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1. Objective structured clinical examination for teaching and assessment: Evidence-based critique

Author

Pooja Dewan, Sumaira Khalil, and Piyush Gupta

Subjects
Competency-based medical education, Reliability, Validity, Virtual OSCE, Public aspects of medicine, RA1-1270
Abstract

Almost 50 years ago, objective structured clinical examination (OSCE) was introduced as a comprehensive and objective tool to assess clinical competencies in a standardized manner. OSCE has not only been used as an assessment tool but also an effective teaching modality. Over the years, the validity, feasibility, reliability and objectivity of OSCE have been questioned. Also, given the need for a large number of stations and examiners, high costs, elaborate checklists, training of examiners and standardization of patients, the acceptance of OSCE has been reluctant. The COVID 19 pandemic saw OSCE in its new avatar and virtual OSCE was used extensively to ensure undisrupted teaching and assessment of medical students worldwide. The recent Competency Based Medical Education (CBME) Guidelines for medical education in India have internalized OSCE as an assessment modality for medical undergraduates. This article focuses on the issues of validity, objectivity, reliability, and standard setting of OSCE and describes the challenges and way ahead for implementation of OSCE in India.

Published
2024
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2. Investigating antiarthritic potential of polyherbal emulgel

Author

Neha Rana, Piyush Gupta, Vijender Singh, and Mohammed Ali

Subjects
Rheumatoid arthritis (RA), Herbal medicines, Polyherbal emulgel, Protein denaturation, Complete Freund's Adjuvant model, Miscellaneous systems and treatments, RZ409.7-999
Abstract

Background: Rheumatoid arthritis (RA) is an inflammation of joints with increased cellularity of synovial tissue. Allopathic drugs possess several adverse effects, which have led to increase in the utilization of herbal medicines. Polyherbal emulgel resolves the bioavailability issue associated with hydrophobic drugs and can be used effectively in the treatment of RA. Objectives: The present study aimed at the formulation of polyherbal emulgel, and evaluation of in vitro anti-inflammatory activity and in vivo antiarthritic activity. Methods: Seven emulgels F-1 to F-7 were optimally formulated. In vitro anti-inflammatory activity was determined using protein denaturation method employing Diclofenac sodium as the standard. In antiarthritic study Complete Freund's Adjuvant (CFA) model was used. The various parameters were assessed, like paw volume, body weight, hematological parameters, antioxidant parameters, Rheumatic factor (RF), and histopathological study of ankle joint. Results: F-4 and F-7 were found to be optimized formulations as compared to other formulations. The in vitro anti-inflammatory activity was found to be highest in F-4 with IC50 7.74 and F-7 with IC50 8.87 in comparison with Diclofenac sodium having IC50 57.0. Both formulations F-7 and F-4 showed a significant reduction in paw volume and normalization of body weights. The formulation F-7 even showed more potent antiarthritic activity than F-4 by decreasing white blood cells (WBC), lymphocytes, increasing packed cell volume (PCV), neutrophils, superoxide dismutase (SOD), catalase and decreasing malondialdehyde (MDA) levels in serum. This was further confirmed by histopathological study. Conclusion: As an anti-inflammatory agent, this newly developed emulgel was found to possess more therapeutic efficacy than commercially available diclofenac sodium.

Published
2023
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3. Prediction of health monitoring with deep learning using edge computing

Author

Piyush Gupta, Ajay Veer Chouhan, Mohammed Abdul Wajeed, Shivam Tiwari, Ankur Singh Bist, and Shiv Charan Puri

Subjects
Edge computing, Healthcare, Health monitoring, IoT and CNN, Electric apparatus and materials. Electric circuits. Electric networks, TK452-454.4
Abstract

Today's modern computing environment provides a smart healthcare monitoring system for early prediction of fall detection. The Internet of Things-based health model plays a significant role in the health care service area and helps to improve the processing of data and its prediction. Transferring reports or data from one place to another takes too much time and energy, and it will cause high latency and energy issues. To handle these kinds of hazards, edge computing provides solutions. In this paper w presents smart healthcare system issues, services, and applications. Furthermore, propose a CNN-based prediction model with the use of edge computing and IoT paradigms. Edge computing is a distributed environment framework that enables rapid resource availability and response time through local edge servers computed at the end of IoT devices. The CNN model is used to analyse the health data collected by IoT devices. Furthermore, the role of edge devices is to provide doctors and patients with timely health-prediction reports via edge servers. The proposed mechanism can be analysed using accuracy and error rate performance parameters. In the proposed mechanism, the accuracy is 99.23% in comparison with other techniques.

