify growth factors involved in the growth and development of infant’s nasal cartilage. Unfortunately, the proposed ... Continue reading READ ALL This manuscript aims to propose a study protocol to analyze exosomes present in blood from mothers with cleft- and non-cleft infants to identify and quantify growth factors involved in the growth and development of infant’s nasal cartilage. Unfortunately, the proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. In addition, it has been known that contents of exosomes change in various physiological and phraseological conditions. Currently, there is no preliminary data to support the hypothesis. At least some preliminary studies would be necessary before starting the study in humans (for instance, in any CL/P animal models or in small scale human data). Lastly, it is unclear how the authors identify particular growth factors and signaling networks through this study. Advanced bioinformatic analyses would be required; however, in this proposal it is unclear. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? No Competing Interests: No competing interests were disclosed. Reviewer Expertise: craniofacial development, cell signaling pathways, animal models, salivary gland, tooth development, microRNA, cleft lip and palate, autophagy, tongue development I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Iwata J. Reviewer Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.147088.r190178 ) The direct URL for this report is: https://f1000research.com/articles/12-531/v1#referee-response-190178 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 18 Jan 2024 nikita soni , Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 18 Jan 2024 Author Response REVIEWER’S QUESTIONS RESPONSE 1.The proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. Methodology - In the methodology section, every ... Continue reading REVIEWER’S QUESTIONS RESPONSE 1.The proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. Methodology - In the methodology section, every step of the procedure is explained, from blood collection to isolating and analyzing growth factors (TGF-BETA, EGF), using the immunoblotting method. Detailed procedure of immunoblotting and the necessary equipment used in it is also elaborated. Data interpretation- Descriptive statistics for continuous variables will be used to offer data interpretations, and the KALMOGOROV-SMIRNOV TEST for continuous data will be used to test the outcome variable. R software version of SPSS software 3.2 will be used to analyze the results. Potential outcomes- identification, quantification, and comparison of growth factors isolated from maternal blood of cleft and non cleft infant mother s. 2.contents of exosomes change in various physiological and phraseological conditions As rightly quoted by the reviewer, due to various physiological conditions like stress, smoking , alcohol, medications etc, the contents of exosomes and accordingly the secretion of various growth factors and their amount may vary in exosomes and correspondingly in maternal blood. The author is also trying to prove that there may be a difference in quantity of growth factors secreted in exosomes in maternal blood of cleft and non cleft infants and this difference in quantity of growth factors in maternal blood can be corelated with the chondrogenesis and occurrence of cleft in infant. 3. There is no preliminary data to support the hypothesis. At least some preliminary studies would be necessary before starting the study in humans There are many articles that discuss the interactions between chemical components found in various exogenous and external stimuli and particular growth factors that change their working pathway and, ultimately, affect the expression of proteins, growth factors, etc.which regulate cell proliferation, differentiation, and migration, leading to a variety of congenital diseases, including cleft lip and palate. For example, The below-mentioned article explains the pathways occurring in pregnancy and their connection with placental nourishment. “Tossetta G, Marzioni D. Signaling Pathways in Pregnancy. Cells. 2022 Apr 20;11(9):1385. doi: 10.3390/cells11091385. PMID: 35563691; PMCID: PMC9101431” There is no evidence available in the literature that directly correlates the alteration in the expression of growth factors and the causation of cleft lip and palate, but indirect evidence depicting the correlation between the amount and expression of growth factors affecting at molecular level and occurrence of congenital abnormalities including cleft lip and palate which forms the basis for the hypothesis investigated in the present study. 