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Archive for the ‘Apoptosis’ Category


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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Biological Pathways

Reporter: Aviva Lev-Ari, PhD, RN

 

Biological Pathways

View larger

SOURCE

https://www.genome.gov/27530687/biological-pathways-fact-sheet/

Figure 3: Examples of biological pathways that are regulated by selective mRNA export.

FromControl of mammalian gene expression by selective mRNA export

Nature Reviews Molecular Cell Biology
16,
431–442
(2015)
doi:10.1038/nrm4010

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Understanding Autophagy to Enhance Clinical Discovery: The 2016 Dr. Paul Janssen Award Symposium, September 22, 2016 | 8:00 AM – 2:15 PM, The New York Academy of Medicine, 1216 Fifth Avenue New York, NY 10029

Reporter: Aviva Lev-Ari, PhD, RN

 

Understanding Autophagy to Enhance Clinical Discovery: The 2016 Dr. Paul Janssen Award Symposium

Thursday, September 22, 2016 | 8:00 AM – 2:15 PM
The New York Academy of Medicine

Presented by the Dr. Paul Janssen Award for Biomedical Research and the New York Academy of Sciences

This symposium will honor Dr. Yoshinori Ohsumi, who will reflect on his initial work on the key players in autophagy, and share his vision for future advancements in the field. Following his award lecture, fellow prominent scientists at the forefront of autophagy research will discuss emerging concepts and technologies.

AGENDA

 

Preliminary Symposium Agenda

* Presentation times are subject to change.


Thursday, September 22, 2016

8:00 AM Registration and Breakfast
9:00 AM Welcome and Introductory Remarks
Anthony Shih, MD, MPH, The New York Academy of Medicine
Representative, Johnson & Johnson
Brooke Grindlinger, PhD, The New York Academy of Sciences

Session I: Elucidating the Underlying Cellular Processes of Autophagy

9:15 AM 2016 Dr. Paul Janssen Award for Biomedical Research Announcement
Representative, Janssen Research & Development
9:30 AM Dr. Paul Janssen Award for Biomedical Research Lecture
Uncovering the Key Molecular and Cellular Components in Autophagy
Yoshinori Ohsumi, PhD, Tokyo Institute of Technology
10:20 AM Coffee and Networking Break

Session II: Understanding the Molecular Landscape of Autophagy: From Basic Mechanisms to Human Health

Session Chair: Representative, The New York Academy of Sciences

10:50 AM Potential Therapeutic Targets in Autophagy
Beth Levine, MD, University of Texas Southwestern Medical Center, Howard Hughes Medical Institute (HHMI)
11:20 AM Autophagy in Cell Survival and Cell Death
Eric H. Baehrecke, PhD, University of Massachusetts Medical School
11:50 AM The Role of Chaperone-mediated Autophagy in Human Pathogenesis
Ana Maria Cuervo, MD, PhD, Albert Einstein College of Medicine
12:20 PM Title to Be Announced
Matthias Versele, PhD, Janssen Research & Development
12:50 PM Panel Discussion: The Future of Autophagy Research

Panelists:
Yoshinori Ohsumi, PhD, Tokyo Institute of Technology
Eric H. Baehrecke, PhD, University of Massachusetts Medical School
Ana Maria Cuervo, MD, PhD, Albert Einstein College of Medicine
Beth Levine, MD, University of Texas Southwestern Medical Center, Howard Hughes Medical Institute (HHMI)

* Additional Panelists to Be Announced

1:15 PM Luncheon
2:15 PM Adjourn

SOURCE

http://www.nyas.org/Events/Detail.aspx?cid=f5480228-c7ed-4f29-80bf-cc42b503e703

 

Other articles On and related to AUTOPHAGY published on this Open Access Online Scientific Journal include the following:

Autophagy

Writer and Curator: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2015/04/03/autophagy/

 

Autophagy-Modulating Proteins and Small Molecules Candidate Targets for Cancer Therapy: Commentary of Bioinformatics Approaches

Author and Curator: Larry H Bernstein, MD, FCAP and Article Architect: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/18/autophagy-modulating-proteins-and-small-molecules-candidate-targets-for-cancer-therapy-commentary-of-bioinformatics-approaches/

 

A Curated Census of Autophagy-Modulating Proteins and Small Molecules Candidate Targets for Cancer Therapy 

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/09/14/a-curated-census-of-autophagy-modulating-proteins-and-small-molecules-candidate-targets-for-cancer-therapy/

 

Autophagy: Selective articles by Larry H. Bernstein, MD, FCAP

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/01/autophagy-selective-articles-by-larry-h-bernstein-md-fcap/

 

 

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