Published
2023
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4. Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries

Author

Emily R Smith, ScD, Anuraj H Shankar, ScD, Lee S-F Wu, MHS, Said Aboud, PhD, Seth Adu-Afarwuah, PhD, Hasmot Ali, MPH, Rina Agustina, PhD, Shams Arifeen, DrPH, Per Ashorn, PhD, Zulfiqar A Bhutta, PhD, Parul Christian, DrPH, Delanjathan Devakumar, PhD, Kathryn G Dewey, PhD, Henrik Friis, PhD, Exnevia Gomo, PhD, Piyush Gupta, MD, Pernille Kæstel, PhD, Patrick Kolsteren, PhD, Hermann Lanou, MD, Kenneth Maleta, PhD, Aissa Mamadoultaibou, MS, Gernard Msamanga, ScD, David Osrin, PhD, Lars-Åke Persson, PhD, Usha Ramakrishnan, PhD, Juan A Rivera, PhD, Arjumand Rizvi, MSC, H P S Sachdev, FRCPCH, Willy Urassa, PhD, Keith P West, Jr, DrPH, Noel Zagre, PhD, Lingxia Zeng, PhD, Zhonghai Zhu, MSc, Wafaie W Fawzi, DrPH, and Dr Christopher R Sudfeld, ScD

Subjects
Public aspects of medicine, RA1-1270
Abstract

Background: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries. Methods: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ2 test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect. Findings: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75–0·96 vs 1·06, 0·95–1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74–0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87–0·97; p=0·03), and 6-month mortality (0·71, 0·60–0·86; p=0·04) in anaemic pregnant women (haemoglobin

Published
2017
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6. Contributors

