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Archive for the ‘Cell Processing System in Cell Therapy Process Development’ Category


Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

 

Reporter: Stephen J. Williams, PhD

 

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#AACR20

@pharma_BI

@AACR

 

Register for FREE at https://www.aacr.org/

 

AACR VIRTUAL ANNUAL MEETING II

 

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

 

This Virtual Meeting is Part II of the AACR Annual Meeting.  Part I was held online in April and was centered only on clinical findings.  This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

 

REGISTER NOW

 

 

 

Virtual Educational Session

Prevention Research, Science Policy, Epidemiology, Survivorship

Carcinogens at Home: Science and Pathways to Prevention

Chemicals known to cause cancer are used and released to the environment in large volumes, exposing people where they live, work, play, and go to school. The science establishing an important role for such exposures in the development of cancers continues to strengthen, yet cancer prevention researchers are largely unfamiliar with the data drawn upon in identifying carcinogens and making decisions about their use. Characterizing and reducing harmful exposures and accelerating the devel

Julia Brody, Kathryn Z. Guyton, Polly J. Hoppin, Bill Walsh, Mary H. Ward

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Molecular and Cellular Biology/Genetics, Clinical Research Excluding Trials

EMT Still Matters: Let’s Explore! – Dedicated to the Memory of Isaiah J. Fidler

During carcinoma progression, initially benign epithelial cells acquire the ability to invade locally and disseminate to distant tissues by activating epithelial-mesenchymal transition (EMT). EMT is a cellular process during which epithelial cells lose their epithelial features and acquire mesenchymal phenotypes and behavior. Growing evidence supports the notion that EMT programs during tumor progression are usually activated to various extents and often partial and reversible, thus pr

Jean-Paul Thiery, Heide L Ford, Jing Yang, Geert Berx

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

Tumor Biology, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

One of These Things Is Not Like the Other: The Many Faces of Senescence in Cancer

Cellular senescence is a stable cell growth arrest that is broadly recognized to act as a barrier against tumorigenesis. Senescent cells acquire a senescence-associated secretory phenotype (SASP), a transcriptional response involving the secretion of inflammatory cytokines, immune modulators, and proteases that can shape the tumor microenvironment. The SASP can initially stimulate tumor immune surveillance and reinforce growth arrest. However, if senescent cells are not removed by the

Clemens A Schmitt, Andrea Alimonti, René Bernards

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Molecular and Cellular Biology/Genetics

Recent Advances in Applications of Cell-Free DNA

The focus of this educational session will be on recent developments in cell-free DNA (cfDNA) analysis that have the potential to impact the care of cancer patients. Tumors continually shed DNA into the circulation, where it can be detected as circulating tumor DNA (ctDNA). Analysis of ctDNA has become a routine part of care for a subset of patients with advanced malignancies. However, there are a number of exciting potential applications that have promising preliminary data but that h

Michael R Speicher, Maximilian Diehn, Aparna Parikh

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Methods Workshop

Clinical Research Excluding Trials, Clinical Trials, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Translating Genetics and Genomics to the Clinic and Population

This session will describe how advances in understanding cancer genomes and in genetic testing technologies are being translated to the clinic. The speakers will illustrate the clinical impact of genomic discoveries for diagnostics and treatment of common tumor types in adults and in children. Cutting-edge technologies for characterization of patient and tumor genomes will be described. New insights into the importance of patient factors for cancer risk and outcome, including predispos

Heather L. Hampel, Gordana Raca, Jaclyn Biegel, Jeffrey M Trent

DETAILS

Monday, June 22

1:30 PM – 3:22 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Drug Development, Epidemiology

Under-representation in Clinical Trials and the Implications for Drug Development

The U.S. Food and Drug Administration relies on data from clinical trials to determine whether medical products are safe and effective. Ideally, patients enrolled in those trials are representative of the population in which the product will be used if approved, including people of different ages, races, ethnic groups, and genders. Unfortunately, with few patients enrolling in clinical trials, many groups are not well-represented in clinical trials. This session will explore challenges

Ajay K. Nooka, Nicole J. Gormley, Kenneth C Anderson, Ruben A. Mesa, Daniel J. George, Yelak Biru, RADM Richardae Araojo, Lola A. Fashoyin-Aje

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Cancer Chemistry

Targeted Protein Degradation: Target Validation Tools and Therapeutic Opportunity

This educational session will cover the exciting emerging field of targeted protein degradation. Key learning topics will include: 1. an introduction to the technology and its relevance to oncology; 2. PROTACS, degraders, and CELMoDs; 3. enzymology and protein-protein interactions in targeted protein degraders; 4. examples of differentiated biology due to degradation vs. inhibition; 5. how to address questions of specificity; and 6. how the field is approaching challenges in optimizing therapies

