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Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

 

The dean of the UCSF med school, Talmadge King, had this to say in his sendoff today:

Coughlin’s “research discoveries revealed a mechanism by which proteases regulate cellular behaviors including a key mechanism that controls blood platelet activation and clot formation. This work led to a new medical therapy for preventing heart attacks and strokes and has been honored by the American Heart Association’s Basic Science Award in 2003 and its Research Achievement Award in 2014. Among his numerous other awards are the Bristol-Myers Squibb Cardiovascular Research Award and the Distinguished Career Award from the International Society on Thrombosis and Haemostasis.”

SOURCE

https://endpts.com/top-ucsf-scientist-shaun-coughlin-joins-migration-to-big-pharma-leaping-to-novartis



Drug regiment consisting of anti-inflammatories (COX-2) and anti-stress medications (β-Adrenergic Blockade) given before and after surgery could reduce cancer recurrence (biomarkers of metastatic processes)

Reporter: Aviva Lev-Ari, PhD, RN

 

“We found that the drugs were very efficient in reducing biomarkers of metastatic processes,” Prof. Ben-Eliyahu said. “For example, we found that the drug treatment reverses EMT — the process that tumor cells go through to slip out of the primary tumor and enter another organ. It is a crucially important step in the metastatic process. We also looked at indices related to the immune system and were able to improve immune competence and reduce inflammation with the drugs.”

The research team has conducted a similar study, which has not yet been published, on colorectal cancer patients and has found similar results.

The researchers are currently considering a larger-scale clinical trial to establish the clinical long-term beneficial effects of this treatment. “Positive outcomes should validate this treatment and lead to its becoming available for most cancer patients,” Prof. Ben-Eliyahu concluded.

 

Abstract

Purpose: Translational studies suggest that excess perioperative release of catecholamines and prostaglandins may facilitate metastasis and reduce disease-free survival. This trial tested the combined perioperative blockade of these pathways in breast cancer patients.

Experimental Design: In a randomized placebo-controlled biomarker trial, 38 early-stage breast cancer patients received 11 days of perioperative treatment with a β-adrenergic antagonist (propranolol) and a COX-2 inhibitor (etodolac), beginning 5 days before surgery. Excised tumors and sequential blood samples were assessed for prometastatic biomarkers.

Results: Drugs were well tolerated with adverse event rates comparable with placebo. Transcriptome profiling of the primary tumor tested a priori hypotheses and indicated that drug treatment significantly

(i) decreased epithelial-to-mesenchymal transition,

(ii) reduced activity of prometastatic/proinflammatory transcription factors (GATA-1, GATA-2, early-growth-response-3/EGR3, signal transducer and activator of transcription-3/STAT-3), and

(iii) decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells.

Drug treatment also significantly

  • abrogated presurgical increases in serum IL6 and
  • C-reactive protein levels,
  • abrogated perioperative declines in stimulated IL12 and IFNγ production,
  • abrogated postoperative mobilization of CD16 “classical” monocytes, and
  • enhanced expression of CD11a on circulating natural killer cells.

Conclusions: Perioperative inhibition of COX-2 and β-adrenergic signaling provides a safe and effective strategy for inhibiting multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage breast cancer. Clin Cancer Res; 1–11. ©2017 AACR.

 

SOURCES

“Anti-Inflammatory and Anti-Stress Drugs Taken Before Surgery May Reduce Metastatic Recurrence.” NeuroscienceNews. NeuroscienceNews, 7 August 2017.

Original Research: Abstract for

“Perioperative COX-2 and β-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial”

by Lee Shaashua, Maytal Shabat-Simon, Rita Haldar, Pini Matzner, Oded Zmora, Moshe Shabtai, Eran Sharon, Tanir Allweis, Iris Barshack, Lucile Hayman, Jesusa Arevalo, Jeffrey Ma, Maya Horowitz, Steven Cole and Shamgar Ben-Eliyahu in Clinical Cancer Research. Published online August 2017 doi:10.1158/1078-0432.CCR-17-0152


Post-zygotic Mutations, spontaneously arising in an embryonic cell after sperm meets egg, are important players in Autism Spectrum Disorder, a HMS & BCH large study suggests

Reporter: Aviva Lev-Ari, PhD, RN

 

Based on their findings, they classified 7.5 percent of ASD subjects’ de novo mutations as PZMs. Of these, 83 percent had not been picked up in the original analysis of their genome sequence.

Some PZMs affected genes already known to be linked to autism or other neurodevelopmental disorders (such as SCN2AHNRNPU and SMARCA4), but sometimes affected these genes in different ways. Many other PZMs were in genes known to be active in brain development (such as KLF16 and MSANTD2) but not previously associated with ASD.

Comparing these with the genomic sequencing data (based mostly on blood DNA samples) allowed the researchers estimate the timing of the PZMs and the brain regions they affected. In the image at right, representing the prenatal brain, the region with the most “hits” was the amygdala (AMY, in red), with minor hits in the striatum (STR) and cerebellar cortex (CBC) that did not reach statistical significance.

