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New proteins discovered that link obesity-driven diabetes to cancer

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The findings, which appear in PLOS ONE, show that reducing levels in pancreatic beta cells of individual BRDs, called BET proteins, previously shown to play a role in cancer, may also help patients who are obese and diabetic.

The research was led by Gerald V. Denis, PhD, associate professor of pharmacology and medicine at Boston University School of Medicine, who was the first to show that BET protein functions are important in cancer development.

Adult-onset diabetes has been known for decades to increase the risk for specific cancers. The three main members of the BET protein family, BRD2, BRD3 and BRD4, are closely related to each other and often cooperate. However at times, they work independently and sometimes against each other.

According to the researchers new small molecule BET inhibitors have been developed that block all three BET proteins in cancer cells, but they interfere with too many functions.

“The BET proteins provide a new pathway to connect adult-onset diabetes with cancer, so properly targeting BET proteins may be helpful for both,” explained Denis, who is the corresponding author of the study.

He believes this discovery shows the need for deeper analysis of individual BET proteins in all human cell types, starting with boosting insulin and improving metabolism in the pancreas of adults who are obese.

“Without better targeted drugs, some ongoing cancer clinical trials for BET inhibitors are premature. These new results offer useful insight into drug treatments that have failed so far to appreciate the complexities in the BET family.”

Source: www.bu.edu

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Blood test can predict risk of developing tuberculosis

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Now, an international team of researchers has identified biological markers in the blood of latently infected people that may give doctors a tool they have long sought: a way to predict who is at high risk of developing active TB. If validated through additional clinical trials, a test based on these blood biomarkers would allow doctors to target therapies to at-risk people, thus preventing them from getting sick.

The decade-long research effort was led by investigators from the South African Tuberculosis Vaccine Initiative at the University of Cape Town, and the Center for Infectious Disease Research, Seattle. It was funded in part by the National Institutes of Health.

The biomarkers were identified in two stages. First, researchers collected blood samples for two years from more than 6,000 Mtb-infected but otherwise healthy adolescent volunteers in South Africa. Analysis of the samples revealed patterns of gene expression that differed between volunteers who eventually developed TB and those who remained healthy. This risk “signature,” confined to a set of 16 genes, could be detected in a blood sample as early as 18 months before the infected person developed active TB.

Next, the team confirmed the genetic risk signature’s predictive ability in a study of more than 4,500 volunteers in South Africa and The Gambia. Volunteers in this study were healthy but lived with people who had recently been diagnosed with active TB. The second study group was more varied in age, health status, ethnicity and exposure to locally common strains of Mtb than volunteers in the first study. Despite the differences, the same risk signature found in the first study was detected in the people who eventually developed active TB during the second trial.

 

Source: www.sciencedaily.com

Does a common parasite play a role in rage disorder?

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T. gondii tissue cyst

In recent years, a common parasitic infection – as many as a third of the world’s population may have it – has been linked to a range of psychiatric disorders, including schizophrenia and bipolar disorder, as well as behavioral dysregulation such as suicide attempts and car accidents. Now a new study has linked it to repeated bouts of rage, a disorder known as intermittent explosive disorder (IED).

The study, released March 23 in the Journal of Clinical Psychiatry, found that people with IED are more than twice as likely to have been exposed to a common parasite than healthy individuals with no psychiatric diagnosis.

“This is the first time we’ve confirmed this idea in humans,” said Teodor Postolache, a professor of psychiatry at the University of Maryland School of Medicine, the last author of the study. “It indicates that this parasite could be having significant effects on anger-related emotions and behavior in people with mental illness.” The study was based on the combined expertise in aggression and inflammation of the authors, University of Chicago psychiatry professor Emil Coccaro, the first author, and Dr. Postolache’s knowledge of T. gondii and neuroimmunology.

The study looked at 358 adults, and found that chronic latent infection with Toxoplasma gondii is associated with intermittent explosive disorder and increased aggression.

Those with IED have recurrent, impulsive, problematic outbursts of verbal or physical aggression that are disproportionate to the situations that trigger them. It affects as many as 16 million Americans.