Author

Mark J. Abzug, Elisabeth E. Adderson, Aastha Agarwal, Allison L. Agwu, Lindsey Albenberg, Jonathan Albert, Kevin Alby, Grace M. Aldrovandi, Upton D. Allen, Gerardo Alvarez-Hernndez, Krow Ampofo, Evan J. Anderson, Grace D. Appiah, Monica I. Ardura, Stephen S. Arnon, Naomi E. Aronson, Ann M. Arvin, Shai Ashkenazi, Liat Ashkenazi-Hoffnung, Edwin J. Asturias, Kestutis Aukstuolis, Vahe Badalyan, Carol J. Baker, Karthik Balakrishnan, Elizabeth D. Barnett, Kirsten Bechtel, William E. Benitz, Rachel Berkovich, David M. Berman, Stephanie R. Bialek, Else M. Bijker, Matthew J. Bizzarro, Karen C. Bloch, Joseph A. Bocchini, Thomas G. Boyce, John S. Bradley, Denise F. Bratcher, Paula K. Braverman, Itzhak Brook, Kevin Edward Brown, Kristina P. Bryant, Andres F. Camacho-Gonzalez, Connie F. Caete-Gibas, Joseph B. Cantey, Paul Cantey, Cristina V. Cardemil, Mary T. Caserta, Luis A. Castagnini, Jessica R. Cataldi, Ellen Gould Chadwick, Rebecca J. Chancey, Cara C. Cherry, Silvia S. Chiang, Mary Choi, John C. Christenson, Susan E. Coffin, Amanda Cohn, Despina G. Contopoulos-Ioannidis, James H. Conway, Margaret M. Cortese, C. Buddy Creech, Jonathan D. Crews, Donna Curtis, Nigel Curtis, Lara A. Danziger-Isakov, Toni Darville, Gregory A. Dasch, Irini Daskalaki, H. Dele Davies, Fatimah S. Dawood, J. Christopher Day, M. Teresa de la Morena, Gregory P. DeMuri, Dickson D. Despommier, Daniel S. Dodson, Stephen J. Dolgner, Clinton Dunn, Jonathan Dyal, Kathryn M. Edwards, Morven S. Edwards, Dawn Z. Eichenfield, Lawrence F. Eichenfield, Dirk M. Elston, Beth Emerson, Leslie A. Enane, Moshe Ephros, Guliz Erdem, Marina E. Eremeeva, Douglas H. Esposito, Monica M. Farley, Anat R. Feingold, Kristina N. Feja, Adam Finn, Marc Fischer, Brian T. Fisher, Randall G. Fisher, Patricia Michele Flynn, Monique A. Foster, LeAnne M. Fox, Michael M. Frank, Douglas R. Fredrick, Robert W. Frenck, James Gaensbauer, Hayley A. Gans, Gregory M. Gauthier, Patrick Gavigan, Jeffrey S. Gerber, Yael Gernez, Francis Gigliotti, Mark A. Gilger, Carol A. Glaser, Jane M. Gould, James Graziano, Amanda M. Green, Michael Green, Daniel Griffin, Patricia M. Griffin, David C. Griffith, Piyush Gupta, Bruce J. Gutelius, Julie R. Gutman, Aron J. Hall, Rana F. Hamdy, Jin-Young Han, Lori K. Handy, Benjamin Hanisch, Marvin B. Harper, Aaron M. Harris, Christopher J. Harrison, David B. Haslam, Julia C. Haston, Sarah.J. Hawkes, Taylor Heald-Sargent, J. Owen Hendley, Adam L. Hersh, Joseph A. Hilinski, Susan L. Hills, David K. Hong, Peter J. Hotez, Katherine K. Hsu, Felicia Scaggs Huang, David A. Hunstad, W. Garrett Hunt, Loris Y. Hwang, Christelle M. Ilboudo, Preeti Jaggi, Sophonie Jean, Ravi Jhaveri, Kateina Jirk-Pomajbkov, Nadia A. Kadry, Mary L. Kamb, Ronak K. Kapadia, Ben Z. Katz, Sophie E. Katz, Ishminder Kaur, Gilbert J. Kersh, Muhammad Ali Khan, Ananta Khurana, David W. Kimberlin, Bruce Klein, Miwako Kobayashi, Larry K. Kociolek, Andrew Y. Koh, Karen L. Kotloff, Andrew T. Kroger, Matthew P. Kronman, Leah Lalor, Christine T. Lauren, Amy Leber, Eyal Leshem, David B. Lewis, Robyn A. Livingston, Eloisa Llata, Kevin Lloyd, Katrina Loh, Sarah S. Long, Benjamin A. Lopman, Yalda C. Lucero, Debra J. Lugo, Jorge Lujn-Zilbermann, Yvonne A. Maldonado, John J. Manaloor, Kalpana Manthiram, Stacey W. Martin, Roshni Mathew, Tony Mazzulli, Elizabeth J. McFarland, Kathleen A. McGann, Lucy A. McNamara, Debrah Meislich, H. Cody Meissner, Asuncion Mejias, Jussi Mertsola, Kevin Messacar, Mohammad Nael Mhaissen, Marian G. Michaels, Melissa B. Miller, Hilary Miller-Handley, Eric Mintz, Parvathi Mohan, Susan P. Montgomery, Jose G. Montoya, Anne C. Moorman, Pedro L. Moro, Anna-Barbara Moscicki, William J. Muller, Angela L. Myers, Simon Nadel, Jennifer Lynn Nayak, Michael Noel Neely, Karen P. Neil, Christina A. Nelson, Noele P. Nelson, Megin Nichols, William Nicholson, Amy Jo Nopper, Laura E. Norton, Theresa J. Ochoa, Liset Olarte, Timothy R. Onarecker, Walter A. Orenstein, Miguel ORyan, William R. Otto, Christopher P. Ouellette, Christopher D. Paddock, Debra L. Palazzi, Suresh Kumar Panuganti, Diane E. Pappas, Michal Paret, Daniel M. Pastula, Thomas F. Patterson, Brett W. Petersen, Mikael Petrosyan, Larry K. Pickering, Talia Pindyck, Swetha Pinninti, Laure F. Pittet, Paul J. Planet, Andrew J. Pollard, Klara M. Posfay-Barbe, Casper S. Poulsen, Susan M. Poutanen, Ann M. Powers, Nina Salinger Prasanphanich, Bobbi S. Pritt, Charles G. Prober, Neha Puar, Laura A.S. Quilter, Octavio Ramilo, Suchitra Rao, Adam J. Ratner, Sarah A. Rawstron, Jennifer S. Read, Ryan F. Relich, Megan E. Reller, Candice L. Robinson, Jos R. Romero, David A. Rosen, Shannon A. Ross, G. Ingrid J.G. Rours, Peter C. Rowe, Anne H. Rowley, Lorry G. Rubin, Edward T. Ryan, Alexandra Sacharok, Thomas J. Sandora, Sarah G.H. Sapp, Kabir Sardana, Jason B. Sauberan, Joshua K. Schaffzin, Sarah Schillie, Jennifer E. Schuster, Kevin L. Schwartz, Bethany K. Sederdahl, Jose Serpa-Alvarez, Kara N. Shah, Samir S. Shah, Nader Shaikh, Andi L. Shane, Eugene D. Shapiro, Jana Shaw, Avinash K. Shetty, Timothy R. Shope, Linda M. Dairiki Shortliffe, Stanford T. Shulman, Gail F. Shust, George Kelly Siberry, Jane D. Siegel, Robert David Siegel, Kari A. Simonsen, Upinder Singh, Christiana Smith, Lauren L. Smith, Eunkyung Song, Emily Souder, Paul Spearman, Joseph W. St. Geme, Mary Allen Staat, J. Erin Staples, Jeffrey R. Starke, Victoria A. Statler, William J. Steinbach, Christen Rune Stensvold, Erin K. Stokes, Bradley P. Stoner, Gregory A. Storch, Anne Straily, Kathleen E. Sullivan, Douglas S. Swanson, Robert R. Tanz, Gillian Taormina, Jacqueline E. Tate, Jeanette Taveras, Marc Tebruegge, Eyasu H. Teshale, George R. Thompson, Robert Thompson-Stone, Isaac Thomsen, Richard B. Thomson, Emily A. Thorell, Vivian Tien, Nicole H. Tobin, Philip Toltzis, James Treat, Stephanie B. Troy, Russell B. Van Dvke, Louise Elaine Vaz, Vini Vijayan, Jennifer Vodzak, Thor A. Wagner, Ellen R. Wald, Rebecca Wallihan, Huanyu Wang, Zoon Wangu, Matthew Washam, Valerie Waters, Joshua R. Watson, Jill E. Weatherhead, Geoffrey A. Weinberg, Mark K. Weng, Nathan P. Wiederhold, Harold C. Wiesenfeld, Cydni Williams, John V. Williams, Rodney E. Willoughby, Robert R. Wittler, James B. Wood, Charles Reece Woods, Kimberly A. Workowski, Terry W. Wright, Hsi-Yang Wu, Huan Xu, Pablo Yagupsky, Jumi Yi, Jonathan Yoder, Edward J. Young, Andrea L. Zaenglein, Petra Zimmermann, and Wenjing Zong

