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Archive for the ‘Cell Biology’ Category


Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Pancreatic cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing.

 

Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (PDAC) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease.

 

The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology.

 

PDAC is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. In the present study to comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, single-cell RNA-seq (scRNA-seq) was employed to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases. The diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, were identified in PDAC.

 

The researchers found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, it was found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, the findings provided a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/31273297

 

https://www.ncbi.nlm.nih.gov/pubmed/21491194

 

https://www.ncbi.nlm.nih.gov/pubmed/27444064

 

https://www.ncbi.nlm.nih.gov/pubmed/28983043

 

https://www.ncbi.nlm.nih.gov/pubmed/24976721

 

https://www.ncbi.nlm.nih.gov/pubmed/27693023

 

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scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Present day technological advances have facilitated unprecedented opportunities for studying biological systems at single-cell level resolution. For example, single-cell RNA sequencing (scRNA-seq) enables the measurement of transcriptomic information of thousands of individual cells in one experiment. Analyses of such data provide information that was not accessible using bulk sequencing, which can only assess average properties of cell populations. Single-cell measurements, however, can capture the heterogeneity of a population of cells. In particular, single-cell studies allow for the identification of novel cell types, states, and dynamics.

 

One of the most prominent uses of the scRNA-seq technology is the identification of subpopulations of cells present in a sample and comparing such subpopulations across samples. Such information is crucial for understanding the heterogeneity of cells in a sample and for comparative analysis of samples from different conditions, tissues, and species. A frequently used approach is to cluster every dataset separately, inspect marker genes for each cluster, and compare these clusters in an attempt to determine which cell types were shared between samples. This approach, however, relies on the existence of predefined or clearly identifiable marker genes and their consistent measurement across subpopulations.

 

Although the aligned data can then be clustered to reveal subpopulations and their correspondence, solving the subpopulation-mapping problem by performing global alignment first and clustering second overlooks the original information about subpopulations existing in each experiment. In contrast, an approach addressing this problem directly might represent a more suitable solution. So, keeping this in mind the researchers developed a computational method, single-cell subpopulations comparison (scPopCorn), that allows for comparative analysis of two or more single-cell populations.

 

The performance of scPopCorn was tested in three distinct settings. First, its potential was demonstrated in identifying and aligning subpopulations from single-cell data from human and mouse pancreatic single-cell data. Next, scPopCorn was applied to the task of aligning biological replicates of mouse kidney single-cell data. scPopCorn achieved the best performance over the previously published tools. Finally, it was applied to compare populations of cells from cancer and healthy brain tissues, revealing the relation of neoplastic cells to neural cells and astrocytes. Consequently, as a result of this integrative approach, scPopCorn provides a powerful tool for comparative analysis of single-cell populations.

 

This scPopCorn is basically a computational method for the identification of subpopulations of cells present within individual single-cell experiments and mapping of these subpopulations across these experiments. Different from other approaches, scPopCorn performs the tasks of population identification and mapping simultaneously by optimizing a function that combines both objectives. When applied to complex biological data, scPopCorn outperforms previous methods. However, it should be kept in mind that scPopCorn assumes the input single-cell data to consist of separable subpopulations and it is not designed to perform a comparative analysis of single cell trajectories datasets that do not fulfill this constraint.

 

Several innovations developed in this work contributed to the performance of scPopCorn. First, unifying the above-mentioned tasks into a single problem statement allowed for integrating the signal from different experiments while identifying subpopulations within each experiment. Such an incorporation aids the reduction of biological and experimental noise. The researchers believe that the ideas introduced in scPopCorn not only enabled the design of a highly accurate identification of subpopulations and mapping approach, but can also provide a stepping stone for other tools to interrogate the relationships between single cell experiments.