George Burslem, Mary Matyskiela, Lyn H. Jones, Stewart L Fisher, Andrew J Phillips

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Bioinformatics and Systems Biology, Experimental and Molecular Therapeutics, Drug Development, Molecular and Cellular Biology/Genetics

Obstacles and opportunities for protein degradation drug discovery

Lyn H. Jones
  • PROTACs ubiquitin mediated by E3 ligases;  first discovered by DeShaies and targeted to specific proteins
  • PROTACs used in drug discovery against a host of types of targets including kinases and membrane receptors
  • PROTACs can be modular but lack molecular structural activity relationships
  • can use chemical probes for target validation
  • four requirements: candidate exposure at site of action (for example lipophilicity for candidates needed to cross membranes and accumulate in lysosomes), target engagement (ternary occupancy as measured by FRET), functional pharmacology, relevant phenotype
  • PROTACs hijack the proteosomal degradation system

Proteolysis-targeting chimeras as therapeutics and tools for biological discovery

George Burslem
  • first PROTAC developed to coopt the VHL ubiquitin ligase system which degrades HIF1alpha but now modified for EREalpha
  • in screen for potential PROTACS there were compounds which bound high affinity but no degradation so phenotypic screening very important
  • when look at molecular dynamics can see where PROTAC can add additional protein protein interaction, verifed by site directed mutagenesis
  • able to target bcr-Abl
  • he says this is a rapidly expanding field because of all the new E3 ligase targets being discovered

Expanding the horizons of cereblon modulators

Mary Matyskiela

Translating cellular targeted protein degradation to in vivo models using an enzymology framework

Stewart L Fisher
  • new targeting compounds have an E3 ligase binding domain, a target binding domain and a linker domain
  • in vivo these compounds are very effective; BRD4 degraders good invitro and in vivo with little effect on body weight
  • degraders are essential activators of E3 ligases as these degraders bring targets in close proximity so activates a catalytic cycle of a multistep process (has now high turnover number)
  • in enzymatic pathway the degraders make a productive complex so instead of a kcat think of measuring a kprod or productivity of degraders linked up an E3 ligase
  • the degraders are also affecting the rebound protein synthesis; so Emax never to zero and see a small rebound of protein synthesis

 

Data-Driven Approaches for Choosing Combinatorial Therapies

Drug combinations remain the gold standard for treating cancer, as they significantly outperform single agents. However, due to the enormous size of drug combination space, it is virtually impossible to interrogate all possible combinations. This session will discuss approaches to identify novel combinations using both experimental and computational approaches. Speakers will discuss i) approaches to drug screening in cell lines, the impact of the microenvironment, and attempts to more

Bence Szalai, James E Korkola, Lisa Tucker-Kellogg, Jeffrey W Tyner

DETAILS

Monday, June 22

3:45 PM – 5:21 PM EDT

Virtual Educational Session

Tumor Biology

Cancer Stem Cells and Therapeutic Resistance

Cancer stem cells are a subpopulation of cells with a high capacity for self-renewal, differentiation and resistance to therapy. In this session, we will define cancer stem cells, discuss cellular plasticity, interactions between cancer stem cells and the tumor microenvironment, and mechanisms that contribute to therapeutic resistance.

Robert S Kerbel, Dolores Hambardzumyan, Jennifer S. Yu

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Drug Development, Experimental and Molecular Therapeutics

Molecular Imaging in Cancer Research

This session will cover the fundamentals as well as the major advances made in the field of molecular imaging. Topics covered will include the basics for optical, nuclear, and ultrasound imaging; the pros and cons of each modality; and the recent translational advancements. Learning objectives include the fundamentals of each imaging modality, recent advances in the technology, the processes involved to translate an imaging agent from bench to bedside, and how molecular imaging can gui

Julie Sutcliffe, Summer L Gibbs, Mark D Pagel, Katherine W Ferrara

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Immunology, Experimental and Molecular Therapeutics, Drug Development

Tumor Endothelium: The Gatekeepers of Tumor Immune Surveillance

Tumor-associated endothelium is a gatekeeper that coordinates the entry and egress of innate and adaptive immune cells within the tumor microenvironment. This is achieved, in part, via the coordinated expression of chemokines and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. Crosstalk between adaptive immune cells and the tumor endothelium is therefore essential for tumor immune surveillance and the success of immune-based thera

Dai Fukumura, Maria M Steele, Wen Jiang, Andrew C Dudley

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Immunology, Experimental and Molecular Therapeutics

Novel Strategies in Cancer Immunotherapy: The Next Generation of Targets for Anticancer Immunotherapy

T-cell immunotherapy in the form of immune checkpoint blockade or cellular T-cell therapies has been tremendously successful in some types of cancer. This success has opened the door to consider what other modalities or types of immune cells can be harnessed for exert antitumor functions. In this session, experts in their respective fields will discuss topics including novel approaches in immunotherapy, including NK cells, macrophage, and viral oncotherapies.