Published
2023
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9. Contributors

Author

Tapan Kumar Adhya, Uzma Afaq, null Archana, Rajesh Bajpai, Debjyoti Bandhu Banerjee, Saptadipa Banerjee, Shirsendu Banerjee, M.K. Bhatt, Sakina Bombaywala, Dhanashree Vijayrao Bomle, Sankha Chakrabortty, Prasenjit Chakraborty, Jorge Alberto Vieira Costa, Amlan Das, Saprativ P. Das, Louella Concepta Goveas, Piyush Gupta, Shahida Hamid, Pradip Hirapure, Gabrielle Guimarães Izaguirres, Syed Khalida Izhar, Hem C. Joshi, Penny Joshi, Yogesh Joshi, Asha Kiran, Navneet Kumar, Ramesh Kumar, Shravan Kumar, Sunil Kumar, Amrita Kumari, Smita Kumari, Rita Lakkakul, Marcella Lopes, Ashootosh Mandpe, Sourav Manna, Somya Mehrotra, Prateek Mishra, Shambhavi Mishra, Biswarup Mitra, Balaram Mohapatra, Michele Greque de Morais, Juliana Botelho Moreira, Jayato Nayak, Sneha Nayak, Parimal Pal, Sonam Paliya, Jigisha Roy Panda, Akanksha Pandey, Om Prakash, Elisângela Martha Radmann, Ramesh C. Rai, Neha Rana, Srinithya Ravinuthala, Shreya Reddy, Narashans Alok Sagar, Romio Saha, Sapna Salar, Priyabrata Sarkar, Sarani Sen, Shubhang Shukla, Saba Siddiqui, H.N. Sindhu, Ragini Singh, Ramveer Singh, Yashpal Singh, Mrutyunjay Suar, Lalit M. Tewari, Nitika Tiwari, Ankita H. Tripathi, Suraj K. Tripathy, Santosh K. Upadhyay, Vijay Upadhye, and Madeeha Zaidi