 

References:

 

https://www.sciencedirect.com/science/article/pii/S2405471219301887

 

https://www.tandfonline.com/doi/abs/10.1080/23307706.2017.1397554

 

https://ieeexplore.ieee.org/abstract/document/4031383

 

https://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-0927-y

 

https://www.sciencedirect.com/science/article/pii/S2405471216302666

 

 

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Biologists Wondered—How Old are Cells in an Organism?

Reporter: Irina Robu, PhD

Scientists form Salk Institute discovered that the mouse brain, live and pancreas contain populations of cells and proteins with extremely long lifespans with some as old as neurons. The research was published in Cell Metabolism on June 6, 2019. The general idea is that most neurons in the brain do not divide during adulthood and experience a long lifespan and age-related decline. Yet, due to limitations the lifespan of cells outside of the brain was difficult to determine.

However, the researchers knew very well that neurons are not replaced during the lifespan, they used them as control to compare other non-dividing cells. The team used an electron isotope labeling with hybrid imaging method to visualize and quantify cell and protein age and turnover in the brain, pancreas and liver in the young and old rodent models.

To confirm that their method is correct, the scientist determined first the age of the neurons and then realized that the cells that line blood vessels, endothelial cells were as old as neurons. According to this research, it means that some non-neuronal cells do not replicate themselves throughout the lifespan. The pancreas, the organ responsible for maintaining blood sugar levels and secreting digestive enzymes showed cells of all ages. Still, some beta cells, replicate during the lifetime and are relatively young, while others do not divide and were long lived. Yet, delta cells found in stomach do not divide at all.
Unlike other type of cells, the liver cells have the capacity to regenerate during adulthood. The researchers expected to observe young liver cells, however the majority of liver cells were found to be as old as the animal, while the cells that line blood vessels and stellate like cells, another liver type cell were short lived.

But on the molecular level, a selection of long-lived cells contains protein complexes displaying age mosaicism. Due to the modern visualizing technologies, scientists were able to pinpoint the age of the cells and their supra-molecular complexes precisely. The ultimate goal to determining the age of the cells and sub-cellular structures is to provide insights into cell maintenance and repair mechanism and utilize these mechanisms to prevent or delay old age-linked decline of organs with limited cell regeneration.

SOURCE

https://www.salk.edu/news-release/how-old-are-your-organs-to-scientists-surprise-organs-are-a-mix-of-young-and-old-cells/

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Celiac Disease Breakthrough: (1) 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids (2) bio-products derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

 

Reporter: Aviva Lev-Ari, PhD, RN

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” said Alessio Fasano, HMS professor of pediatrics at Mass General, director of MIBRC and co-senior author of the paper.

https://hms.harvard.edu/news/major-shift?utm_source=Silverpop&utm_medium=email&utm_term=field_news_item_3&utm_content=HMNews05132019

 

 

Image Source: iStock/wildpixel

Article OPEN Published: 

Human gut derived-organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease

Scientific Reports volume 9, Article number: 7029 (2019Download Citation

Abstract

Celiac disease (CD) is an immune-mediated disorder triggered by gluten exposure. The contribution of the adaptive immune response to CD pathogenesis has been extensively studied, but the absence of valid experimental models has hampered our understanding of the early steps leading to loss of gluten tolerance. Using intestinal organoids developed from duodenal biopsies from both non-celiac (NC) and celiac (CD) patients, we explored the contribution of gut epithelium to CD pathogenesis and the role of microbiota-derived molecules in modulating the epithelium’s response to gluten. When compared to NC, RNA sequencing of CD organoids revealed significantly altered expression of genes associated with gut barrier, innate immune response, and stem cell functions. Monolayers derived from CD organoids exposed to gliadin showed increased intestinal permeability and enhanced secretion of pro-inflammatory cytokines compared to NC controls. Microbiota-derived bioproducts butyrate, lactate, and polysaccharide A improved barrier function and reduced gliadin-induced cytokine secretion. We concluded that: (1) patient-derived organoids faithfully express established and newly identified molecular signatures characteristic of CD. (2) microbiota-derived bioproducts can be used to modulate the epithelial response to gluten. Finally, we validated the use of patient-derived organoids monolayers as a novel tool for the study of CD.