4. it is unclear how the authors identify particular growth factors and signaling networks through this study. Advanced bioinformatic analyses would be required The growth factors will be found using the immunoblotting approach. The goal of this research is not to understand signalling networks. REVIEWER’S QUESTIONS RESPONSE 1.The proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. Methodology - In the methodology section, every step of the procedure is explained, from blood collection to isolating and analyzing growth factors (TGF-BETA, EGF), using the immunoblotting method. Detailed procedure of immunoblotting and the necessary equipment used in it is also elaborated. Data interpretation- Descriptive statistics for continuous variables will be used to offer data interpretations, and the KALMOGOROV-SMIRNOV TEST for continuous data will be used to test the outcome variable. R software version of SPSS software 3.2 will be used to analyze the results. Potential outcomes- identification, quantification, and comparison of growth factors isolated from maternal blood of cleft and non cleft infant mother s. 2.contents of exosomes change in various physiological and phraseological conditions As rightly quoted by the reviewer, due to various physiological conditions like stress, smoking , alcohol, medications etc, the contents of exosomes and accordingly the secretion of various growth factors and their amount may vary in exosomes and correspondingly in maternal blood. The author is also trying to prove that there may be a difference in quantity of growth factors secreted in exosomes in maternal blood of cleft and non cleft infants and this difference in quantity of growth factors in maternal blood can be corelated with the chondrogenesis and occurrence of cleft in infant. 3. There is no preliminary data to support the hypothesis. At least some preliminary studies would be necessary before starting the study in humans There are many articles that discuss the interactions between chemical components found in various exogenous and external stimuli and particular growth factors that change their working pathway and, ultimately, affect the expression of proteins, growth factors, etc.which regulate cell proliferation, differentiation, and migration, leading to a variety of congenital diseases, including cleft lip and palate. For example, The below-mentioned article explains the pathways occurring in pregnancy and their connection with placental nourishment. “Tossetta G, Marzioni D. Signaling Pathways in Pregnancy. Cells. 2022 Apr 20;11(9):1385. doi: 10.3390/cells11091385. PMID: 35563691; PMCID: PMC9101431” There is no evidence available in the literature that directly correlates the alteration in the expression of growth factors and the causation of cleft lip and palate, but indirect evidence depicting the correlation between the amount and expression of growth factors affecting at molecular level and occurrence of congenital abnormalities including cleft lip and palate which forms the basis for the hypothesis investigated in the present study. 4. it is unclear how the authors identify particular growth factors and signaling networks through this study. Advanced bioinformatic analyses would be required The growth factors will be found using the immunoblotting approach. The goal of this research is not to understand signalling networks. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 18 Jan 2024 nikita soni , Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India 18 Jan 2024 Author Response REVIEWER’S QUESTIONS RESPONSE 1.The proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. Methodology - In the methodology section, every ... Continue reading REVIEWER’S QUESTIONS RESPONSE 1.The proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. Methodology - In the methodology section, every step of the procedure is explained, from blood collection to isolating and analyzing growth factors (TGF-BETA, EGF), using the immunoblotting method. Detailed procedure of immunoblotting and the necessary equipment used in it is also elaborated. Data interpretation- Descriptive statistics for continuous variables will be used to offer data interpretations, and the KALMOGOROV-SMIRNOV TEST for continuous data will be used to test the outcome variable. R software version of SPSS software 3.2 will be used to analyze the results. Potential outcomes- identification, quantification, and comparison of growth factors isolated from maternal blood of cleft and non cleft infant mother s. 2.contents of exosomes change in various physiological and phraseological conditions As rightly quoted by the reviewer, due to various physiological conditions like stress, smoking , alcohol, medications etc, the contents of exosomes and accordingly the secretion of various growth factors and their amount may vary in exosomes and correspondingly in maternal blood. The author is also trying to prove that there may be a difference in quantity of growth factors secreted in exosomes in maternal blood of cleft and non cleft infants and this difference in quantity of growth factors in maternal blood can be corelated with the chondrogenesis and occurrence of cleft in infant. 3. There is no preliminary data to support the hypothesis. At least some preliminary studies would be necessary before starting the study in humans There are many articles that discuss the interactions between chemical components found in various exogenous and external stimuli and particular growth factors that change their working pathway and, ultimately, affect the expression of proteins, growth factors, etc.which regulate cell proliferation, differentiation, and migration, leading to a variety of congenital diseases, including cleft lip and palate. For example, The below-mentioned article explains the pathways occurring in pregnancy and their connection with placental nourishment. “Tossetta G, Marzioni D. Signaling Pathways in Pregnancy. Cells. 2022 Apr 20;11(9):1385. doi: 10.3390/cells11091385. PMID: 35563691; PMCID: PMC9101431” There is no evidence available in the literature that directly correlates the alteration in the expression of growth factors and the causation of cleft lip and palate, but indirect evidence depicting the correlation between the amount and expression of growth factors affecting at molecular level and occurrence of congenital abnormalities including cleft lip and palate which forms the basis for the hypothesis investigated in the present study. 