Bacteria deploy viruses to trick the immune system

Viruses act as decoys, study finds, helping bacteria evade the immune system

Eric Boodman, Stat News

These viruses weren’t supposed to affect humans. They were supposed to ride along inside bacteria — unobtrusive hitchhikers taking advantage of another microbe’s machinery. But that wasn’t what Dr. Paul Bollyky and his colleagues saw in their lab dishes three or four years ago. The viruses seemed to be changing the behavior of human immune cells. Instead of gobbling up bacteria as they normally did, white blood cells just sat there.

“They basically don’t eat anything. They don’t move around much either,” said Bollyky, an immunologist and infectious disease specialist at Stanford University. “They would just ignore … the bacteria that were in the dish with them.”

Now, with a paper published Thursday in Science, what began as a chance observation has yielded a startling window into the inner lives of infections — one in which viruses tag-team with bacteria to trick the immune system by providing a decoy. Bollyky describes it as having someone trip the fire alarm so that the rest of the team can pull off a robbery in the chaos that ensues.

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Cancer evading the Immune System, covered in the New York Times

Cancer’s Trick for Dodging the Immune System

Matt Richtel, The New York Times

Cancer immunotherapy drugs, which spur the body’s own immune system to attack tumors, hold great promise but still fail many patients. New research may help explain why some cancers elude the new class of therapies, and offer some clues to a solution.

The study, published on Thursday in the journal Cell, focuses on colorectal and prostate cancer. These are among the cancers that seem largely impervious to a key mechanism of immunotherapy drugs.

The drugs block a signal that tumors send to stymie the immune system. That signal gets sent via a particular molecule that is found on the surface of some tumor cells.

The trouble is that the molecule, called PD-L1, does not appear on the surface of all tumors, and in those cases, the drugs have trouble interfering with the signal sent by the cancer.

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Long non-coding RNA triggers Cancer Resistance

Long non-coding RNA GBCDRlnc1 induces chemoresistance of gallbladder cancer cells by activating autophagy

Qiang Cai, Shouhua Wang, Longyang Jin, Mingzhe Weng, Di Zhou, Jiandong Wang, Zhaohui Tang and Zhiwei Quan

Molecular Cancer (Research Article)

Background

Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells.

Methods

We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA.

Results

The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate.

Conclusions

Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.

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Potential progress for Pancreatic Cancer treatment

CRI-Sponsored Trial Reveals Promising Potential of Immunotherapy Combination in Metastatic Pancreatic Cancer

Arthur N. Brodsky, Cancer Research Institute Blog

A novel combination of immunotherapy and chemotherapy shows promise as a first-line option in patients with metastatic pancreatic cancer, according to interim results from a Cancer Research Institute-funded clinical trial that are being revealed today at the 2019 Annual Meeting of the American Association for Cancer Research (AACR19) in Atlanta.

This phase Ib trial is the first to emerge from the partnership between the Cancer Research Institute (CRI), the Parker Institute for Cancer Immunotherapy (PICI), and Bristol-Myers Squibb (BMS) that was formed in 2017 in order to accelerate promising immunotherapy to benefit the patients who need them most.

In this study, patients were treated with combinations of four different drugs, including two standard-of-care chemotherapies and two immunotherapies—one that inhibits the PD-1 immune checkpoint (nivolumab, BMS) and an experimental treatment that activates the CD40 pathway (APX005M, Apexigen).

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Looking Everywhere for Cancer Drugs

Nature’s Bounty: Revitalizing the Discovery of New Cancer Drugs from Natural Products

Cancer Currents Blog

Dr. Grkovic has spent the last several years intimately involved in improving processes for analyzing products of nature—from marine creatures to soil-dwelling fungi to plant leaves—to see whether chemical compounds within them might be starting blocks for new cancer drugs. (The Natural Products Support Group is part of the Frederick National Laboratory for Cancer Research, an NCI-sponsored contractor-operated facility.)