Mass. General researchers develop 3D “mini-gut” model to study autoimmune response to gluten in celiac and non-celiac patient tissue

Gene expression of intestinal organoids reflects functional differences found in celiac disease

In pursuit of a novel tool for the research and treatment of celiac disease, scientists at the Mucosal Immunology and Biology Research Center (MIBRC) at Massachusetts General Hospital (MGH) have validated the use of intestinal organoids. These three-dimensional tissue cultures are miniature, simplified versions of the intestine produced in vitro. Taking tissue from duodenal biopsies of celiac and non-celiac patients, researchers created the “mini-guts” to explore how the gut epithelium and microbiota-derived molecules respond to gluten, a complex class of proteins found in wheat and other grains.

“We currently have no animal model that can recapitulate the response to gluten that we see in humans,” says Stefania Senger, PhD, co-senior author of the study published in Scientific Reports this week. “Using this human tissue model, we observed that intestinal organoids express the same molecular markers as actual epithelium in the celiac tissue, and the signature gene expression reflects the functional differences that occur when epithelia of celiac disease patients are exposed to gliadin.” Gliadin and glutenin proteins are main components of gluten.

Celiac disease is triggered when genetically predisposed individuals consume gluten. The condition affects approximately 1 percent of the U.S. population. Based on current data, the onset of celiac disease is thought to be preceded by the release of the protein zonulin, which is triggered by the activation of undigested gliadin to induce an autoimmune response. This leads to increased intestinal permeability and a disrupted barrier function. Novel evidence suggests that the microorganisms in the gastrointestinal tract may play a role in the onset of celiac disease.

Earlier studies from the MIBRC group and others have shown that human organoids “retain a gene expression that recapitulates the expression of the tissue of origin, including a diseased state,” the authors write. Through RNA sequencing, the new findings validate the organoid model as a “faithful in vitro model for celiac disease,” Senger says.
Using whole-transcriptome analysis, the researchers identified 472 genes regulated differently in organoids reflecting celiac disease than in non-celiac control organoids. These included novel genes associated with epithelial functions related to the pathogenesis of celiac disease – including gut barrier maintenance, stem cell regeneration and innate immune response. A second finding of the study shows that bioproducts derived from gut microorganisms can be employed to modify the epithelial response to gluten, a finding that could lead to future treatment strategies.

“These results confirm our hypothesis that genes and exposure to gluten are necessary but not sufficient, since changes in both the composition and function of the gut microbiome are also needed to switch from genetic predisposition to clinical outcome, as shown by our data,” says Alessio Fasano, MD, director of the Mucosal Immunology and Biology Research Center and co-senior author.

Senger adds, “We believe our observations represent a major shift in the study of celiac disease. We are confident that with adequate funding we could achieve major goals that include the development and implementation of high-throughput drug screenings to quickly identify new treatments for patients and expand the organoid repository to develop more complex models and pursue personalized treatment.”
Additional co-authors of the paper are first author Rachel Freire, PhD, along with Laura Ingano and Gloria Serena, PhD, of the MGH MIBRC; Murat Cetinbas, PhD, and Ruslan Sadreyev, PhD, MGH Department of Molecular Biology; Anthony Anselmo, PhD, formerly of MGH Molecular Biology and now with PatientsLikeMe, Cambridge, Mass.; and Anna Sapone, MD, PhD, Takeda Pharmaceuticals International. Support for the study includes National Institutes of Health grants RO1 DK104344-01A1 and 1U19 AI082655-02 and the Egan Family Foundation.

