Researchers at the Stanford University School of Medicine have linked chronic fatigue syndrome to variations in 17 immune-system signalling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity.
The findings provide evidence that inflammation is a powerful driver of this mysterious condition, whose underpinnings have eluded researchers for 35 years.
“Chronic fatigue syndrome can turn a life of productive activity into one of dependency and desolation,” said Jose Montoya, MD, professor of infectious diseases, who is the study’s lead author. Some spontaneous recoveries occur during the first year, he said, but rarely after the condition has persisted more than five years.
The study’s senior author is Mark Davis, PhD, professor of immunology and microbiology and director of Stanford’s Institute for Immunity, Transplantation and Infection.
“There’s been a great deal of controversy and confusion surrounding myalgic encephalomyelitis (ME) CFS — even whether it is an actual disease,” said Davis. “Our findings show clearly that it’s an inflammatory disease and provide a solid basis for a diagnostic blood test.”
Many, but not all, ME/CFS patients experience flulike symptoms common in inflammation-driven diseases, Montoya said. But because its symptoms are so diffuse —sometimes manifesting as heart problems, sometimes as mental impairment nicknamed “brain fog,” other times as indigestion, diarrhea, constipation, muscle pain, tender lymph nodes and so forth — it often goes undiagnosed, even among patients who’ve visited a half-dozen or more different specialists in an effort to determine what’s wrong with them.
The sporadic effectiveness of antiviral and anti-inflammatory drugs has spurred Montoya to undertake a systematic study to see if the inflammation that’s been a will-o’-the-wisp in those previous searches could be definitively pinned down.
To attack this problem, he called on Davis, who helped create the Human Immune Monitoring Center. Since its inception a decade ago, the centre has served as an engine for large-scale, data-intensive immunological analysis of human blood and tissue samples. Directed by study co-author Holden Maecker, PhD, a professor of microbiology and immunology, the centre is equipped to rapidly assess gene variations and activity levels, frequencies of numerous immune cell types, blood concentrations of scores of immune proteins, activation states of intercellular signalling models, and more on a massive scale.
This approach is akin to being able to look for and find larger patterns — analogous to whole words or sentences — in order to locate a desired paragraph in a lengthy manuscript, rather than just try to locate it by counting the number of times in which the letter A appears in every paragraph.
The scientists analysed blood samples from 192 of Montoya’s patients, as well as from 392 healthy control subjects. The average age of patients and controls was about 50. Patients’ average duration of symptoms was somewhat more than 10 years.
Importantly, the study design took into account patients’ disease severity and duration. The scientists found that some cytokine levels were lower in patients with mild forms of ME/CFS than in the control subjects, but elevated in ME/CFS patients with relatively severe manifestations. Averaging the results for patients versus controls with respect to these measures would have obscured this phenomenon, which Montoya said he thinks may reflect different genetic predispositions, among patients, to progress to mild versus severe disease.
When comparing patients versus control subjects, the researchers found that only two of the 51 cytokines they measured were different. Tumour growth factor beta was higher and resistin was lower in ME/CFS patients. However, the investigators found that the concentrations of 17 of the cytokines tracked disease severity. Thirteen of those 17 cytokines are pro-inflammatory.
TGF-beta is often thought of as an anti-inflammatory rather than a pro-inflammatory cytokine. But it’s known to take on a pro-inflammatory character in some cases, including certain cancers. ME/CFS patients have a higher than normal incidence of lymphoma, and Montoya speculated that TGF-beta’s elevation in ME/CFS patients could turn out to be a link.
One of the cytokines whose levels corresponded to disease severity, leptin, is secreted by fat tissue. Best known as a satiety reporter that tells the brain when somebody’s stomach is full, leptin is also an active pro-inflammatory substance. Generally, leptin is more abundant in women’s blood than in men’s, which could throw light on why more women than men have ME/CFS.