Published
2022
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10. BCL11B Drives Human Mammary Stem Cell Self-Renewal In Vitro by Inhibiting Basal Differentiation

Author

Charlotte Kuperwasser, Piyush Gupta, Ethan S. Sokol, Daniel H. Miller, D Superville, Rebecca A. Gorelov, Janel R. Cabrera, Dexter X. Jin, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Miller, Daniel Handel, Jin, Dexter X., Sokol, Ethan Samuel, Superville, Daphne A., and Gupta, Piyush

Subjects
0301 basic medicine, three-dimensional cell culture, Lineage (genetic), Mammary gland, Biology, Biochemistry, Article, 03 medical and health sciences, Cell Line, Tumor, Genetics, medicine, Compartment (development), Humans, Cell Lineage, Epigenetics, Progenitor cell, Cell Self Renewal, Mammary Glands, Human, lcsh:QH301-705.5, Transcription factor, lcsh:R5-920, epigenetics, single-cell genomics, Stem Cells, Tumor Suppressor Proteins, Cell Differentiation, Epithelial Cells, Cell Biology, BCL11B, human mammary gland biology, Stem Cell Self-Renewal, epithelial differentiation, Cell biology, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, lcsh:Biology (General), Female, Stem cell, lcsh:Medicine (General), mammary epithelial stem cells, Developmental Biology, Transcription Factors
Abstract

Summary The epithelial compartment of the mammary gland contains basal and luminal cell lineages, as well as stem and progenitor cells that reside upstream in the differentiation hierarchy. Stem and progenitor cell differentiation is regulated to maintain adult tissue and mediate expansion during pregnancy and lactation. The genetic factors that regulate the transition of cells between differentiation states remain incompletely understood. Here, we present a genome-scale method to discover genes driving cell-state specification. Applying this method, we identify a transcription factor, BCL11B, which drives stem cell self-renewal in vitro, by inhibiting differentiation into the basal lineage. To validate BCL11B's functional role, we use two-dimensional colony-forming and three-dimensional tissue differentiation assays to assess the lineage differentiation potential and functional abilities of primary human mammary cells. These findings show that BCL11B regulates mammary cell differentiation and demonstrate the utility of our proposed genome-scale strategy for identifying lineage regulators in mammalian tissues., Highlights • Novel strategy to identify lineage-specifying genes • BCL11B drives primary human mammary stem cell self-renewal in vitro • BCL11B inhibits basal differentiation of mammary stem cells in vitro, Miller et al. describe a strategy to identify candidate master regulators of cell lineage specification. This approach identified BCL11B as a key regulator of human mammary stem cell self-renewal in in vitro progenitor and differentiation assays. Using a combination of 2D and 3D primary cell culture techniques, they show that BCL11B drives stem cell self-renewal by inhibiting basal lineage commitment.

