Patients with colorectal cancer have the same consistent changes in the gut bacteria across continents, cultures, and diets — a team of international researchers, from University of Copenhagen among others, find in a new study. The hope is the results in the future can be used to develop a new method of diagnosing colorectal cancer.
Cancers have long been known to arise due to environmental exposures such as unhealthy diet or smoking. Lately, the microbes living in and on our body have entered the stage as key players. But the role that gut microbes play in the development of colorectal cancer – the third most common cancer worldwide – is unclear. To determine their influence, association studies have aimed to map how the microbes colonizing the gut of colorectal cancer patients are different from those that inhabit healthy subjects.
Now, researchers from University of Copenhagen, EMBL, the University of Trento, and their international collaborators have analysed multiple existing microbiome association studies of colorectal cancer together with newly generated data. Their meta-analyses establish disease-specific microbiome changes, which are globally robust – consistent across seven countries on three continents – despite differences in environment, diet and life style.
“During disease our microbiome may change. If these changes are consistent in each person getting the same disease then it is a signature of disease. What we show in our study is that the gut microbiome signatures in colorectal cancer seem to be universal. This is despite geography, culture and life style. In the future we hope we can use these signatures as biomarkers and as a diagnostic tool for colorectal cancer,” says Manimozhiyan Arumugam, Associate Professor at the Novo Nordisk Foundation Center for Basic Metabolic Research.
It is the first time a meta-analyses for colorectal cancer has been done on this scale. In the study, the researchers have analyzed and used data from seven cohorts from the countries China, Austria, France, Germany, the US, Italy and Japan.
“We used a rigorous machine learning analysis to identify microbial signatures for colorectal cancer. We validated these signatures in early cancer stages and in multiple studies, so they can serve as the basis for future non-invasive cancer screening,” explains Georg Zeller from the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany.
University of Copenhagen https://tinyurl.com/y4mx25au

Leeches are blood-feeding organisms that have a suite of anticoagulant compounds they secrete from their salivary glands that prevent blood clotting. This allows them to maximize feeding time and blood volume. Leeches are still used in modern medicine, and knowledge about their anticoagulants is important in many ways, from rodent control to understanding host-parasite relationships. A recent study expands our knowledge about the diversity of anticoagulants in two families of leeches.
The authors of an article recently published in the Journal of Parasitology collected leeches from natural and aquarium settings in the United States and Canada. The researchers examined the physical characteristics of each leech to determine their species, dissected the leech salivary glands, extracted the RNA and sequenced the genomic material. Next, they identified the salivary gland components by comparing their sequences with those of other leeches and various animals.
The researchers identified the collected leeches as nine species from the Piscicolidae and Ozobranchidae families, which are composed of saltwater species that feed on fish and turtles, respectively. Despite the fact that these leeches have different host preferences, no differences were found in the diversity of anticoagulants. There was an average of 43 anticoagulants in each species, and the researchers identified several anticoagulants that didn’t match any sequences and others that had never before been linked to leeches. For example, they found sequences that matched ohanin, which is a protein found in king cobra venom. These results suggest that there is a possible connection between anticoagulants in leeches and snake venom and should be explored further.
Michael Tessler, one of the authors of this article, points out why this study is unique among the literature on anticoagulants: “What I believe makes this paper stand out is the broad scope. Our results highlight that looking at individual species is not a great proxy for family-level anticoagulant diversity and that studies need to take a broader look to fully understand what is going on.” Sampling many species and comparing sequences to a broad array of organisms, therefore, could help uncover new information.
The authors also constructed phylogenetic trees, diagrams that show evolutionary relationships, and concluded that leeches may have evolved to have anticoagulants that are beneficial to them. These new leech anticoagulant sequences not only aid in our understanding of the diversity of these compounds, but also provide clues about how leech evolution plays a role in the host-parasite relationship.
http://www.journalofparasitology.org/doi/full/10.1645/17-64