Stanford Medicinehttp://tinyurl.com/y7agngxn

In a newly published study, Cleveland Clinic researchers have uncovered differences in the bacterial composition of breast tissue of healthy women vs. women with breast cancer. The research team has discovered for the first time that healthy breast tissue contains more of the bacterial species Methylobacterium, a finding which could offer a new perspective in the battle against breast cancer.
Bacteria that live in the body, known as the microbiome, influence many diseases.
Most research has been done on the “gut” microbiome, or bacteria in the digestive tract. Researchers have long suspected that a “microbiome” exists within breast tissue and plays a role in breast cancer but it has not yet been characterized. The research team has taken the first step toward understanding the composition of the bacteria in breast cancer by uncovering distinct microbial differences in healthy and cancerous breast tissue.
“To my knowledge, this is the first study to examine both breast tissue and distant sites of the body for bacterial differences in breast cancer,” said co-senior author Charis Eng, M.D., Ph.D., chair of Cleveland Clinic’s Genomic Medicine Institute and director of the Center for Personalized Genetic Healthcare. “Our hope is to find a biomarker that would help us diagnose breast cancer quickly and easily.  In our wildest dreams, we hope we can use microbiomics right before breast cancer forms and then prevent cancer with probiotics or antibiotics.”
The study examined the tissues of 78 patients who underwent mastectomy for invasive carcinoma or elective cosmetic breast surgery. In addition, they examined oral rinse and urine to determine the bacterial composition of these distant sites in the body.
In addition to the Methylobacterium finding, the team discovered that cancer patients’ urine samples had increased levels of gram-positive bacteria, including Staphylococcus and Actinomyces. Further studies are needed to determine the role these organisms may play in breast cancer.
Co-senior author Stephen Grobymer, M.D., said, “If we can target specific pro-cancer bacteria, we may be able to make the environment less hospitable to cancer and enhance existing treatments. Larger studies are needed but this work is a solid first step in better understanding the significant role of bacterial imbalances in breast cancer.” Dr. Grobmyer is section head of Surgical Oncology and director of Breast Services at Cleveland Clinic.

Cleveland Clinic
newsroom.clevelandclinic.org/2017/10/05/cleveland-clinic-researchers-find-link-between-bacterial-imbalances-and-breast-cancer/

An international team that just conducted the largest study of Tourette Syndrome has identified genetic abnormalities that are the first definitive risk genes for the disorder.
Although Tourette has long been thought to have a genetic basis — because the syndrome tends to appear in families — before now no definitive risk genes had been found. The breakthrough came when researchers focused on a relatively new area of genomics research that takes a broader look at the entire genome, rather than searching for a particular gene, says Peristera Paschou, Purdue University associate biology professor.
"Most times we focus on a mutation of a single base pair, which are the building blocks of DNA, and look for a mutation. But in recent years we’ve realized that there is another type of variation of the human genome," Paschou says.
Scientists have been exploring how often short sections of genes are repeated through the entire genome, how these repetitions might vary among individuals, and whether these repetitions, which are called copy number variants, have an effect on health.
"These variations may involve a large part of the DNA sequence and may even include whole genes. We have only very recently begun to understand how copy number variation may relate to disease," she says. "In the case of this research on Tourette Syndrome, we scanned the entire genome, and through physical analysis, we were able to identify where this variation lies.
"We rarely find variants that are associated at such a high level. This is why this is such a big breakthrough."
Dr. Jeremiah Scharf, of the Psychiatric & Neurodevelopmental Genetics Unit in the Massachusetts General Hospital Departments of Psychiatry and Neurology and the Massachusetts General Hospital Center for Genomic Medicine, co-senior author of the report, says this is a significant finding.
"The challenge of recognizing that Tourette Syndrome is not a single gene disorder, and that a stringent statistical certainty is required in order to declare a gene to be significantly associated with it, has been our long-term aim," he says. "We believe that what sets our study apart from prior studies is that the two genes we have identified both surpassed the stringent threshold of ‘genome-wide significance,’ and so, represent the first two definitive Tourette Syndrome susceptibility genes."

Purdue University
www.purdue.edu/newsroom/releases/2017/Q2/tourette-syndrome-risk-increases-in-people-with-genetic-copy-variations.html