Transmitted through the feces of infected cats, undercooked meat or contaminated water, chronic toxoplasmosis is typically latent and harmless for healthy adults. However, Toxoplasma it is known to reside in slow growing forms in brain tissue, and has the potential to intermittently reactivate.

The research team examined 358 adults, who were evaluated for IED, personality disorder, depression and other psychiatric disorders. Subjects were also analyzed for personality traits, including anger, aggression and impulsivity. Participants fell into one of three groups: about a third had IED. A third were healthy controls with no psychiatric history. The remaining third were individuals diagnosed with some psychiatric disorder, but not IED. This last group served as a control to distinguish IED from other psychiatric factors.

The study found that the IED group was more than twice as likely to test positive for toxoplasmosis, compared to the healthy control group. Around 16 percent of the psychiatric control group tested positive for toxoplasmosis, but had similar aggression and impulsivity scores to the healthy control group. IED-diagnosed subjects scored much higher on both measures than either control group.

Coccaro and Postolache caution that the study results do not address whether Toxoplasma infection actually cause increased aggression or IED.

Postolache and his colleagues are continuing their work on the relationship between Toxoplasma gondii, impulsivity and aggression in collaborations with researchers from Sweden (people who have recently attempted suicide) and Germany (aggression, impulsivity, and the neurotransmitter dopamine. If better understood, this connection may inform new strategies to predict and manage aggression and impulsivity, major factors implicated in violence towards self and others.

Source: Eurekalert

 

New sensitive method for early detection of amyloidosis in humans

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This new probe is extremely sensitive and was used at very low concentrations to correctly identify every positive amyloidosis sample when compared to the traditional clinical tests. The probe also picked up some amyloidosis signals that the traditional methods were unable to detect. This result means that the new probe could be used to detect amyloidosis before symptoms present, leading to faster and hence more effective treatment.

Amyloidosis is a general term for several different types of disease. Aggregates of amyloid proteins form and deposit in different tissues which can affect the normal function. As the disease progresses and amyloid deposits grow, tissues become irreversibly damaged. Amyloid deposits can be found in many different organs leading to a wide range of possible symptoms and making diagnosis challenging.

To date, the primary mode of diagnosis for amyloidosis has been the Congo red stain. However, evidence from the Linköping team, presented in Amyloid Journal show that their new probe is much more sensitive, being able to detect small amyloid deposits in samples that were previously determined to be amyloid-free.

“Given the sensitivity of the probe, we think this would make an excellent complement to traditional methods and could eventually be a replacement”, says lead investigator Per Hammarström, professor at Linköping University.

According to the U.S. Office of Rare Diseases (ORD), a subsidiary of the National Institute of Health (NIH), amyloidosis is a rare disease, affecting less than 200,000 people in the U.S.. However, The Amyloidosis Foundation suspects that the figures are underreported and that amyloidosis is not that rare – just rarely diagnosed. A more sensitive diagnostic method would help to uncover the reality of the situation.

The Linköping team are optimistic about the use of the probe. “It could also be used to identify new types of amyloids and presymptomatic patients who are at risk of developing the disease”, says Hammarström and collaborator professor Peter Nilsson.

Research is continuing in this important field. In the future, the researchers hope to apply this to other diseases where amyloids are present and develop real-time, non-invasive diagnostic probes.

Source: sciencedaily.com

 

Study finds vast diversity among viruses that infect bacteria

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Now, a new study at Washington University School of Medicine in St. Louis suggests that bacteriophages made of RNA – a close chemical cousin of DNA – likely play a much larger role in shaping the bacterial makeup of worldwide habitats than previously recognized.

The research, publishing on March 24 in the Open Access journal PLOS Biology, identifies 122 new types of RNA bacteriophages in diverse ecological niches, providing an opportunity to define their contributions to ecology, and potentially to fight bacterial infections, particularly those resistant to antibiotics.

“Lots of DNA bacteriophages have been identified, but there’s an incredible lack of understanding about RNA bacteriophages,” explained senior author David Wang, PhD, associate professor of molecular microbiology. “They have been largely ignored – relatively few were known to exist, and for the most part scientists haven’t bothered to look for them. This study puts RNA bacteriophages on the map and opens many new avenues of exploration.”