The work has been part of an ambitious, Cancer MoonshotSM-funded initiative, called the NCI Program for Natural Products Discovery (NPNPD), to make it easier for other researchers to mine nature for leads on new cancer drugs.

A big part of that story has taken place in the well-worn home of NCI’s Natural Products Branch, on the NCI campus in Frederick, MD.

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"Elite" stem cells help dominate the reprogramming niche

Not all stem cells are created equal

Researchers have discovered a population of cells – dubbed to be “elite” – that play a key role in the process of transforming differentiated cells into stem cells. The finding has important implications for regenerative medicine.

Stem cells have the ability to transform into specialized cells – from lung to brain. Stem cells are common in embryos, but within the last 15 years, a technique called cell reprogramming has enabled scientists to turn mature cells back into so-called pluripotent stem cells, with the power to develop into any cell type.

While reprogramming is well understood, less is known about the intricacies of how individual reprogramming cells behave in a population setting. Researchers found a group of cells that appear to have a competitive advantage in reprogramming. The research is published in Science.

The team used cells extracted from mouse skin, known as mouse embryonic fibroblasts (MEFs). They used DNA-barcoding technologies to give each MEF a unique tag, track individual cells during reprogramming and associate them with their parent population. They also used computational modelling to help understand the complex data generated and to make predictions that were tested in the lab.

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Nanopore pioneers ultrafast tumor analyses

Same-day genomic and epigenomic analysis of brain tumors

via GIPHY

A plethora of technologies are currently required to assess different genomic and epigenomic alterations; however, the associated costs and long turnaround times combined with extensive infrastructure and training requirements have, to date, hindered their implementation1 . To address these challenges, Dr. Philippe Euskirchen and co-workers at the ICM Brain and Spine Institute, France, assessed the potential of nanopore sequencing technology to deliver comprehensive and cost-effective characterisation of genetic alterations in brain cancer samples — including analysis of copy number (CN) alterations, epigenetic base modifications, and single nucleotide variations (SNVs)1,2. Furthermore, all nanopore sequencing workflows were designed to go from sample to result within a single day.

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Selective Serotonin reuptake of by Chromatin

Mood-Altering Messenger Goes Nuclear

Francis Collins, NIH Director's Blog

Serotonin is best known for its role as a chemical messenger in the brain, helping to regulate mood, appetite, sleep, and many other functions. It exerts these influences by binding to its receptor on the surface of neural cells. But startling new work suggests the impact of serotonin does not end there: the molecule also can enter a cell’s nucleus and directly switch on genes.

While much more study is needed, this is a potentially groundbreaking discovery. Not only could it have implications for managing depression and other mood disorders, it may also open new avenues for treating substance abuse and neurodegenerative diseases.

To understand how serotonin contributes to switching genes on and off, a lesson on epigenetics is helpful. Keep in mind that the DNA instruction book of all cells is essentially the same, yet the chapters of the book are read in very different ways by cells in different parts of the body. Epigenetics refers to chemical marks on DNA itself or on the protein “spools” called histones that package DNA. These marks influence the activity of genes in a particular cell without changing the underlying DNA sequence, switching them on and off or acting as “volume knobs” to turn the activity of particular genes up or down.

The marks include various chemical groups—including acetyl, phosphate, or methyl—which are added at precise locations to those spool-like proteins called histones. The addition of such groups alters the accessibility of the DNA for copying into messenger RNA and producing needed proteins.

In the study reported in Nature, researchers led by Ian Maze and postdoctoral researcher Lorna Farrelly, Icahn School of Medicine at Mount Sinai, New York, followed a hunch that serotonin molecules might also get added to histones [1]. There had been hints that it might be possible. For instance, earlier evidence suggested that inside cells, serotonin could enter the nucleus. There also was evidence that serotonin could attach to proteins outside the nucleus in a process called serotonylation.