SOURCE

https://www.massgeneral.org/about/pressrelease.aspx?id=2403

 

Other related articles and e-Books by LPBI Group’s Authors published on this Open Access Online Scientific Journal include the following:

 

Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases

  • Metabolomics 

VOLUME 1: Metabolic Genomics and Pharmaceutics. On Amazon.com since 7/21/2015

http://www.amazon.com/dp/B012BB0ZF0

Gluten-free Diets

Writer and Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/03/01/gluten-free-diets/

 

Breakthrough Digestive Disorders Research: Conditions affecting the Gastrointestinal Tract.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/12/breakthrough-digestive-disorders-research-conditions-affecting-the-gastrointestinal-tract/

 

Collagen-binding Molecular Chaperone HSP47: Role in Intestinal Fibrosis – colonic epithelial cells and subepithelial myofibroblasts

Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/25/collagen-binding-molecular-chaperone-hsp47-role-in-intestinal-fibrosis-colonic-epithelial-cells-and-subepithelial-myofibroblasts/

Expanding area of Tolerance-inducing Autoimmune Disease Therapeutics: Key Players

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/17/expanding-area-of-tolerance-inducing-autoimmune-disease-therapeutics-key-players/

 

What is the key method to harness Inflammation to close the doors for many complex diseases?

Author and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/03/21/what-is-the-key-method-to-harness-inflammation-to-close-the-doors-for-many-complex-diseases/

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Use of 3D Bioprinting for Development of Toxicity Prediction Models

Curator: Stephen J. Williams, PhD

SOT FDA Colloquium on 3D Bioprinted Tissue Models: Tuesday, April 9, 2019

The Society of Toxicology (SOT) and the U.S. Food and Drug Administration (FDA) will hold a workshop on “Alternative Methods for Predictive Safety Testing: 3D Bioprinted Tissue Models” on Tuesday, April 9, at the FDA Center for Food Safety and Applied Nutrition in College Park, Maryland. This workshop is the latest in the series, “SOT FDA Colloquia on Emerging Toxicological Science: Challenges in Food and Ingredient Safety.”

Human 3D bioprinted tissues represent a valuable in vitro approach for chemical, personal care product, cosmetic, and preclinical toxicity/safety testing. Bioprinting of skin, liver, and kidney is already appearing in toxicity testing applications for chemical exposures and disease modeling. The use of 3D bioprinted tissues and organs may provide future alternative approaches for testing that may more closely resemble and simulate intact human tissues to more accurately predict human responses to chemical and drug exposures.

A synopsis of the schedule and related works from the speakers is given below:

 

8:40 AM–9:20 AM Overview and Challenges of Bioprinting
Sharon Presnell, Amnion Foundation, Winston-Salem, NC
9:20 AM–10:00 AM Putting 3D Bioprinting to the Use of Tissue Model Fabrication
Y. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology, Boston, MA
10:00 AM–10:20 AM Break
10:20 AM–11:00 AM Uses of Bioprinted Liver Tissue in Drug Development
Jean-Louis Klein, GlaxoSmithKline, Collegeville, PA
11:00 AM–11:40 AM Biofabrication of 3D Tissue Models for Disease Modeling and Chemical Screening
Marc Ferrer, National Center for Advancing Translational Sciences, NIH, Rockville, MD

Sharon Presnell, Ph.D. President, Amnion Foundation

Dr. Sharon Presnell was most recently the Chief Scientific Officer at Organovo, Inc., and the President of their wholly-owned subsidiary, Samsara Sciences. She received a Ph.D. in Cell & Molecular Pathology from the Medical College of Virginia and completed her undergraduate degree in biology at NC State. In addition to her most recent roles, Presnell has served as the director of cell biology R&D at Becton Dickinson’s corporate research center in RTP, and as the SVP of R&D at Tengion. Her roles have always involved the commercial and clinical translation of basic research and early development in the cell biology space. She serves on the board of the Coulter Foundation at the University of Virginia and is a member of the College of Life Sciences Foundation Board at NC State. In January 2019, Dr. Presnell will begin a new role as President of the Amnion Foundation, a non-profit organization in Winston-Salem.