Wang estimates that of the more than 1,500 bacteriophages that have been identified, 99 percent of them have DNA genomes. The advent of large-scale genome sequencing has helped scientists identify DNA bacteriophages in the human gut, skin and blood as well as in the environment, but few researchers have looked for RNA bacteriophages in those samples.

First author Siddharth Krishnamurthy and the team, including Dan Barouch, MD, PhD, Beth Israel Deaconess Medical Center and Harvard Medical School, identified RNA bacteriophages by analyzing data from oceans, sewage, soils, crabs, sponges and barnacles, as well as insects, mice and rhesus macaques.

RNA bacteriophages have been shown to infect gram-negative bacteria, which have become increasingly resistant to antibiotics and are the source of many infections in health care settings. But the researchers also showed for the first time that these bacteriophages may also infect gram-positive bacteria, responsible for strep and staph infections as well as MRSA.

“What we know about RNA bacteriophages in any environment is limited,” Wang said. “But you can think of bacteriophages and bacteria as having a predator-prey relationship. We need to understand the dynamics of that relationship. Eventually, we’d like to manipulate that dynamic to use phages to selectively kill particular bacteria.”

Source:

 

Current hepatitis C virus testing guidelines miss too many cases, study suggest

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A review of blood samples for nearly 5,000 patients seen at The Johns Hopkins Hospital Emergency Department suggests that federal guidelines for hepatitis C virus (HCV) screening may be missing up to a quarter of all cases and argues for updated universal screening.

A report on the study is published online ahead of print in the journal Clinical Infectious Diseases.

Currently, the U.S. Centers for Disease Control and Prevention (CDC) recommends one-time HCV testing for all adults born between 1945 and 1965, or for those with risk factors such as injection drug use, HIV or use of clotting factors. But up to one-quarter of infections could remain undiagnosed, according to results of the new study, and the authors say that universal one-time testing of all U.S. adults seeking care at inner-city emergency rooms might identify many more people who have the virus, getting them into management and treatment. Better screening would also reduce the risk of spreading the infection to others.

In November 2015, The Johns Hopkins Hospital expanded its testing for HCV to all eligible Emergency Department adults 18 and older who have their blood drawn as part of routine clinical care and are not known to be HCV antibody-positive. Johns Hopkins Bayview Medical Center adopted this expanded testing protocol in February 2016. The Johns Hopkins team specifically found that nearly 14 percent of patients among the 5,000 tested positive for HCV, one-third of whom were unaware they were infected.

“Hepatitis C has a very long clinical arc, so if you get infected, you may not have obvious signs of illness for five to 10 years. Ultimately, it eats away at the liver in many people and can cause liver cancer,” says senior study author Thomas C. Quinn, M.D., professor of medicine and pathology at the Johns Hopkins University School of Medicine. “This is an infection that can now be cured if detected early, rendering people noninfectious and thereby preventing the dire consequences that are associated with the virus. However, we found a large proportion of undocumented, undiagnosed hepatitis C infection in the population attending this ED.”

Many people with risk factors like injection drug use don’t disclose their risk information to emergency department staff, so universal testing, “in addition to the CDC recommendations, is the only way to identify as many HCV infections as possible,” adds lead study author Yu-Hsiang Hsieh, Ph.D., an associate professor in Johns Hopkins’ Department of Emergency Medicine.

“We found high prevalence rates of HCV even in young adult patients, suggesting we need to expand testing beyond the baby boomer cohort,” Hsieh says. “Urban EDs should consider expanding CDC HCV testing recommendations to permit more robust identification of patients with unknown HCV status.”

For the study, the researchers examined blood samples from 4,713 patients older than 17 presenting to The Johns Hopkins Hospital’s Emergency Department between June and August 2013. Of these patients, 652 (13.8 percent) were HCV antibody-positive, meaning they either had HCV currently or at a prior time, and 204 (31.3 percent) of those who tested positive had undocumented HCV infection. Patients born between 1945 and 1965 had an HCV prevalence of about 25 percent compared with adults born outside this range, who had an HCV prevalence of 7 percent. These baby boomers also had a higher prevalence of undocumented HCV — about 7 percent versus 2.6 percent in other adults tested. Non-African-American men and women as young as 18 to 34 (born between 1979 and 1995) had a high HCV prevalence of up to 7.6 percent.