Evanthia Galanis, Kerry S Campbell, Milan G Chheda, Jennifer L Guerriero

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Drug Development, Immunology, Clinical Research Excluding Trials

Benign Cells as Drivers of Cancer Progression: Fat and Beyond

Carcinomas develop metastases and resistance to therapy as a result of interaction with tumor microenvironment, composed of various nonmalignant cell types. Understanding the complexity and origins of tumor stromal cells is a prerequisite for development of effective treatments. The link between obesity and cancer progression has revealed the engagement of adipose stromal cells (ASC) and adipocytes from adjacent fat tissue. However, the molecular mechanisms through which they stimulate

Guojun Wu, Matteo Ligorio, Mikhail Kolonin, Maria T Diaz-Meco

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Experimental and Molecular Therapeutics, Tumor Biology

Dharma Master Jiantai Symposium on Lung Cancer: Know Thy Organ – Lessons Learned from Lung and Pancreatic Cancer Research

The term “cancer” encompasses hundreds of distinct disease entities involving almost every possible site in the human body. Effectively interrogating cancer, either in animals models or human specimens, requires a deep understanding of the involved organ. This includes both the normal cellular constituents of the affected tissue as well as unique aspects of tissue-specific tumorigenesis. It is critical to “Know Thy Organ” when studying cancer. This session will focus on two of the most

Trudy G Oliver, Hossein Borghaei, Laura Delong Wood, Howard C Crawford

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Clinical Trials

Clinical Trial Design: Part 1: Novel Approaches and Methods in Clinical Trial Design

Good clinical trial design has always had to balance the competing interests of effectively and convincingly answering the question with the limitations imposed by scarce resources, complex logistics, and risks and potential benefits to participants. New targeted therapies, immuno-oncology, and novel combination treatments add new challenges on top of the old ones. This session will introduce these concerns and 1) suggest ways to consider what outcomes are relevant, 2) how we can best

Mary W. Redman, Nolan A. Wages, Susan G Hilsenbeck, Karyn A. Goodman

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Tumor Biology, Drug Development

High-Throughput Screens for Drivers of Progression and Resistance

The sequencing of human cancers now provides a landscape of the genetic alterations that occur in human cancer, and increasingly knowledge of somatic genetic alterations is becoming part of the evaluation of cancer patients. In some cases, this information leads directly to the selection of particular therapeutic approaches; however, we still lack the ability to decipher the significance of genetic alterations in many cancers. This session will focus on recent developments that permit the identification of molecular targets in specific cancers. This information, coupled with genomic characterization of cancer, will facilitate the development of new therapeutic agents and provide a path to implement precision cancer medicine to all patients.

William C Hahn, Mark A Dawson, Mariella Filbin, Michael Bassik

DETAILS

Monday, June 22

3:45 PM – 5:15 PM EDT

Defining a cancer dependency map

William C Hahn

Introduction

William C Hahn

Genome-scale CRISPR screens in 3D spheroids identify cancer vulnerabilities

Michael Bassik

Utilizing single-cell RNAseq and CRISPR screens to target cancer stem cells in pediatric brain tumors

Mariella Filbin
  • many gliomas are defined by discreet mutational spectra that also discriminates based on age and site as well (for example many cortical tumors have mainly V600E Braf mutations while thalamus will be FGFR1
  • they did single cell RNAseq on needle biopsy from 7 gliomas which gave about 3500 high quality single cells; obtained full length RNA
  • tumors clustered mainly where the patient it came from but had stromal cell contamination probably so did a deconvolution?  Copy number variation showed which were tumor cells and did principle component analysis
  • it seems they used a human glioma model as training set
  • identified a stem cell like glioma cell so concentrated on the genes altered in these for translational studies
  • developed multiple PDX models from patients
  • PDX transcriptome closest to patient transcriptome but organoid grown in serum free very close while organoids grown in serum very distinct transcriptome
  • developed a CRISPR barcoded library to determine genes for survival genes
  • pulled out BMI1  and EZH2 (polycomb complex proteins) as good targets

Virtual Methods Workshop

Prevention Research, Survivorship, Clinical Research Excluding Trials, Epidemiology