A few of her relevant publications:

Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis

Integrating Kupffer cells into a 3D bioprinted model of human liver recapitulates fibrotic responses of certain toxicants in a time and context dependent manner.  This work establishes that the presence of Kupffer cells or macrophages are important mediators in fibrotic responses to certain hepatotoxins and both should be incorporated into bioprinted human liver models for toxicology testing.

Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro

Abstract: Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.

A great interview with Dr. Presnell and the 3D Models 2017 Symposium is located here:

Please click here for Web based and PDF version of interview

Some highlights of the interview include

  • Exciting advances in field showing we can model complex tissue-level disease-state phenotypes that develop in response to chronic long term injury or exposure
  • Sees the field developing a means to converge both the biology and physiology of tissues, namely modeling the connectivity between tissues such as fluid flow
  • Future work will need to be dedicated to develop comprehensive analytics for 3D tissue analysis. As she states “we are very conditioned to get information in a simple way from biochemical readouts in two dimension, monocellular systems”  however how we address the complexity of various cellular responses in a 3D multicellular environment will be pertinent.
  • Additional challenges include the scalability of such systems and making such system accessible in a larger way
  1. Shrike Zhang, Brigham and Women’s Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology

Dr. Zhang currently holds an Assistant Professor position at Harvard Medical School and is an Associate Bioengineer at Brigham and Women’s Hospital. His research interests include organ-on-a-chip, 3D bioprinting, biomaterials, regenerative engineering, biomedical imaging, biosensing, nanomedicine, and developmental biology. His scientific contributions have been recognized by >40 international, national, and regional awards. He has been invited to deliver >70 lectures worldwide, and has served as reviewer for >400 manuscripts for >30 journals. He is serving as Editor-in-Chief for Microphysiological Systems, and Associate Editor for Bio-Design and Manufacturing. He is also on Editorial Board of BioprintingHeliyonBMC Materials, and Essays in Biochemistry, and on Advisory Panel of Nanotechnology.

Some relevant references from Dr. Zhang

Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform.

Skardal A, Murphy SV, Devarasetty M, Mead I, Kang HW, Seol YJ, Shrike Zhang Y, Shin SR, Zhao L, Aleman J, Hall AR, Shupe TD, Kleensang A, Dokmeci MR, Jin Lee S, Jackson JD, Yoo JJ, Hartung T, Khademhosseini A, Soker S, Bishop CE, Atala A.

Sci Rep. 2017 Aug 18;7(1):8837. doi: 10.1038/s41598-017-08879-x.

 

Reconstruction of Large-scale Defects with a Novel Hybrid Scaffold Made from Poly(L-lactic acid)/Nanohydroxyapatite/Alendronate-loaded Chitosan Microsphere: in vitro and in vivo Studies.

Wu H, Lei P, Liu G, Shrike Zhang Y, Yang J, Zhang L, Xie J, Niu W, Liu H, Ruan J, Hu Y, Zhang C.

Sci Rep. 2017 Mar 23;7(1):359. doi: 10.1038/s41598-017-00506-z.

 

 

A liver-on-a-chip platform with bioprinted hepatic spheroids.

Bhise NS, Manoharan V, Massa S, Tamayol A, Ghaderi M, Miscuglio M, Lang Q, Shrike Zhang Y, Shin SR, Calzone G, Annabi N, Shupe TD, Bishop CE, Atala A, Dokmeci MR, Khademhosseini A.

Biofabrication. 2016 Jan 12;8(1):014101. doi: 10.1088/1758-5090/8/1/014101.

 

Marc Ferrer, National Center for Advancing Translational Sciences, NIH

Marc Ferrer is a team leader in the NCATS Chemical Genomics Center, which was part of the National Human Genome Research Institute when Ferrer began working there in 2010. He has extensive experience in drug discovery, both in the pharmaceutical industry and academic research. Before joining NIH, he was director of assay development and screening at Merck Research Laboratories. For 10 years at Merck, Ferrer led the development of assays for high-throughput screening of small molecules and small interfering RNA (siRNA) to support programs for lead and target identification across all disease areas.