Among the 204 Emergency Department patients with undocumented HCV infection, 128 (63 percent) were in the 1945 to 1965 birth cohort, 45 (22 percent) were injection drug users and 10 (5 percent) were known to be infected with HIV. Further assessments by the researchers found that 99 (49 percent) would be diagnosed based on birth cohort testing alone, with an additional 54 (26 percent) identified based on modified CDC risk-based testing (based on injection drug use or known HIV status).

“Had we established an emergency room HCV testing program with just these guidelines, 51 patients (25 percent) with undocumented HCV would not have been identified during our study period,” Hsieh says. “Given an estimated 7,727 unique ED patients with HCV infection in a one-year period, birth cohort testing would identify 1,815 undocumented infections, but universal testing would identify an additional 526 cases.”

The results also underscore the need for federal and state HCV management and treatment resources to support emergency departments and HCV patients, Quinn and Hsieh say. “It sounds easy to do HCV testing for every eligible patient, but it takes a lot of effort,” Hsieh says.

In the near future, the investigators hope to examine the cost-effectiveness of different HCV screening approaches in the emergency department setting, including universal testing and CDC-recommended birth cohort testing. But with a projected 3.2 million people infected with HCV in the U.S. alone, it’s critical for all of these patients to be identified, treated and cured, say the researchers.

“It’s not often that we get to say we can cure a medical condition,” says Hsieh. “So when we can, we should implement protocols that allow us to easily identify those in need.”

Source: hopkinsmedicine.org

 

2016 AACR Annual Meeting presentations highlight advances in cancer DNA biomarker research using Bio-Rad’s Droplet Digital PCR technology

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Featuring research from 20 global oncology investigators, the presentations will focus on the application of ddPCR to detect cancer biomarkers in liquid biopsies and monitor patient response to treatment.

“As a practicing thoracic oncologist, I’ve seen DNA biomarkers emerge as some of our most powerful tools for predicting benefit from targeted therapies,” said Geoffrey Oxnard, MD, Assistant Professor of Medicine at the Dana-Farber Cancer Institute and Harvard Medical School.

Many cancer researchers have turned to cfDNA in blood, urine, and other body fluids as noninvasive biomarkers to understand how genetic changes — mutations, rearrangements, and copy number variations — influence cancer development and its evolution.

Early Prostate Cancer Biomarkers Discovered

Conventional approaches for prostate cancer detection are invasive and often lack specificity. Instead of relying on tumor samples, Tulane University researchers investigated the potential of monitoring cfDNA from urine. Using ddPCR, the team screened urine samples of prostate cancer patients for single nucleotide polymorphisms (SNPs) they had established as being associated with prostate cancer. The group identified two SNPs with the potential of being developed as a noninvasive diagnostic assay for early detection of prostate cancer.

ddPCR Allows Detection of Single Cancer DNA Molecules

One of the difficulties in detecting DNA-based cancer biomarkers is their low abundance compared to DNA from healthy cells. A Stanford University research team has developed a ddPCR assay that is capable of detecting and quantifying cancer mutations in samples with low mutation abundance such as archival tissue DNA and circulating tumor DNA. This assay can detect nearly any cancer mutation down to single DNA molecule resolution, including known actionable mutations in oncogenes such as BRAF and KRAS.

cfDNA Shown To Be a Valuable Pharmacodynamic Biomarker of KRAS-Mutant Lung Cancer

Phase 1 clinical trials have historically focused on toxicity studies but are increasingly collecting information on pharmacodynamics (PD), the dose-dependent effect a drug has on the body. A team of Dana-Farber Cancer Institute (DFCI) researchers, including Dr. Oxnard and colleagues from the Belfer Center for Applied Cancer Science, have shown proof of principle in early phase clinical trials that plasma cfDNA, as measured by ddPCR, is a valuable PD biomarker in KRAS-mutant non-small-cell lung cancer in early phase clinical trials.