Implementation Science Methods for Cancer Prevention and Control in Diverse Populations: Integration of Implementation Science Methods in Care Settings

Through this Education Session we will use examples from ongoing research to provide an overview of implementation science approaches to cancer prevention and control research. We draw on examples to highlight study design approaches, research methods, and real-world solutions when applying implementation science to achieve health equity. Approaches to defining change in the care setting and measuring sustained changes are also emphasized. Using real examples of patient navigation prog

Graham A Colditz, Sanja Percac-Lima, Nathalie Huguet

DETAILS

Monday, June 22

3:45 PM – 5:30 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Epidemiology

COVID-19 and Cancer: Guidance for Clinical Trial Conduct and Considerations for RWE

This session will consider the use of real-world evidence in the context of oncology clinical trials affected by the COVID-19 pandemic. Key aspects of the FDA’s recent “Guidance on Conduct of Clinical Trials of Medical Products of Medical Products during COVID-19 Public Health Emergency” will be discussed, including telemedicine, accounting for missing data, obtaining laboratory tests and images locally, using remote informed consent procedures, and additional considerations for contin

Wendy Rubinstein, Paul G. Kluetz, Amy P. Abernethy, Jonathan Hirsch, C.K. Wang

 

 

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

 

Parkinson’s Disease (PD), characterized by both motor and non-motor system pathology, is a common neurodegenerative disorder affecting about 1% of the population over age 60. Its prevalence presents an increasing social burden as the population ages. Since its introduction in the 1960’s, dopamine (DA)-replacement therapy (e.g., L-DOPA) has remained the gold standard treatment. While improving PD patients’ quality of life, the effects of treatment fade with disease progression and prolonged usage of these medications often (>80%) results in side effects including dyskinesias and motor fluctuations. Since the selective degeneration of A9 mDA neurons (mDANs) in the substantia nigra (SN) is a key pathological feature of the disease and is directly associated with the cardinal motor symptoms, dopaminergic cell transplantation has been proposed as a therapeutic strategy.

 

Researchers showed that mammalian fibroblasts can be converted into embryonic stem cell (ESC)-like induced pluripotent stem cells (iPSCs) by introducing four transcription factors i.e., Oct4, Sox2, Klf4, and c-Myc. This was then accomplished with human somatic cells, reprogramming them into human iPSCs (hiPSCs), offering the possibility of generating patient-specific stem cells. There are several major barriers to implementation of hiPSC-based cell therapy for PD. First, probably due to the limited understanding of the reprogramming process, wide variability exists between the differentiation potential of individual hiPSC lines. Second, the safety of hiPSC-based cell therapy has yet to be fully established. In particular, since any hiPSCs that remain undifferentiated or bear sub-clonal tumorigenic mutations have neoplastic potential, it is critical to eliminate completely such cells from a therapeutic product.

 

In the present study the researchers established human induced pluripotent stem cell (hiPSC)-based autologous cell therapy. Researchers reported a platform of core techniques for the production of mDA progenitors as a safe and effective therapeutic product. First, by combining metabolism-regulating microRNAs with reprogramming factors, a method was developed to more efficiently generate clinical grade iPSCs, as evidenced by genomic integrity and unbiased pluripotent potential. Second, a “spotting”-based in vitro differentiation methodology was established to generate functional and healthy mDA cells in a scalable manner. Third, a chemical method was developed that safely eliminates undifferentiated cells from the final product. Dopaminergic cells thus produced can express high levels of characteristic mDA markers, produce and secrete dopamine, and exhibit electrophysiological features typical of mDA cells. Transplantation of these cells into rodent models of PD robustly restored motor dysfunction and reinnervated host brain, while showing no evidence of tumor formation or redistribution of the implanted cells.

 

Together these results supported the promise of these techniques to provide clinically applicable personalized autologous cell therapy for PD. It was recognized by researchers that this methodology is likely to be more costly in dollars and manpower than techniques using off-the-shelf methods and allogenic cell lines. Nevertheless, the cost for autologous cell therapy may be expected to decrease steadily with technological refinement and automation. Given the significant advantages inherent in a cell source free of ethical concerns and with the potential to obviate the need for immunosuppression, with its attendant costs and dangers, it was proposed that this platform is suitable for the successful implementation of human personalized autologous cell therapy for PD.

 

References:

 

https://www.jci.org/articles/view/130767/pdf?elqTrackId=2fd7d0edee744f9cb6d70a686d7b273b

 

https://www.ncbi.nlm.nih.gov/pubmed/31714896

 

https://www.ncbi.nlm.nih.gov/pubmed/23666606

 

https://www.ncbi.nlm.nih.gov/pubmed/27343168

 

https://www.ncbi.nlm.nih.gov/pubmed/21495962

 

https://www.ncbi.nlm.nih.gov/pubmed/28083784

 

https://www.ncbi.nlm.nih.gov/pubmed/20336395

 

https://www.ncbi.nlm.nih.gov/pubmed/28585381

 

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

 

Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.