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American Society of Human Genetics to expand Developing Country Awards Program

ASHG Announces Expansion to Developing Country Awards Program
25 Travel Awards Will Enhance Africa’s Participation in Scientific Dialogue

ROCKVILLE, Md. – The American Society of Human Genetics (ASHG), in collaboration with the National Human Genome Research Institute (NHGRI), is pleased to announce the addition of 25 awards to its annual Developing Country Awards Program. The new awards will enable 25 genetics trainees and/or early- to mid-career investigators from Africa who are currently working in Africa to attend the ASHG 2019 Annual Meeting, taking place October 15-19, 2019, in Houston, Texas. They will be supported by NHGRI; the Human, Heredity, and Health in Africa (H3Africa) consortium; and ASHG; and administered via the H3Africa Coordinating Center at the University of Cape Town.

“Through these awards, we hope to enhance the participation and visibility of promising African geneticists at the world’s largest genetics meeting,” said Kiran Musunuru, MD, PhD, 2019 Chair of the ASHG Program Committee. “By working to enrich the diversity of voices engaged in research worldwide, we reaffirm our commitment to global science, and we hope to grow similar partnerships in other regions in the future,” he said.

“In Africa, there is a growing research community using genomic methods in biomedical research to address the substantial disease burden,” explained Jennifer Troyer, PhD, H3Africa Program Director at NHGRI. “Over the past decade, the H3Africa Consortium and other international global health efforts have increased support for research leaders in Africa to address vital research topics there and to provide training for the next generation of African researchers, leading to the growth of genetics and genomics research on the continent,” said Dr. Troyer.

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Blood tests versus biopsies

Could a simple blood test replace the invasive tissue biopsy?

Answer: It’s complicated …

Jake Siegel / Fred Hutch News Service

For years, the idea seemed as far-fetched as a fairy tale.

Once upon a time, there was a tumor cell that died. It’s innards spilled out into the bloodstream of the body where it had lived. The owner of that body went to a doctor and got a blood draw for a test, which identified the cell’s floating DNA fragments as cancer. The doctor then drew up a personalized treatment plan based on those bits of DNA, and the patient lived happily ever after …

The appeal of a simple blood test to detect and analyze cancer is obvious. It could replace the necessary evil of tissue biopsies — invasive, often risky and painful procedures to collect tumor cells with a needle or through surgery. A vial of blood sounds like a better trade than a chunk of tissue.

Recently, the idea of these so-called “liquid biopsies” seems less like a fantasy. 

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Cleveland Clinic Commentary for Cancer Screening

Personalizing guideline-driven cancer screening

Gautam Mankaney, MD Carol A. Burke, MD, FACG, FACP, FASGE

Cleveland Clinic Journal of Medicine (Commentary)

Reports of cancer date back thousands of years to Egyptian texts. Its existence baffled scientists until the 1950s, when Watson, Crick, and Franklin discovered the structure of DNA, laying the groundwork for identifying the genetic pathways leading to cancer. Currently, cancer is a leading global cause of death and the second leading cause of death in the United States.

In an effort to curtail cancer and its related morbidity and mortality, population-based screening programs have been implemented with tests that identify precancerous lesions and, preferably, early-stage rather than late-stage cancer.

Screening for cancer can lead to early diagnosis and prevent death from cancer, but the topic continues to provoke controversy.

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OncoCell Presents Noninvasive Blood-Based Assay for Prostate Cancer

OncoCell Announces Late-Breaking Poster Presentation at AACR 2019 on a Noninvasive Blood-Based Assay for Prostate Cancer Prognosis

ATLANTA--(BUSINESS WIRE)--Apr 1, 2019--OncoCell MDx, a company developing novel noninvasive diagnostic and prognostic tests, will present results from a feasibility study of a new prostate cancer prognostic assay in a late-breaking poster session at the American Association of Cancer Research (AACR) Annual Meeting tomorrow. The study demonstrates that the blood-based immunogenomics RNA expression assay provides a prognostic summary comparable to that of prostate biopsy.