Published
2018

11. The Hippo Transducer TAZ Interacts with the SWI/SNF Complex to Regulate Breast Epithelial Lineage Commitment

Author

Jerrica L. Breindel, Patricia Galván, Charlotte Kuperwasser, Adam Skibinski, Joshua LaBaer, Andreas Rolfs, Elizabeth E. Smith, Piyush Gupta, Aleix Prat, Universitat de Barcelona, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Rolfs, Andreas, and Gupta, Piyush

Subjects
Malalties de la mama, Chromosomal Proteins, Non-Histone, Cellular differentiation, Gene Expression, WWTR1, Protein Serine-Threonine Kinases, Biology, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, Mice, 03 medical and health sciences, Mammary Glands, Animal, 0302 clinical medicine, Transcripció genètica, medicine, Breast diseases, Genetics, Animals, Humans, Cell Lineage, Hippo Signaling Pathway, Breast, Transcription factor, lcsh:QH301-705.5, 030304 developmental biology, 0303 health sciences, SWI/SNF complex, Genetic transcription, Myoepithelial cell, Cell Differentiation, Epithelial Cells, Expressió gènica, 3. Good health, Cell biology, DNA-Binding Proteins, Cell Transformation, Neoplastic, lcsh:Biology (General), Hippo signaling, 030220 oncology & carcinogenesis, Female, Gene expression, Signal transduction, Carcinogenesis, Acyltransferases, Genètica, Signal Transduction, Transcription Factors
Abstract

Lineage-committed cells of many tissues exhibit substantial plasticity in contexts such as wound healing and tumorigenesis, but the regulation of this process is not well understood. We identified the Hippo transducer WWTR1/TAZ in a screen of transcription factors that are able to prompt lineage switching of mammary epithelial cells. Forced expression of TAZ in luminal cells induces them to adopt basal characteristics, and depletion of TAZ in basal and/or myoepithelial cells leads to luminal differentiation. In human and mouse tissues, TAZ is active only in basal cells and is critical for basal cell maintenance during homeostasis. Accordingly, loss of TAZ affects mammary gland development, leading to an imbalance of luminal and basal populations as well as branching defects. Mechanistically, TAZ interacts with components of the SWI/SNF complex to modulate lineage-specific gene expression. Collectively, these findings uncover a new role for Hippo signaling in the determination of lineage identity through recruitment of chromatin-remodeling complexes., Breast Cancer Research Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (Grant R01HD073035), National Cancer Institute (U.S.) (Grant P01CA092644)

Published
2014

12. Cell-state transitions regulated by SLUG are critical for tissue regeneration and tumor initiation

Author

Charlotte Kuperwasser, Ania Wronski, Maja Sedic, Sohini Mazumdar, Theresa A. Proia, Grace Gill, Piyush Gupta, Adam Skibinski, Stephanie H. Shirley, Aleix Prat, Sarah Phillips, Charles M. Perou, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Gupta, Piyush, and Universitat de Barcelona

Subjects
Cellular differentiation, Mice, SCID, Epithelial cells, medicine.disease_cause, Biochemistry, Histones, Mice, Breast cancer, Mice, Inbred NOD, Neoplasms, lcsh:QH301-705.5, Mice, Knockout, lcsh:R5-920, Cèl·lules epitelials, biology, Stem Cells, Cell Differentiation, 3. Good health, Cell biology, Regeneration (Biology), Cell Transformation, Neoplastic, Diferenciació cel·lular, Stem cell, lcsh:Medicine (General), animal structures, Slug, Transplantation, Heterologous, Article, Disease-Free Survival, Cell Line, Càncer de mama, Proto-Oncogene Proteins c-myc, Cell diferentiation, Genetics, medicine, Animals, Humans, Regeneration, Cell Lineage, RNA, Messenger, Progenitor cell, Mammary Glands, Human, Transcription factor, Regeneració (Biologia), Regeneration (biology), fungi, Cell Biology, biology.organism_classification, Molecular biology, lcsh:Biology (General), Gene Expression Regulation, Cell culture, Snail Family Transcription Factors, Carcinogenesis, Developmental Biology, Stem Cell Transplantation, Transcription Factors
Abstract

Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1) to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis., Breast Cancer Research Foundation, Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (R01HD073035), National Cancer Institute (U.S.). Breast SPORE Program (P50-CA58223-09A1), National Cancer Institute (U.S.) (Grant R01-CA148761), National Cancer Institute (U.S.) (R01CA125554), National Center for Research Resources (U.S.) (Grant UL1 RR025752), National Center for Advancing Translational Sciences (U.S.) (Grant UL1 TR000073)

Published
2014

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