4. it is unclear how the authors identify particular growth factors and signaling networks through this study. Advanced bioinformatic analyses would be required The growth factors will be found using the immunoblotting approach. The goal of this research is not to understand signalling networks. REVIEWER’S QUESTIONS RESPONSE 1.The proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. Methodology - In the methodology section, every step of the procedure is explained, from blood collection to isolating and analyzing growth factors (TGF-BETA, EGF), using the immunoblotting method. Detailed procedure of immunoblotting and the necessary equipment used in it is also elaborated. Data interpretation- Descriptive statistics for continuous variables will be used to offer data interpretations, and the KALMOGOROV-SMIRNOV TEST for continuous data will be used to test the outcome variable. R software version of SPSS software 3.2 will be used to analyze the results. Potential outcomes- identification, quantification, and comparison of growth factors isolated from maternal blood of cleft and non cleft infant mother s. 2.contents of exosomes change in various physiological and phraseological conditions As rightly quoted by the reviewer, due to various physiological conditions like stress, smoking , alcohol, medications etc, the contents of exosomes and accordingly the secretion of various growth factors and their amount may vary in exosomes and correspondingly in maternal blood. The author is also trying to prove that there may be a difference in quantity of growth factors secreted in exosomes in maternal blood of cleft and non cleft infants and this difference in quantity of growth factors in maternal blood can be corelated with the chondrogenesis and occurrence of cleft in infant. 3. There is no preliminary data to support the hypothesis. At least some preliminary studies would be necessary before starting the study in humans There are many articles that discuss the interactions between chemical components found in various exogenous and external stimuli and particular growth factors that change their working pathway and, ultimately, affect the expression of proteins, growth factors, etc.which regulate cell proliferation, differentiation, and migration, leading to a variety of congenital diseases, including cleft lip and palate. For example, The below-mentioned article explains the pathways occurring in pregnancy and their connection with placental nourishment. “Tossetta G, Marzioni D. Signaling Pathways in Pregnancy. Cells. 2022 Apr 20;11(9):1385. doi: 10.3390/cells11091385. PMID: 35563691; PMCID: PMC9101431” There is no evidence available in the literature that directly correlates the alteration in the expression of growth factors and the causation of cleft lip and palate, but indirect evidence depicting the correlation between the amount and expression of growth factors affecting at molecular level and occurrence of congenital abnormalities including cleft lip and palate which forms the basis for the hypothesis investigated in the present study. 4. it is unclear how the authors identify particular growth factors and signaling networks through this study. Advanced bioinformatic analyses would be required The growth factors will be found using the immunoblotting approach. The goal of this research is not to understand signalling networks. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 23 May 2023 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 4 Version 2 (revision) 18 Jan 24 read read Version 1 23 May 23 read read Junichi Iwata , The University of Texas Health Science Center at Houston, School of Dentistry, Houston, Texas, USA Mohsen Sheykhhasan , Hamadan University of Medical Sciences, Hamadan, Iran Māra Pilmane , Riga Stradiņš University, Riga, Latvia Yongchu Pan , Nanjing Medical University (NMU), Nanjing, China Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Pan Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 04 Feb 2025 | for Version 2 Yongchu Pan , Department of Orthodontics, Nanjing Medical University (NMU), Nanjing, China 0 Views copyright © 2025 Pan Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The study aims to demonstrate the therapeutic potential of exosomes, as carriers of intra-cellular factors, in transporting growth factors to the required site for managing C.L.P. Generally, It is clearly written and straightforward. It has a clear aim, and reasonable sample size. They need to present more information on the treatment of cleft with exosomes detailed and method should be more detailed. Is the rationale for, and objectives of, the study clearly described? Yes Is the study design appropriate for the research question? Yes Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise genetics of orofacial cleft I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Pan Y. Peer Review Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.161273.r359461) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-531/v2#referee-response-359461 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Pilmane M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 31 Dec 2024 | for Version 2 Māra Pilmane , Riga Stradiņš University, Riga, Latvia 0 Views copyright © 2025 Pilmane