 

In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

 

Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.

 

References:

 

https://www.biorxiv.org/content/10.1101/849844v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25656706

 

https://www.ncbi.nlm.nih.gov/pubmed/27653600

 

https://www.ncbi.nlm.nih.gov/pubmed/26912368

 

https://www.ncbi.nlm.nih.gov/pubmed/26799208

 

https://www.ncbi.nlm.nih.gov/pubmed/23001146

 

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

 

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. These enzymes are crucial for a number of cellular activities, including cell survival, proliferation and migration — functions that must be carefully controlled if cells get out of control and form a tumor. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Researchers at University of California San Diego School of Medicine found that another enzyme, called PHLPP1, acts as a “proofreader” to keep careful tabs on PKC.

 

The researchers discovered that in pancreatic cancer high PHLPP1 levels lead to low PKC levels, which is associated with poor patient survival. They reported that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. They discovered that any time an over-active PKC is inadvertently produced, the PHLPP1 “proofreader” tags it for destruction. That means the amount of PHLPP1 in patient’s cells determines his amount of PKC and it turns out those enzyme levels are especially important in pancreatic cancer.

 

This team of researchers reversed a 30-year paradigm when they reported evidence that PKC actually suppresses, rather than promotes, tumors. For decades before this revelation, many researchers had attempted to develop drugs that inhibit PKC as a means to treat cancer. Their study implied that anti-cancer drugs would actually need to do the opposite — boost PKC activity. This study sets the stage for clinicians to one day use a pancreatic cancer patient’s PHLPP1/PKC levels as a predictor for prognosis, and for researchers to develop new therapeutic drugs that inhibit PHLPP1 and boost PKC as a means to treat the disease.

 

The ratio — high PHLPP1/low PKC — correlated with poor prognoses: no pancreatic patient with low PKC in the database survived longer than five-and-a-half years. On the flip side, 50 percent of the patients with low PHLPP1/high PKC survived longer than that. While still in the earliest stages, the researchers hope that this information might one day aid pancreatic diagnostics and treatment. The researchers are next planning to screen chemical compounds to find those that inhibit PHLPP1 and restore PKC levels in low-PKC-pancreatic cancer cells in the lab. These might form the basis of a new therapeutic drug for pancreatic cancer.

 

References:

 

https://health.ucsd.edu/news/releases/Pages/2019-03-20-two-enzymes-linked-to-pancreatic-cancer-survival.aspx?elqTrackId=b6864b278958402787f61dd7b7624666

 

https://www.ncbi.nlm.nih.gov/pubmed/30904392

 

https://www.ncbi.nlm.nih.gov/pubmed/29513138

 

https://www.ncbi.nlm.nih.gov/pubmed/18511290

 

https://www.ncbi.nlm.nih.gov/pubmed/28476658

 

https://www.ncbi.nlm.nih.gov/pubmed/28283201

 

https://www.ncbi.nlm.nih.gov/pubmed/24231509

 

https://www.ncbi.nlm.nih.gov/pubmed/28112438

 

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Immunoediting can be a constant defense in the cancer landscape


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

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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New CRISPR Approach Transforms Skin Cells into Pluripotent Stem Cells

Reporter: Irina Robu, PhD

Dr. Timo Otonkoski, University of Helsinki and Dr.Juha Kere, King’s College London succeeded on reprograming skin cells into pluripotent stem cells by activating cell’s own genes using gene editing technology, CRISPR-Cas9-based gene activation (CRISPRa) that can be used to activate genes. The method uses a blunt version of Cas9 ‘gene scissors’ that does not cut DNA and can consequently be used to activate gene expression without mutating the genome. Previously, reprogramming was only possible by artificially introducing the critical transformation genes known as Yamanaka Factors into skin cells where they are normally inactive.

According to a study that is published in Nature Communication, called Human Pluripotent Reprogramming with CRISPR activators which show that CRISPRa is an attractive tool for cellular reprogramming applications due to its high multiplex capacity and direct alignment of endogenous loci. In the article, it is presented that reprogramming of primary human dermal fibroblasts to induced pluripotent stem cells with CRISPRa, the aimed at endogenous cells. The data shows that human body cells can only be reprogrammed into iPS cells with CRISPRa, and the findings reveal the involvement of EEA motif-associated mechanisms in cellular reprogramming.