OncoCell’s Subtraction-Normalized Expression of Phagocytes (SNEP) based platform, invented by Professor Amin Kassis, while at Harvard Medical School, uses a proprietary algorithm to interrogate changes in gene expression of two immune cell types consequent to prostate cancer including phagocytic (CD14) and non-phagocytic (CD2) cells, filters out intrinsic genomic variation not related to the disease, and identifies and validates prostate cancer-specific signatures. A study of blood samples from 713 prostate cancer patients showed the platform provides a prognostic summary including tumor Gleason grade distribution, size/volume and heterogeneity that is comparable to prostate biopsy information, and that it stratifies patients with aggressive disease that need life-saving treatment from those with indolent disease.

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Clinical application of tumor evolution analysis

Translating insights into tumor evolution to clinical practice: promises and challenges

Matthew W. Fittall and Peter Van Loo

Genome Medicine (Review Article)

Abstract—Accelerating technological advances have allowed the widespread genomic profiling of tumors. As yet, however, the vast catalogues of mutations that have been identified have made only a modest impact on clinical medicine. Massively parallel sequencing has informed our understanding of the genetic evolution and heterogeneity of cancers, allowing us to place these mutational catalogues into a meaningful context. Here, we review the methods used to measure tumor evolution and heterogeneity, and the potential and challenges for translating the insights gained to achieve clinical impact for cancer therapy, monitoring, early detection, risk stratification, and prevention. We discuss how tumor evolution can guide cancer therapy by targeting clonal and subclonal mutations both individually and in combination…

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Next Generation Sequencing Assay for Blood Cancers

Researchers Develop Targeted Next Generation Sequencing Assay for Myeloid Neoplasms

via GIPHY

Researchers from South Korea said they have developed a next-generation sequencing (NGS) assay to detect somatic mutations, translocations, and germline mutations in a single assay for the purpose of supplementing or replacing conventional tests in patients with myeloid neoplasms.

Writing in a recent issue of PLoS One, the researchers said were able to discover a high frequency of germline mutations in cancer predisposition genes. Patients with these mutations exhibited different clinical characteristics, suggesting that germline predisposition has significant clinical implications.

Lowering the barrier to stem cell therapies

Team develops iPS cells with less chance of being rejected

Researchers developed a way to produce induced pluripotent stem (iPS) cells with a lower risk of rejection, overcoming a major obstacle to the clinical application of regenerative medicine.

A team headed by Akitsu Hotta, a junior associate professor at Kyoto University’s Center for iPS Cell Research and Application (CiRA), used genome editing technology to change the structure of genes to create safer iPS cells. The findings were published in the U.S. scientific journal Cell Stem Cell on March 8.

Although using donor blood of third-party individuals results in cheaper and faster iPS cell production, the procedure poses a higher risk of immune rejection after transplantation.

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Deep sequencing of Adult Gliomas has promising results

Prospective Clinical Sequencing of Adult Glioma

Siyuan Zheng, Kristin Alfaro-Munoz, Wei Wei, Xiaojing Wang, Fang Wang, Agda Karina Eterovic, Kenna R Mills Shaw, Funda Meric-Bernstam, Gregory N Fuller, Ken Chen, Roel G. Verhaak, Gordon B. Mills, W.K. Alfred Yung, Shiao-Pei Weathers and John F. de Groot

Molecular Cancer Therapeutics (Research Article)

Abstract—Malignant gliomas are a group of intracranial cancers associated with disproportionately high mortality and morbidity. Here we report ultradeep targeted sequencing of a prospective cohort of 237 tumors from 234 patients consisting of both glioblastoma (GBM) and lower-grade glioma (LGG) using our customized gene panels. We identified 2485 somatic mutations including single nucleotide substitutions and small indels using a validated in-house protocol. Sixty one percent of the mutations were contributed by 12 hypermutators. The hypermutators were enriched for recurrent tumors, had comparable outcome, and most were associated with temozolomide exposure. TP53 was the most frequently mutated gene in our cohort, followed by IDH1 and EGFR. We detected at least one EGFR mutation in 23% of LGGs, which was significantly higher than 6% seen in TCGA, a pattern that can be partially explained by the different patient composition and sequencing depth. IDH hotspot mutations were found with higher frequencies in LGG (83%) and secondary GBM (77%) than primary GBM (9%). Multivariate analyses controlling for age, histology, and tumor grade confirm the prognostic value of IDH mutation. We predicted 1p/19q status using the panel sequencing data, and received only modest performance by benchmarking the prediction to Fluorescent In Situ Hybridization (FISH) results of 50 tumors. Targeted therapy based on the sequencing data resulted in three responders out of 14 participants. In conclusion, our study suggests ultradeep targeted sequencing can recapitulate previous findings and can be a useful approach in the clinical setting.