M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Despite the research topic might be of interests, the presentation and design is under the high criticism. So, Introduction: doesn't reveal the topicality of the research question. It seems rather a compilation of data about CLP without strict development of necessity information. Also it is not clear how the authors plan to link the content of exosomes in mother milk with CLP; why different genes are mentioned, especially for non-syndromic CLP and what could be link of them with exosomes; how in all this CLP picture the affected cartilage is involved and how does it quality correlate to the mother milk exosomes content!? Material and Methods: Rise the question what is done by authors themselves if the material was sent to the company!? references for the methods are absent, like the careful description of the patient and controls... The main objection is that there is no any possibility to repeat the research by following the authors description! Results: This part is almost lacked, it just contains some mathematical formula and unclear example for the research; please, move it for the M+M part together with statistics; Discussion: Unclear, as there are no clarified points for the possible results! References.: Not acceptable as there is numerous of sources about the research questions not described by authors. Commonly, the research proposal requests normal english grammar, step-by-step Introduction and careful description of repeatable methodology along with all References for the protocols. Is the rationale for, and objectives of, the study clearly described? No Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? No Competing Interests No competing interests were disclosed. Reviewer Expertise cleft lip palate, morphology of tissue and body fluids I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Pilmane M. Peer Review Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.161273.r352739) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-531/v2#referee-response-352739 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Sheykhhasan M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 01 Aug 2023 | for Version 1 Mohsen Sheykhhasan , Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran 0 Views copyright © 2023 Sheykhhasan M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The study protocol entitled “Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage\" appears to be interesting, but there are many flaws and concerns on it. Study can be greatly improved if following suggestions were incorporated: Title: the title is not appropriate. I suggesting making up it. Paper is replete with grammatical mistakes. Needs rewriting and thorough evaluation. Some references missing. For example, “Cleft lip and palate (C.L.P.) constitute one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child.” And etc. Protocol section requires more information: To confirm the success of exosome isolation, in addition to the NTA and transmission electron microscopy, it is necessary to confirm using the Western blot analysis and DLS. As a result, it is better to include the results of the NTA, transmission electron microscopy, the Western blot analysis and DLS in the Protocol section of the present paper. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? Partly Are the datasets clearly presented in a useable and accessible format? Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise stem cell biology, extracellular vesicle, exosome, cancer, immunotherapy. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 18 Jan 2024 nikita soni, Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India REVIEWER’S QUESTIONS RESPONSE 1. Title: the title is not appropriate. I suggesting making up it. The title of article gives a much clearer summary of my research. It answers questions like: What I’m doing In whom am I doing this study? Reason for choosing and doing this study. 2.Paper is replete with grammatical mistakes. Needs rewriting and thorough evaluation The article has been proofread several times, and software was used to check for grammatical errors. 3.Some references missing. For example, “Cleft lip and palate (C.L.P.) constitute one of the common congenital disabilities associated with inherited genetic conditions affecting the orofacial region of a child.” And etc The words you specified are fully cited under reference (1) and similarly. 4. Protocol section requires more information: To confirm the success of exosome isolation, in addition to the NTA and transmission electron microscopy, it is necessary to confirm using the Western blot analysis and DLS. As a result, it is better to include the results of the NTA, transmission electron microscopy, the Western blot analysis and DLS in the Protocol section of the present paper Even though NTA and TEM yield better results, they will be chosen for subsequent research. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Sheykhhasan M. Peer Review Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.147088.r174820) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-531/v1#referee-response-174820 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Iwata J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 01 Aug 2023 | for Version 1 Junichi Iwata , Department of Diagnostic & Biomedical Sciences, The University of Texas Health Science Center at Houston, School of Dentistry, Houston, Texas, USA 0 Views copyright © 2023 Iwata J. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This manuscript aims to propose a study protocol to analyze exosomes present in blood from mothers with cleft- and non-cleft infants to identify and quantify growth factors involved in the growth and development of infant’s nasal cartilage. Unfortunately, the proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. In addition, it has been known that contents of exosomes change in various physiological and phraseological conditions. Currently, there is no preliminary data to support the hypothesis. At least some preliminary studies would be necessary before starting the study in humans (for instance, in any CL/P animal models or in small scale human data). Lastly, it is unclear how the authors identify particular growth factors and signaling networks through this study. Advanced bioinformatic analyses would be required; however, in this proposal it is unclear. Is the rationale for, and objectives of, the study clearly described? Partly Is the study design appropriate for the research question? No Are sufficient details of the methods provided to allow replication by others? No Are the datasets clearly presented in a useable and accessible format? No Competing Interests No competing interests were disclosed. Reviewer Expertise craniofacial development, cell signaling pathways, animal models, salivary gland, tooth development, microRNA, cleft lip and palate, autophagy, tongue development I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 18 Jan 2024 nikita soni, Postgraduate, Department of Orthodontics and Dentofacial Orthopaedics, Sharad Pawar Dental College and Hospital, Datta Meghe Institute of Higher Education and Research, Wardha, 442001, India REVIEWER’S QUESTIONS RESPONSE 1.The proposed protocol lacks detailed information for the evaluation of the methodology, data interpretation, potential outcomes, etc. Methodology - In the methodology section, every step of the procedure is explained, from blood collection to isolating and analyzing growth factors (TGF-BETA, EGF), using the immunoblotting method. Detailed procedure of immunoblotting and the necessary equipment used in it is also elaborated. Data interpretation- Descriptive statistics for continuous variables will be used to offer data interpretations, and the KALMOGOROV-SMIRNOV TEST for continuous data will be used to test the outcome variable. R software version of SPSS software 3.2 will be used to analyze the results. Potential outcomes- identification, quantification, and comparison of growth factors isolated from maternal blood of cleft and non cleft infant mother s. 2.contents of exosomes change in various physiological and phraseological conditions As rightly quoted by the reviewer, due to various physiological conditions like stress, smoking , alcohol, medications etc, the contents of exosomes and accordingly the secretion of various growth factors and their amount may vary in exosomes and correspondingly in maternal blood. The author is also trying to prove that there may be a difference in quantity of growth factors secreted in exosomes in maternal blood of cleft and non cleft infants and this difference in quantity of growth factors in maternal blood can be corelated with the chondrogenesis and occurrence of cleft in infant. 3. There is no preliminary data to support the hypothesis. At least some preliminary studies would be necessary before starting the study in humans There are many articles that discuss the interactions between chemical components found in various exogenous and external stimuli and particular growth factors that change their working pathway and, ultimately, affect the expression of proteins, growth factors, etc.which regulate cell proliferation, differentiation, and migration, leading to a variety of congenital diseases, including cleft lip and palate. For example, The below-mentioned article explains the pathways occurring in pregnancy and their connection with placental nourishment. “Tossetta G, Marzioni D. Signaling Pathways in Pregnancy. Cells. 2022 Apr 20;11(9):1385. doi: 10.3390/cells11091385. PMID: 35563691; PMCID: PMC9101431” There is no evidence available in the literature that directly correlates the alteration in the expression of growth factors and the causation of cleft lip and palate, but indirect evidence depicting the correlation between the amount and expression of growth factors affecting at molecular level and occurrence of congenital abnormalities including cleft lip and palate which forms the basis for the hypothesis investigated in the present study. 4. it is unclear how the authors identify particular growth factors and signaling networks through this study. Advanced bioinformatic analyses would be required The growth factors will be found using the immunoblotting approach. The goal of this research is not to understand signalling networks. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Iwata J. Peer Review Report For: Comparison of growth factors isolated from exosomes present in maternal blood of cleft and non-cleft infants for identification and quantification of growth factors involved in the growth and development of cartilage. [version 2; peer review: 2 approved with reservations, 2 not approved] . F1000Research 2024, 12 :531 ( https://doi.org/10.5256/f1000research.147088.r190178) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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