The discovery also advocates that it might be likely to improve many other reprogramming tasks by addressing genetic elements that are typical of the intended target cell type. According to Jere Weltner, PhD student working on the project “the technology can find practical application in biobanking and many other applications of tissue technology.

SOURCE

https://www.sciencedaily.com/releases/2018/07/180706091723.htm

 

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

 

The CRISPR-Cas9 system has proven to be a powerful tool for genome editing allowing for the precise modification of specific DNA sequences within a cell. Many efforts are currently underway to use the CRISPR-Cas9 system for the therapeutic correction of human genetic diseases. CRISPR/Cas9 has revolutionized our ability to engineer genomes and conduct genome-wide screens in human cells.

 

CRISPR–Cas9 induces a p53-mediated DNA damage response and cell cycle arrest in immortalized human retinal pigment epithelial cells, leading to a selection against cells with a functional p53 pathway. Inhibition of p53 prevents the damage response and increases the rate of homologous recombination from a donor template. These results suggest that p53 inhibition may improve the efficiency of genome editing of untransformed cells and that p53 function should be monitored when developing cell-based therapies utilizing CRISPR–Cas9.

 

Whereas some cell types are amenable to genome engineering, genomes of human pluripotent stem cells (hPSCs) have been difficult to engineer, with reduced efficiencies relative to tumour cell lines or mouse embryonic stem cells. Using hPSC lines with stable integration of Cas9 or transient delivery of Cas9-ribonucleoproteins (RNPs), an average insertion or deletion (indel) efficiency greater than 80% was achieved. This high efficiency of insertion or deletion generation revealed that double-strand breaks (DSBs) induced by Cas9 are toxic and kill most hPSCs.

 

The toxic response to DSBs was P53/TP53-dependent, such that the efficiency of precise genome engineering in hPSCs with a wild-type P53 gene was severely reduced. These results indicate that Cas9 toxicity creates an obstacle to the high-throughput use of CRISPR/Cas9 for genome engineering and screening in hPSCs. As hPSCs can acquire P53 mutations, cell replacement therapies using CRISPR/Cas9-enginereed hPSCs should proceed with caution, and such engineered hPSCs should be monitored for P53 function.

 

CRISPR-based editing of T cells to treat cancer, as scientists at the University of Pennsylvania are studying in a clinical trial, should also not have a p53 problem. Nor should any therapy developed with CRISPR base editing, which does not make the double-stranded breaks that trigger p53. But, there are pre-existing humoral and cell-mediated adaptive immune responses to Cas9 in humans, a factor which must be taken into account as the CRISPR-Cas9 system moves forward into clinical trials.

 

References:

 

https://techonomy.com/2018/06/new-cancer-concerns-shake-crispr-prognosis/

 

https://www.statnews.com/2018/06/11/crispr-hurdle-edited-cells-might-cause-cancer/

 

https://www.biorxiv.org/content/early/2017/07/26/168443

 

https://www.nature.com/articles/s41591-018-0049-z.epdf?referrer_access_token=s92jDP_yPBmDmi-USafzK9RgN0jAjWel9jnR3ZoTv0MRjuB3dEnTctGtoy16n3DDbmISsvbln9SCISHVDd73tdQRNS7LB8qBlX1vpbLE0nK_CwKThDGcf344KR6RAm9k3wZiwyu-Kb1f2Dl7pArs5yYSiSLSdgeH7gst7lOBEh9qIc6kDpsytWLHqX_tyggu&tracking_referrer=www.statnews.com

 

https://www.nature.com/articles/s41591-018-0050-6.epdf?referrer_access_token=2KJ0L-tmvjtQdzqlkVXWVNRgN0jAjWel9jnR3ZoTv0Phq6GCpDlJx7lIwhCzBRjHJv0mv4zO0wzJJCeuxJjzoUWLeemH8T4I3i61ftUBkYkETi6qnweELRYMj4v0kLk7naHF-ujuz4WUf75mXsIRJ3HH0kQGq1TNYg7tk3kamoelcgGp4M7UTiTmG8j0oog_&tracking_referrer=www.statnews.com

 

https://www.biorxiv.org/content/early/2018/01/05/243345

 

https://www.nature.com/articles/nmeth.4293.epdf

 

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UPDATED on 3/17/2019

https://www.medpagetoday.com/cardiology/prevention/78202?xid=nl_mpt_SRCardiology_2019-02-25&eun=g99985d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=CardioUpdate_022519&utm_term=NL_Spec_Cardiology_Update_Active

Transgender hormone therapy appears to increase cardiovascular risk. (Circulation)