Neuroscientists have uncovered the genetic basis for why many long-term survivors of childhood cancer develop meningiomas, the most common adult brain tumour, decades after their treatment with cranial radiation.
The findings show that radiation causes genetic rearrangements in DNA that result in meningiomas, say co-principal investigators Gelareh Zadeh, neurosurgeon-scientist, Head of Surgical Oncology, and Ken Aldape, neuropathologist-scientist, Director, MacFeeters-Hamilton Neuro-Oncology Research Program, Princess Margaret Cancer Centre, University Health Network.
Dr. Zadeh is an Associate Professor, Division of Neurosurgery, and holds the Wilkins Family Chair in Brain Tumor Research; and Dr. Aldape, Professor, Laboratory Medicine and Pathobiology, both at University of Toronto.
The study compared and contrasted the biology of radiation-induced meningiomas (RIMs) to those that appear sporadically in the general population.
"Radiation-induced meningiomas appear the same on MRI and pathology, feel the same during surgery and look the same under the operating microscope. What’s different is they are more aggressive, tend to recur in multiples and invade the brain, causing significant morbidity and limitations (or impairments) for individuals who survive following childhood radiation," says Dr. Zadeh.
The research team analysed RIMs from patients who had received cranial-spinal radiation as children; the majority of whom (74 per cent) had survived either leukaemia or paediatric brain cancer. The study also showed that RIMs developed regardless of the radiation dose by collaborating with scientists in Germany where low-dose radiation was a common treatment many years ago for scalp ringworm.
"By understanding the biology, the goal is to identify a therapeutic strategy that could be implemented early on after childhood radiation to prevent the formation of these tumours in the first place," says Dr. Zadeh.
Dr. Aldape says: "It is an important clinical problem because it presents a paradoxical dilemma that while cranial-spinal radiation is needed to cure many childhood cancers, an unfortunate consequence is that 10-to-15-years following radiation treatment some survivors develop meningiomas.
"Our research identified a specific rearrangement involving the NF2 gene that causes radiation-induced meningiomas. But there are likely other genetic rearrangements that are occurring as a result of that radiation-induced DNA damage. So one of the next steps is to identify what the radiation is doing to the DNA of the meninges."
He adds: "In addition, identifying the subset of childhood cancer patients who are at highest risk to develop meningioma is critical so that they could be followed closely for early detection and management."

Princess Margaret Cancer Centre, University Health Network
www.uhn.ca/corporate/News/PressReleases/Pages/brain-tumour-scientists-map-mutation-that-drives-tumours-in-childhood-cancer-survivors-treated-with-radiation-decades-earl.aspx

For the first time, scientists have provided unbiased estimates of the number of mutations needed for cancers to develop, in a study of more than 7,500 tumours across 29 cancer types. Researchers from the Wellcome Trust Sanger Institute and their collaborators adapted a technique from the field of evolution to confirm that, on average, 1 to 10 mutations are needed for cancer to emerge.
The results also show the number of mutations driving cancer varies considerably across different cancer types.
In the study, the team developed an approach to discovering which genes are implicated in cancer evolution and how many mutations in those genes drive cancer. In the future, such approaches could be used in the clinic to identify which few mutations in an individual patient are driving his or her cancer, from amongst the thousands of mutations present.
Over 150 years ago, Charles Darwin described how different species evolve through the process of natural selection. Cancers also develop by natural selection, acting on the mutations that accumulate in the cells of our bodies over time. In this study, scientists applied an evolutionary perspective to quantifying natural selection in 7,664 tumours across 29 different cancers.
One of the striking findings of the study was that mutations are usually well-tolerated by cells in the body. This was surprising because mutations that individuals inherit from their parents are often poorly tolerated, and are generally lost from the human species over time. In the body’s cells, however, as a cancer develops, nearly all mutations persist without impacting on the survival of the cell.
The team also catalogued the main cancer genes responsible for 29 different cancer types. Researchers discovered several new cancer genes and determined how complete the current lists of cancer genes are.
“We have addressed a long-standing question in cancer research that has been debated since the 1950s: how many mutations are needed for a normal cell to turn into a cancer cell? The answer is – a small handful. For example, about four mutations per patient on average drive liver cancers, whereas colorectal cancers typically require 10 or so driver mutations.”
Dr Peter Campbell, lead author on the study, from the Wellcome Trust Sanger Institute
“In the study, we revealed that around half of these key mutations driving cancer occur in genes that are not yet identified as cancer genes. There is already much insight into the most important genes involved in cancer; but there are many more genes yet to be discovered. We will need to bring together even larger numbers of cancers studied by DNA sequencing, into the tens of thousands, to find these elusive genes.”

Sanger Institute
www.sanger.ac.uk/news/view/1-10-mutations-are-needed-drive-cancer-scientists-find