G-protein-coupled receptors (GPCRs) are everywhere in our bodies. They are embedded in our cell membranes, where they act as signal transducers, allowing cells to respond to their external environments. GPCRs play a crucial role in most biological functions, including heart rate, blood pressure, vision, smell, taste and allergic responses. GPCR malfunction can lead to a number of diseases, and many therapeutic drugs work because they influence these proteins. Yet the basics of GPCR structure and functions are not well understood.
Researchers at University of California San Diego School of Medicine have unravelled new insights into the way cells leverage GPCRs and their cellular waste disposal systems to control inflammation. The findings suggest some existing cancer drugs that inhibit these cellular activities might be repurposed to treat vascular inflammation, which occurs when artery-blocking plaques form in atherosclerosis.
“We were surprised to discover that GPCRs and inflammation are influenced by ubiquitination — a process that was previously thought to only mark proteins for destruction,” said senior author JoAnn Trejo, PhD, professor in the Department of Pharmacology and associate dean of faculty affairs at UC San Diego School of Medicine. “Instead, we’ve unveiled new insights into both GPCR function and ubiquitination.”
When a molecule, such as a nutrient, binds to a GPCR on the outside of the cell, the GPCR changes shape. On the other side of the membrane, inside the cell, a G-protein docks on the newly re-positioned GPCR. Depending on the type of signal and cell, that G-protein then kicks off a cascade of molecular events.
Trejo and team focused on endothelial cells, the type that line blood vessels. In that context, they studied how GPCR functions are influenced by ubiquitination — a process in which enzymes tag proteins with small molecules called ubiquitin. Usually, an ubiquitin tag tells the cell’s garbage disposal machinery that a protein is ready for degradation. But in this case, ubiquitination has a different function.
The researchers found that the GPCR turns on an E3 ligase, the very enzyme that does the ubiquitinating, which triggers a cascade of molecular events that ultimately turn on another protein, p38, which in turn promotes inflammation.
According to Trejo, a handful of drugs that inhibit E3 ubiquitin ligases have been approved by the Food and Drug Administration (FDA) for the treatment of some cancers, including multiple myeloma and mantle cell lymphoma, and several others have entered clinical trials.
“But given the large number of E3 ligases in the human body — there are between 600 and 700 — and their diverse functions, the number of E3-targeting drugs approved or in clinical trials is remarkably small,” Trejo said. “And this is the first time E3 ligases have been shown to also play a role in vascular inflammation, which broadens the potential applications for drugs that inhibit these enzymes. The field is really in its infancy.”

University of California – San Diego
medschool.ucsd.edu/som/medicine/Pages/default.aspx

An international study led by University of Manchester scientists has discovered the identity of genes that predispose people to chronic kidney disease.
The discovery is a major advance in understanding the significantly under-diagnosed disorder which, if left undetected, can lead to failing kidneys that need dialysis or kidney transplantation.
The discovery of 35 kidney genes is an important step forward to the future development of new diagnostic tests and treatments for the disease that affects around one in ten adults.
The team, based in Poland, Australia and the UK have published the Kidney Research UK-funded study in Nature Communications.
Lead researcher Professor Maciej Tomaszewski from The University of Manchester said: “Chronic kidney disease is known for its strong genetic component. Our limited knowledge of its exact genetic mechanisms partly explains why progress in the development of new diagnostic tests and treatments of chronic kidney disease has been so slow. The findings were made possible by using a state-of-the art technology known as “next-generation RNA sequencing” applied to one of the largest ever collections of human kidneys. We hope that some of the kidney genes we discovered may become attractive targets for the development of future diagnostics and treatment for patients with chronic kidney disease.”
Co-author Professor Adrian Woolf from Manchester Children’s Hospital and The University of Manchester said: “One of the genes – mucin-1- is especially interesting. It makes a sticky protein called mucin that coats urinary tubes inside the kidney. Mutations of this gene have already been found in rare families with inherited kidney failure.”
University of Manchester

The use of genetic tests aimed at detecting the presence of mutations in the BRCA1 and BRCA2 genes in women with breast cancer is rapidly declining in favour of tests that can detect multiple cancer-associated mutations, according to researchers at the Stanford University School of Medicine and five other U.S. medical centres.
Some researchers had wondered whether multigene testing, which may identify genetic mutations of uncertain clinical significance, would lead more women to consider prophylactic mastectomies — a surgery in which both breasts are removed to prevent future cancers — out of an abundance of caution. However, the current study did not show an increase in mastectomies associated with testing more genes. 
The shift reflects a growing acknowledgement by clinicians that multigene panel tests can yield more clinically useful information for patients and their unaffected relatives, the researchers said.
Overall, multigene panels were about twice as likely as the tests for BRCA1 and BRCA2 to identify disease-associated genetic variants, the study found. However, multigene testing was more likely than the BRCA-only testing to be delayed until after surgery to remove the tumour. This time lag may limit a patient’s treatment options, the researchers said.
 “In general, multigene panel tests yield more clinically useful results and are rapidly becoming the norm,” said Allison Kurian, MD, associate professor of medicine and of health research and policy at Stanford. “Newly diagnosed women should ask their doctors whether they may be appropriate candidates for genetic testing. They should also advocate for the opportunity to discuss genetic testing and its implications with an experienced clinician, such as a genetic counselor, in a timely manner.”
In general, multigene panel tests yield more clinically useful results and are rapidly becoming the norm.
Multigene panel tests are more likely than BRCA-only tests to yield information about both a patient and her family members, who may be unwitting carriers of disease-associated mutations. “This is very important because it offers the opportunity for genetically targeted, primary cancer prevention in unaffected relatives,” said Kurian, who is a member of the Stanford Cancer Institute. “Some prior research has shown that this ‘cascade testing’ of unaffected relatives is cost-effective, and there are currently several initiatives underway to improve upon the delivery and success rates of cascade testing.”

Stanford School of Medicine
med.stanford.edu/news/all-news/2018/05/multigene-testing-replacing-brca-tests-for-breast-cancer-risk.html