A mobile app with a step-by-step guide to prepping vasoactive drugs for CPR of children in the emergency room substantially cut medication errors, drug preparation time, and delivery time compared with using infusion-rate tables in a study using manikins. (The Lancet Child & Adolescent Health)

 

Artificial ovary instead of conventional hormone replacement

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

During menopause a woman’s ovaries stop working—leading to hot flashes, sleep problems, weight gain, and worse, bone deterioration. Now scientists are exploring whether transplanting lab-made ovaries might stop those symptoms. In one of the first efforts to explore the potential of such a technique, researchers say they used tissue engineering to construct artificial rat ovaries able to supply female hormones like estrogen and progesterone. A research carried out at Wake Forest Baptist Medical Center, suggests a potential alternative to the synthetic hormones millions of women take after reaching middle age. A paper describing the findings was published in Nature Communications.

 

Women going through menopause, as well as those who have undergone cancer treatment or had their ovaries removed for medical purposes, lose the ability to produce important hormones, including estrogen and progesterone. Lower levels of these hormones can affect a number of different body functions. To counteract unpleasant symptoms, many women turn to combinations of hormone replacement medications—synthetic estrogen and progestin. Pharmacologic hormone replacement therapy (pHRT) with estrogen alone or estrogen and progestogens is known to effectively ameliorate the unpleasant symptoms. But hormone replacement carries an increased risk of heart disease and breast cancer, so it’s not recommended for long-term use. In these circumstances artificial ovaries could be safer and more effective.

 

Regenerative medicine approaches that use cell-based hormone replacement therapy (cHRT) offer a potential solution to temporal control of hormone delivery and the ability to restore the HPO (Hypothalamo-Pituitary-Ovarian) axis in a way not possible with pHRT. Scientists have previously described an approach to achieve microencapsulation of ovarian cells that results in bioengineered constructs that replicate key structure-function relationships of ovarian follicles as an approach to cHRT. In the present study the scientists have adapted an isogeneic cell-based construct to provide a proof-of-concept for the potential benefits of cHRT.

 

Tissue or cell encapsulation may offer effective strategies to fabricate ovarian constructs for the purpose of fertility and/or hormone replacement. Approaches using segmental ovarian tissue or whole-follicle implantation (typically with a focus on cryopreservation of the tissue for reproductive purposes) have resulted in detectable hormone levels in the blood after transplantation. Previous studies have also shown that autotransplantation of frozen-thawed ovarian tissue can lead to hormone secretion for over 5 years in humans.

 

Although these approaches can be used to achieve the dual purpose of fertility and hormone replacement in premenopausal women undergoing premature ovarian failure, they would have limited application in postmenopausal women who only need hormone replacement to manage menopausal symptoms and in whom fertility is not desirable. In full development, the technology described in this research is focused on hormone replacement, would meet the needs of the latter group of women that is the postmenopausal women.

 

The cell-based system of hormone replacement described in this report offers an attractive alternative to traditional pharmacological approaches and is consistent with current guidelines in the U.S. and Europe recommending the lowest possible doses of hormone for replacement therapy. In the present research sustained stable hormone release over the course of 90 days of study was demonstrated. The study also demonstrated the effective end-organ outcomes in body fat composition, uterine health, and bone health. However, additional studies will be required to determine the sustainability of the hormone secretion of the constructs by measuring hormone levels from implanted constructs for periods longer than 3 months in the rat model.

 

This study highlights the potential utility of cHRT for the treatment and study of conditions associated with functional loss of the ovaries. Although longer-term studies would be of future interest, the 90-day duration of this rodent model study is consistent with others investigating osteoporosis in an ovariectomy model. However, this study provides a proof-of-concept for cHRT, it suffers the limitation that it is only an isogeneic-based construct implantation. Scientists think that further studies in either allogeneic or xenogeneic settings would be required with the construct design described in this report in the path towards clinical translation given that patients who would receive this type of treatment are unlikely to have sufficient autologous ovarian cells for transplantation.

 

Researchers from Copenhagen, Denmark, were recently able to isolate viable, early stage follicles in ovarian tissue. They have successfully stripped ovarian tissue from its cancerous cells and used the remaining scaffold to support the growth and survival of human follicles. This “artificial ovary” may help y to help women who have become infertile due to cancer and chemotherapy. But, the research is presently at a very preliminary stage and much research is still required to ensure that cancer cells are not reintroduced during the grafting process.