Image Credit: Mohammed Uddin

 

SOURCES

Late-breaking mutations may play an important role in autism

https://vector.childrenshospital.org/2017/07/post-zygotic-somatic-mutations-autism/

Late in the Game, Post-conception mutations may play an important role in autism

https://hms.harvard.edu/news/late-game?utm_source=Silverpop&utm_medium=email&utm_term=s3&utm_content=8.7.17.HMS

Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder

Nature Neuroscience (2017) doi:10.1038/nn.4598
Published online: 17 July 2017

Agios Pharmaceuticals target the metabolism of cancer cells for making drugs that essentially try to repair cancer cells

Reporter: Aviva Lev-Ari, PhD, RN

A small biotech behind a groundbreaking approach to tackling cancer just got its first drug approved

http://www.businessinsider.com/fda-approves-agios-pharmaceuticals-drug-targeting-cancer-cell-metabolism-2017-8

See

Cancer Metabolism

http://www.agios.com/research/cancer-metabolism/

Metabolic Immuno-Oncology

http://www.agios.com/research/metabolic-immuno-oncology/

 

 

The VOICE of Larry H. Bernstein, MD, FCAP

Cancer cells didn’t need as much oxygen to metabolize sugar as normal cells. 

Not correct. Cancer cells metabolize glucose by aerobic glycolysis (4 ATP) with an impaired mitochondrial oxygen utilization (36 ATP). 

There is a reverse Warburg effect in which the underlying stromal cell carries out crosstalk with the epithelial cell. 

There is also a 3rd dimension. Cells undergo a series of adaptive changes tied to proteostasis. This involves the sulfur amino acid cysteine and disulfide bonds, which is involved with protein oligomerization in the ER, and also signaling in the mitochondria with mDNA and the nucleus. 


Curator: Aviva Lev-Ari, PhD, RN

 

Transcriptomic Biomarkers to Discriminate Bacterial from Nonbacterial Infection in Adults Hospitalized with Respiratory Illness

Published online: 26 July 2017

URMC Researchers Developing New Tool to Fight Antibiotic Resistance

Goal is to Distinguish Between Viral and Bacterial Infections, Reduce Unnecessary Use of Antibiotics

Friday, July 28, 2017

“It’s extremely difficult to interpret what’s causing a respiratory tract infection, especially in very ill patients who come to the hospital with a high fever, cough, shortness of breath and other concerning symptoms,” said Ann R. Falsey, M.D., lead study author, professor and interim chief of the Infectious Diseases Division at UR Medicine’s Strong Memorial Hospital.

“My goal is to develop a tool that physicians can use to rule out a bacterial infection with enough certainty that they are comfortable, and their patients are comfortable, foregoing an antibiotic.”

Lead researcher Ann Falsey, M.D.

Ann R. Falsey, M.D.

Falsey’s project caught the attention of the federal government; she’s one of 10 semifinalists in the Antimicrobial Resistance Diagnostic Challenge, a competition sponsored by NIH and the Biomedical Advanced Research and Development Authority to help combat the development and spread of drug resistant bacteria. Selected from among 74 submissions, Falsey received $50,000 to continue her research and develop a prototype diagnostic test, such as a blood test, using the genetic markers her team identified.

SOURCE

https://www.urmc.rochester.edu/news/story/5108/urmc-researchers-developing-new-tool-to-fight-antibiotic-resistance.aspx

Lower respiratory tract infection (LRTI)

We enrolled 94 subjects who were microbiologically classified; 53 as “non-bacterial” and 41 as “bacterial”. RNAseq and qPCR confirmed significant differences in mean expression for 10 genes previously identified as discriminatory for bacterial LRTI. A novel dimension reduction strategy selected three pathways (lymphocyte, α-linoleic acid metabolism, IGF regulation) including eleven genes as optimal markers for discriminating bacterial infection (naïve AUC = 0.94; nested CV-AUC = 0.86). Using these genes, we constructed a classifier for bacterial LRTI with 90% (79% CV) sensitivity and 83% (76% CV) specificity. This novel, pathway-based gene set displays promise as a method to distinguish bacterial from nonbacterial LRTI.

https://www.nature.com/articles/s41598-017-06738-3#Sec8

IMAGE SOURCE

https://www.nature.com/articles/s41598-017-06738-3#Sec8

 

SOURCES

http://sciencemission.com/site/index.php?page=news&type=view&id=microbiology-virology%2Fnew-tool-to-distinguish&filter=8%2C9%2C10%2C11%2C12%2C13%2C14%2C16%2C17%2C18%2C19%2C20%2C27&redirected=1&redirected=1

https://www.urmc.rochester.edu/news/story/5108/urmc-researchers-developing-new-tool-to-fight-antibiotic-resistance.aspx

https://www.nature.com/articles/s41598-017-06738-3

Bacterial or Viral Infection? A New Study May Help Physicians …

 

Other related articles published in this Open Access Online Scientific Journal include the following:

Series D, VOLUME 2:

Infectious Diseases and Therapeutics

Author, Curator and Editor: Larry H Bernstein, MD, FCAP and CuratorSudipta Saha, PhD

 

Series D, VOLUME 3:

The Immune System and Therapeutics

Author, Curator and Editor: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/biomed-e-books/series-d-e-books-on-biomedicine/human-immune-system-in-health-and-in-disease/