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CRISPR cut slows aging

Recently Developed Gene Therapy Assists To Slow Down Aging Process

Aging is a key risk factor for numerous debilitating conditions. It includes cancer, heart disease, and Alzheimer’s disease. This situation triggers the anti-aging treatments all the more critical. Recently, the researchers at Salk Institute proclaimed that they have developed a novel gene therapy to assist decelerate this aging process.

The findings of this research can be accessed in the journal Nature Medicine. The study highlights a new CRISPR/Cas9 genome-editing therapy. It holds an ability to curb the accelerated aging observed in mice suffering from Hutchinson-Gilford progeria syndrome. This is an uncommon genetic disorder that is found to be afflicting humans as well. The latest treatment offers key insight into the molecular pathways engaged in accelerated aging. It also highlights how to minimize toxic proteins using gene therapy. Juan Carlos Izpisua Belmonte, Professor, Gene Expression Laboratory, Salk, is the senior author of this study. He proclaimed that aging is a complicated process in which cells begin losing their functionality.

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Or read the original article HERE …

RNA-based method for killing cancer cells

Scientists may have found a way to kill cancer cells without chemotherapy

• Researchers at Northwestern have discovered a genetic "kill code" that might enable the destruction of cancer cells.

• This novel new therapy "downstream" of chemo might destroy cancer cells without affecting the body's immune system.

• While no animal trials have been conducted, this potential therapy could signal the demise of chemotherapy.

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6mer seed toxicity in tumor suppressive microRNAs

6mer seed toxicity in tumor suppressive microRNAs

Quan Q. Gao, William E. Putzbach, Andrea E. Murmann, Siquan Chen, Aishe A. Sarshad, Johannes M. Peter, Elizabeth T. Bartom, Markus Hafner, & Marcus E. Peter

Nature Communications (Research Article)

Abstract—Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2–7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing a preference for guanine in positions 1 and 2 and a high overall G or C content in the seed of the most toxic siRNAs for four tested human and mouse cell lines. Toxicity of these siRNAs stems from targeting survival genes with C-rich 3′UTRs. The master tumor suppressor miRNA miR-34a-5p is toxic through such a G-rich 6mer seed and is upregulated in cells subjected to genotoxic stress. An analysis of all mature miRNAs suggests that during evolution most miRNAs evolved to avoid guanine at the 5′ end of the 6mer seed sequence of the guide strand. In contrast, for certain tumor-suppressive miRNAs the guide strand contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.

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‘Jumping genes’ drive many cancers

‘Jumping genes’ drive many cancers

Mistakes in DNA are known to drive cancer growth. But a new study, from Washington University School of Medicine in St. Louis, heavily implicates a genetic phenomenon commonly known as “jumping genes” in the growth of tumors.

The study is published March 29 in the journal Nature Genetics.

Since jumping genes aren’t mutations — mistakes in the letters of the DNA sequence — they can’t be identified by traditional cancer genome sequencing. As such, this study opens up new lines of research for future cancer therapies that might target such genes.

Jumping genes, which scientists call transposable elements, are short sections of the DNA sequence that have been incorporated randomly into the genome over the long course of human evolution. The evolutionary histories of jumping genes are the subject of much current research, but viral infection is thought to play an important role in their origins.

Researchers led by Ting Wang, PhD, the Sanford C. and Karen P. Loewentheil Distinguished Professor of Medicine, have plumbed genomic databases, looking specifically for tumors whose jumping genes are driving cancer growth.

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