ddPCR Validates Copy Number Variations in Hereditary Prostate Cancer

Prostate cancer is the second leading cause of death in American men — more than 27,000 men will die of the disease in the U.S. this year, according to the National Cancer Institute. A family history of prostate cancer is a prominent risk factor, but identifying an individual’s genetic susceptibility to prostate cancer has been challenging due to genetic heterogeneity. Louisiana State University Health Sciences Center New Orleans researchers will present findings that show how using ddPCR for absolute quantification of copy number variations in germ line DNA may help facilitate screening in hereditary prostate cancer families.

“Ideally, in the long term, our findings will play a significant role in the diagnosis of prostate cancer in the world of precision medicine,” said Diptasri Mandal, PhD, Professor of Genetics at LSU Health Sciences Center New Orleans.

Bio-Rad To Host Exhibitor Spotlight Presentation: “Moving Toward Clinically Actionable Liquid Biopsies with Digital PCR”

Filip Janku, MD, PhD, from the University of Texas MD Anderson Cancer Center, will discuss liquid biopsy applications in patients with advanced cancers. These applications include detection of targets for cancer therapy, prognostic evaluation, therapeutic monitoring, and real-time monitoring of clonal evolution. David Polsky, MD, PhD, from the Ronald O. Perelman Department of Dermatology at NYU Langone Medical Center, will present a recent study that compares the clinical sensitivity of BRAF and NRAS mutant detection in cfDNA with the current standard blood biomarker for monitoring disease in patients with metastatic melanoma.

 

For more information about ddPCR, please visit http://www.bio-rad.com/AACR2016PR.

The QX200 Droplet Digital PCR System and Automated Droplet Generator are for research use only and are not intended for use in diagnostic procedures.

Source: Eurekalert

 

New asthma biomarkers discovered, could ease detection

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There are currently no definitive diagnostic tests for asthma, a common chronic inflammatory lung disease that affects 25 million Americans.

“Right now, we diagnose asthma based on someone’s history and breathing tests — and both of those have limitations,” said Faoud T. Ishmael, associate professor of medicine and biochemistry and molecular biology.

There are also several sub-types of the condition, such as allergic or non-allergic asthma or the presence or absence of immune cells called eosinophils. The different variations make asthma harder to treat.

Some asthma patients do not find relief from inhaled corticosteroids, the mainstay of asthma treatment. Asthma sub-types could play a role in this but “there’s not a good way right now to understand what those different sub-types are,” Ishmael said. “This goes back to the underlying issue, which is that we don’t have a good blood test to tell us what’s really going on in the lungs.”

To that end, Ishmael set his sights on microRNAs (miRNAs) — molecules that help regulate gene expression. miRNAs were once considered “junk DNA”, but over the past decade, scientists have come to realize that they play an important role in many human diseases.

More than 150 miRNAs can be identified in blood, and they are beginning to be used as molecular footprints to diagnose and characterize diseases such as cancer.

“The role of miRNAs in asthma is not well understood, although it looks as though these molecules play very important roles in inflammation and in immune responses,” Ishmael said.

His team previously showed that miRNAs in the lungs and blood can be used as asthma biomarkers, and that they may regulate proteins involved in allergic inflammation. However, important questions remained. For example, would people with asthma have different miRNA than people with other related conditions?

In their new study, the researchers looked at miRNAs in the blood of 79 people. The subjects included asthmatics, people with nasal allergies but no asthma and people with no nasal allergies and no asthma. Results were published in The Journal of Allergy and Clinical Immunology.

Narrowing in on 30 miRNAs important in allergies and asthma, the researchers found different expression patterns among the three groups. Based on these patterns, they were able to predict with 91 percent accuracy whether or not a person had asthma, opening the door to the development of a diagnostic blood test.

“We found that there was a subset of these miRNAs that were unique to asthma, and that we could use them to predict if someone had it based on if they were high or low compared to the other two groups,” Ishmael said. “There’s a different molecular fingerprint if you have asthma compared to if you have allergic rhinitis or neither.”