At NCATS, Ferrer leads the implementation of probe development programs, discovery of drug combinations and development of innovative assay paradigms for more effective drug discovery. He advises collaborators on strategies for discovering small molecule therapeutics, including assays for screening and lead identification and optimization. Ferrer has experience implementing high-throughput screens for a broad range of disease areas with a wide array of assay technologies. He has led and managed highly productive teams by setting clear research strategies and goals and by establishing effective collaborations between scientists from diverse disciplines within industry, academia and technology providers.

Ferrer has a Ph.D. in biological chemistry from the University of Minnesota, Twin Cities, and completed postdoctoral training at Harvard University’s Department of Molecular and Cellular Biology. He received a B.Sc. degree in organic chemistry from the University of Barcelona in Spain.

 

Some relevant references for Dr. Ferrer

Fully 3D Bioprinted Skin Equivalent Constructs with Validated Morphology and Barrier Function.

Derr K, Zou J, Luo K, Song MJ, Sittampalam GS, Zhou C, Michael S, Ferrer M, Derr P.

Tissue Eng Part C Methods. 2019 Apr 22. doi: 10.1089/ten.TEC.2018.0318. [Epub ahead of print]

 

Determination of the Elasticity Modulus of 3D-Printed Octet-Truss Structures for Use in Porous Prosthesis Implants.

Bagheri A, Buj-Corral I, Ferrer M, Pastor MM, Roure F.

Materials (Basel). 2018 Nov 29;11(12). pii: E2420. doi: 10.3390/ma11122420.

 

Mutation Profiles in Glioblastoma 3D Oncospheres Modulate Drug Efficacy.

Wilson KM, Mathews-Griner LA, Williamson T, Guha R, Chen L, Shinn P, McKnight C, Michael S, Klumpp-Thomas C, Binder ZA, Ferrer M, Gallia GL, Thomas CJ, Riggins GJ.

SLAS Technol. 2019 Feb;24(1):28-40. doi: 10.1177/2472630318803749. Epub 2018 Oct 5.

 

A high-throughput imaging and nuclear segmentation analysis protocol for cleared 3D culture models.

Boutin ME, Voss TC, Titus SA, Cruz-Gutierrez K, Michael S, Ferrer M.

Sci Rep. 2018 Jul 24;8(1):11135. doi: 10.1038/s41598-018-29169-0.

A High-Throughput Screening Model of the Tumor Microenvironment for Ovarian Cancer Cell Growth.

Lal-Nag M, McGee L, Guha R, Lengyel E, Kenny HA, Ferrer M.

SLAS Discov. 2017 Jun;22(5):494-506. doi: 10.1177/2472555216687082. Epub 2017 Jan 31.

 

Exploring Drug Dosing Regimens In Vitro Using Real-Time 3D Spheroid Tumor Growth Assays.

Lal-Nag M, McGee L, Titus SA, Brimacombe K, Michael S, Sittampalam G, Ferrer M.

SLAS Discov. 2017 Jun;22(5):537-546. doi: 10.1177/2472555217698818. Epub 2017 Mar 15.

 

RNAi High-Throughput Screening of Single- and Multi-Cell-Type Tumor Spheroids: A Comprehensive Analysis in Two and Three Dimensions.

Fu J, Fernandez D, Ferrer M, Titus SA, Buehler E, Lal-Nag MA.

SLAS Discov. 2017 Jun;22(5):525-536. doi: 10.1177/2472555217696796. Epub 2017 Mar 9.