 

References:

 

https://www.technologyreview.com/the-download/609677/will-artificial-ovaries-mean-no-more-menopause/

 

https://www.nature.com/articles/s41467-017-01851-3

 

https://www.ncbi.nlm.nih.gov/pubmed/23274068

 

https://www.ncbi.nlm.nih.gov/pubmed/26210678

 

https://www.ncbi.nlm.nih.gov/pubmed/21954279

 

http://www.frontlinegenomics.com/news/24423/artificial-ovaries-hope-to-help-infertile-women-conceive-following-chemotherapy/

 

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Knowing the genetic vulnerability of bladder cancer for therapeutic intervention

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

 

A mutated gene called RAS gives rise to a signalling protein Ral which is involved in tumour growth in the bladder. Many researchers tried and failed to target and stop this wayward gene. Signalling proteins such as Ral usually shift between active and inactive states.

 

So, researchers next tried to stop Ral to get into active state. In inacvtive state Ral exposes a pocket which gets closed when active. After five years, the researchers found a small molecule dubbed BQU57 that can wedge itself into the pocket to prevent Ral from closing and becoming active. Now, BQU57 has been licensed for further development.

 

Researchers have a growing genetic data on bladder cancer, some of which threaten to overturn the supposed causes of bladder cancer. Genetics has also allowed bladder cancer to be reclassified from two categories into five distinct subtypes, each with different characteristics and weak spots. All these advances bode well for drug development and for improved diagnosis and prognosis.

 

Among the groups studying the genetics of bladder cancer are two large international teams: Uromol (named for urology and molecular biology), which is based at Aarhus University Hospital in Denmark, and The Cancer Genome Atlas (TCGA), based at institutions in Texas and Boston. Each team tackled a different type of cancer, based on the traditional classification of whether or not a tumour has grown into the muscle wall of the bladder. Uromol worked on the more common, earlier form, non-muscle-invasive bladder cancer, whereas TCGA is looking at muscle-invasive bladder cancer, which has a lower survival rate.

 

The Uromol team sought to identify people whose non-invasive tumours might return after treatment, becoming invasive or even metastatic. Bladder cancer has a high risk of recurrence, so people whose non-invasive cancer has been treated need to be monitored for many years, undergoing cystoscopy every few months. They looked for predictive genetic footprints in the transcriptome of the cancer, which contains all of a cell’s RNA and can tell researchers which genes are turned on or off.

 

They found three subgroups with distinct basal and luminal features, as proposed by other groups, each with different clinical outcomes in early-stage bladder cancer. These features sort bladder cancer into genetic categories that can help predict whether the cancer will return. The researchers also identified mutations that are linked to tumour progression. Mutations in the so-called APOBEC genes, which code for enzymes that modify RNA or DNA molecules. This effect could lead to cancer and cause it to be aggressive.

 

The second major research group, TCGA, led by the National Cancer Institute and the National Human Genome Research Institute, that involves thousands of researchers across USA. The project has already mapped genomic changes in 33 cancer types, including breast, skin and lung cancers. The TCGA researchers, who study muscle-invasive bladder cancer, have looked at tumours that were already identified as fast-growing and invasive.

 

The work by Uromol, TCGA and other labs has provided a clearer view of the genetic landscape of early- and late-stage bladder cancer. There are five subtypes for the muscle-invasive form: luminal, luminal–papillary, luminal–infiltrated, basal–squamous, and neuronal, each of which is genetically distinct and might require different therapeutic approaches.

 

Bladder cancer has the third-highest mutation rate of any cancer, behind only lung cancer and melanoma. The TCGA team has confirmed Uromol research showing that most bladder-cancer mutations occur in the APOBEC genes. It is not yet clear why APOBEC mutations are so common in bladder cancer, but studies of the mutations have yielded one startling implication. The APOBEC enzyme causes mutations early during the development of bladder cancer, and independent of cigarette smoke or other known exposures.

 

The TCGA researchers found a subset of bladder-cancer patients, those with the greatest number of APOBEC mutations, had an extremely high five-year survival rate of about 75%. Other patients with fewer APOBEC mutations fared less well which is pretty surprising.

 

This detailed knowledge of bladder-cancer genetics may help to pinpoint the specific vulnerabilities of cancer cells in different people. Over the past decade, Broad Institute researchers have identified more than 760 genes that cancer needs to grow and survive. Their genetic map might take another ten years to finish, but it will list every genetic vulnerability that can be exploited. The goal of cancer precision medicine is to take the patient’s tumour and decode the genetics, so the clinician can make a decision based on that information.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/29117162

 

https://www.ncbi.nlm.nih.gov/pubmed/27321955

 

https://www.ncbi.nlm.nih.gov/pubmed/28583312

 

https://www.ncbi.nlm.nih.gov/pubmed/24476821

 

https://www.ncbi.nlm.nih.gov/pubmed/28988769

 

https://www.ncbi.nlm.nih.gov/pubmed/28753430

 

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