Importantly, within asthmatics there were two main clusters of miRNA expression that correlated with different levels of eosinophil immune cells.

“Eosinophils play very important roles in some kind of allergic reactions, and they might have implications for how people respond to some of the treatments that are already on the market for asthma,” Ishmael said. “We think this may be useful technology to distinguish between some of these different sub-types so we know from the beginning when a treatment won’t work for a patient.”

Ishmael also hopes the research will lead to new asthma treatments. miRNAs are not just biomarkers — some of them are directly involved in the development of disease. Now that a panel of asthma-related miRNAs is emerging, researchers may be able to develop drugs to target these specific molecules.

“We know that a lot of these microRNAs actually have roles in inflammation,” Ishmael said. “Some of them promote inflammation and some of them inhibit inflammation. If you’re lacking one that’s important in maintaining a normal state, you might actually be able to replace that.”

The researchers plan to further investigate the role of different miRNAs in asthma and find out what happens when those molecules are inhibited.

They’re also working to validate the diagnostic value of miRNA testing for asthma in a larger group of people.

“Our goal is to have a blood test for asthma developed in the next five years,” Ishmael said. “You might be able to take a drop of blood from a finger stick and analyze it in the clinic to determine whether someone has asthma at that visit. That would be the ultimate goal.”

Source: news.psu.edu

 

Researchers find new clue in lupus autoantibody production

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Systemic lupus erythematosus (SLE) is the most common form of lupus. In patients with SLE, the immune system forms autoantibodies that attack the body’s own cells, causing inflammation and tissue damage. How these rogue antibodies form is an important area of interest for lupus researchers.

When a pathogen like a virus invades the body, immune cells called B lymphocytes multiply to fight the foreigner. These groups of B lymphocytes produce antibodies specifically designed to fight the invader or turn into antibody-secreting cells and memory B cells that will help protect the next time the same pathogen is encountered.

In both humans and mice with lupus, groups of B lymphocytes (B cells) spontaneously arise in the absence of a pathogenic infection. Instead of producing antibodies to fight an infection, these groups pump out specialized autoantibodies that attack healthy tissue. These attacks on the body’s own cells are the hallmark of an autoimmune disorder.

Autoantibody-secreting B cells and memory B cells that continuously generate autoantibodies are also created, setting the body up for ongoing attacks, chronic inflammation and — over time — organ damage.

But what factors drive the development of those B cells, called autoreactive B cells that produce autoantibodies?

In work led by Ziaur S.M. Rahman, assistant professor of microbiology and immunology, a team at Penn State College of Medicine found that a cytokine — a cell-signaling protein — called interferon gamma may play a role. The research was published online April 11 in the Journal of Experimental Medicine.

Interferon gamma stimulates immune cells as part of the normal immune response to infection. Earlier studies showed that people with SLE tend to have higher levels of interferon gamma, and lupus mice that are deficient in it have reduced autoantibody production and less severe renal disease, a major lupus complication.

To find out if interferon gamma is behind the formation of B lymphocyte groups that produce autoantibodies, the researchers looked at lupus mice whose interferon gamma receptors on B cells had been removed.

These mice did not form the damaging B cell groups, while lupus mice that still had intact interferon gamma receptors did. The mice without interferon gamma receptors also had lower levels of autoantibodies involved in lupus compared to the lupus mice with normal numbers of receptors.

“This suggests that interferon gamma signaling in B cells is critical for the formation of spontaneously-developed B lymphocyte groups and autoimmunity,” Rahman said. “If you could target this interferon gamma signaling pathway in B cells, you could potentially treat lupus.”

The researchers also discovered that normal B lymphocyte groups could produce antibodies to fight real infections even in the absence of interferon gamma signaling.

The current treatment options for SLE are limited to the use of immunosuppressive agents that reduce immune function in general and make patients susceptible to infection. An intervention targeting the interferon gamma pathway could be an improvement for lupus patients, as it would eliminate spontaneously developed groups of B cells that produce autoantibodies and keep normal B cell responses intact to fight against infection, Rahman said.

 

Source: PennState

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