 

Other Articles on 3D Bioprinting on this Open Access Journal include:

Global Technology Conferences on 3D BioPrinting 2015 – 2016

3D Medical BioPrinting Technology Reporting by Irina Robu, PhD – a forthcoming Article in “Medical 3D BioPrinting – The Revolution in Medicine, Technologies for Patient-centered Medicine: From R&D in Biologics to New Medical Devices”

Bio-Inks and 3D BioPrinting

New Scaffold-Free 3D Bioprinting Method Available to Researchers

Gene Editing for Gene Therapies with 3D BioPrinting

 

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Leigh syndrome is one of the hundreds of so-called mitochondrial diseases, which are caused by defects in the mitochondria that produce 90 percent of the body’s energy. These disorders are rare; about 1,000 to 4,000 babies in the United States are born with one every year. But they are devastating and can result in grave impairment of nearly any bodily system. They are largely untreatable, uniformly incurable and very difficult to screen.

 

Leigh syndrome is a terrible disease. It emerges shortly after birth and claims one major organ after another. Movement becomes difficult, and then impossible. A tracheotomy and feeding tube are often necessary by toddlerhood, and as the disease progresses, lungs frequently have to be suctioned manually. Most children with the condition die by the age of 5 or 6.

 

Scientists have devised a procedure called mitochondrial replacement therapy (M.R.T.) that involves transplanting the nucleus of an affected egg (mitochondrial diseases are passed down from the mother’s side) into an unaffected one whose nucleus has been removed. The procedure is sometimes called “three-parent in vitro fertilization”. Mitochondria contain a minuscule amount of DNA, any resulting embryo would have mitochondrial DNA from the donor egg and nuclear DNA from each of its parents.

 

After decades of careful study in cell and animal research M.R.T. is now finally being tested in human clinical trials by doctors in Britain (no births confirmed yet officially). In the United States, however, this procedure is effectively illegal. M.R.T. does not involve altering any genetic code. Defective mitochondria are swapped out for healthy ones.

 

Mitochondrial DNA governs only a handful of basic cellular functions. It is separate from nuclear DNA, which helps determine individual traits like physical appearance, intelligence and personality. That means M.R.T. cannot be used to produce the genetically enhanced “designer babies” and thus should be allowed in humans. But, there is no way to know how safe or effective M.R.T. is until doctors and scientists test it in humans.

 

References:

 

 

https://pharmaceuticalintelligence.com/2016/10/07/the-three-parent-technique-to-avoid-mitochondrial-disease-in-embryo/

 

 

 

 

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Lesson 8 Cell Signaling and Motility: Lesson and Supplemental Information on Cell Junctions and ECM: #TUBiol3373

Curator: Stephen J. Williams, Ph.D.

Please click on the following link for the PowerPoint Presentation for Lecture 8 on Cell Junctions and the  Extracellular Matrix: (this is same lesson from 2018 so don’t worry that file says 2018)

cell signaling 8 lesson 2018

 

Some other reading on this lesson on this Open Access Journal Include:

On Cell Junctions:

Translational Research on the Mechanism of Water and Electrolyte Movements into the Cell     

(pay particular attention to article by Fischbarg on importance of tight junctions for proper water and electrolyte movement)

The Role of Tight Junction Proteins in Water and Electrolyte Transport

(pay attention to article of role of tight junction in kidney in the Loop of Henle and the collecting tubule)

EpCAM [7.4]

(a tight junction protein)

Signaling and Signaling Pathways

(for this lesson pay attention to the part that shows how Receptor Tyrosine Kinase activation (RTK) can lead to signaling to an integrin and also how the thrombin receptor leads to cellular signals both to GPCR (G-protein coupled receptors like the thrombin receptor, the ADP receptor; but also the signaling cascades that lead to integrin activation of integrins leading to adhesion to insoluble fibrin mesh of the newly formed clot and subsequent adhesion of platelets, forming the platelet plug during thrombosis.)

On the Extracellular Matrix

Three-Dimensional Fibroblast Matrix Improves Left Ventricular Function Post MI

Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

 

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