Study: Aspirin Reduces Cancer Risk

The largest and longest study of long-term, regular aspirin use finds that the drug may lead to a modestly reduced risk for some types of gastrointestinal cancers.

Regularly taking aspirin for years may protect users people from some types of gastrointestinal (GI) cancers, especially colorectal cancer, according to Harvard researchers presenting their work yesterday (April 19) at the annual American Association for Cancer Research (AACR) meeting being held in Philadelphia. But long-term aspirin use may also come with an elevated risk of adverse effects, such as GI bleeding, cautioned Yin Cao, a research fellow at the Harvard School of Public Health who coauthored the study. “You need to consider the risk of [prolonged aspirin use],” Cao told The Scientist during an AACR poster session where she presented the work.“Previous studies of aspirin and cancer have been limited in terms of their size, length of follow-up, or ability to examine aspirin use in the context of other lifestyle factors,” she said in a statement. “Our research provides critical information regarding the full constellation of potential benefits of aspirin use, at a range of doses, timing, and duration of use, within a large population of individuals.”

Cao and her colleagues considered data collected from more than 100,000 men and women who had enrolled in separate studies in the 1980s. The researchers found an overall 5 percent decreased risk for all cancers in people who reported taking two or more aspirin tablets per week. This decrease was driven mostly by a 20 percent reduction in risk for GI cancers (including a 25 percent drop in colorectal cancer risk). There were no reductions in risk for breast, advanced prostate, lung, or other non-GI cancers associated with aspirin use, Cao added.Other studies had collected data on cancer in relation to aspirin use, but the Harvard study followed more people for longer (up to 32 years). Cao and her colleagues showed that significant risk reductions for developing cancer came only after 16 years of using the drug, and the effects dissipated four years after discontinuing aspirin use. “Dose and duration both help,” Cao said.She added that her team, which includes Andrew Chan of Harvard Medical School, is now working to genetically characterize subsets of patients who may show an enhanced response to long-term, regular aspirin use with regard to cancer.

Chan, who has previously served as a consultant for Bayer Healthcare, Pfizer, and Pozen, is today (April 20) presenting on some of the ways the team is researching the mechanisms behind aspirin’s apparent effects on cancer risk reduction.

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Drugs that activate brain stem cells may reverse multiple sclerosis

Washington, DC – Two drugs already on the market – an antifungal and a steroid – may potentially take on new roles as treatments for multiple sclerosis. According to a study published in Nature today, researchers discovered that these drugs may activate stem cells in the brain to stimulate myelin producing cells and repair white matter, which is damaged in multiple sclerosis. The study was partially funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

Specialized cells called oligodendrocytes lay down multiple layers of a fatty white substance known as myelin around axons, the long “wires” that connect brain cells. Myelin acts as an insulator and enables fast communication between brain cells. In multiple sclerosis there is breakdown of myelin and this deterioration leads to muscle weakness, numbness and problems with vision, coordination and balance.

“To replace damaged cells, the scientific field has focused on direct transplantation of stem cell-derived tissues for regenerative medicine, and that approach is likely to provide enormous benefit down the road. We asked if we could find a faster and less invasive approach by using drugs to activate native nervous system stem cells and direct them to form new myelin. Our ultimate goal was to enhance the body’s ability to repair itself,” said Paul J. Tesar, Ph.D., associate professor at Case Western Reserve School of Medicine in Cleveland, and senior author of the study.

It is unknown how myelin-producing cells are damaged, but research suggests they may be targeted by malfunctioning immune cells and that multiple sclerosis may start as an autoimmune disorder. Current therapies for multiple sclerosis include anti-inflammatory drugs, which help prevent the episodic relapses common in multiple sclerosis, but are less effective at preventing long-term disability. Scientists believe that therapies that promote myelin repair might improve neurologic disability in people with multiple sclerosis.

Adult brains contain oligodendrocyte progenitor cells (OPCs), which are stem cells that generate myelin-producing cells. OPCs are found to multiply in the brains of multiple sclerosis patients as if to respond to myelin damage, but for unknown reasons they are not effective in restoring white matter. In the current study, Dr. Tesar wanted to see if drugs already approved for other uses were able to stimulate OPCs to increase myelination.

OPCs have been difficult to isolate and study, but Dr. Tesar and his colleagues, in collaboration with Robert Miller, Ph.D., professor at George Washington University School of Medicine and Health Sciences in Washington, D.C., developed a novel method to investigate these cells in a petri dish. Using this technique, they were able to quickly test the effects of hundreds of drugs on the stem cells.

The compounds screened in this study were obtained from a drug library maintained by NIH’s National Center for Advancing Translational Sciences (NCATS). All are approved for use in humans. NCATS and Dr. Tesar have an ongoing collaboration and plan to expand the library of drugs screened against OPCs in the near future to identify other promising compounds.

Dr. Tesar’s team found that two compounds in particular, miconazole (an antifungal) and clobetasol (a steroid), stimulated mouse and human OPCs into generating myelin-producing cells.

Next, they examined whether the drugs, when injected into a mouse model of multiple sclerosis, could improve re-myelination. They found that both drugs were effective in activating OPCs to enhance myelination and reverse paralysis. As a result, almost all of the animals regained the use of their hind limbs. They also found that the drugs acted through two very different molecular mechanisms.

“The ability to activate white matter cells in the brain, as shown in this study, opens up an exciting new avenue of therapy development for myelin disorders such as multiple sclerosis,” said Ursula Utz, Ph.D., program director at the NINDS.

Dr. Tesar and his colleagues caution that more research is needed before miconazole and clobetasol can be tested in multiple sclerosis clinical trials. They are currently approved for use as creams or powders on the surfaces of the body but their safety administered in other forms, such as injections, in humans is unknown.

“Off-label use of the current forms of these drugs is more likely to increase other health concerns than alleviate multiple sclerosis symptoms. We are working tirelessly to ready a safe and effective drug for clinical use,” Dr. Tesar said.

This work was supported by the NINDS (NS085246, NS030800, NS026543), the New York Stem Cell Foundation and the Myelin Repair Foundation, New York City.

The NINDS is the nation’s leading funder of research on the brain and nervous system. The mission of NINDS is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.

The National Center for Advancing Translational Sciences is a distinctly different entity in the research ecosystem. Rather than targeting a particular disease or fundamental science, NCATS focuses on what is common across diseases and the translational process. The Center emphasizes innovation and deliverables, relying on the power of data and new technologies to develop, demonstrate and disseminate advancements in translational science that bring about tangible improvements in human health. For more information, visit http://www.ncats.nih.gov.

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Previously unknown effect of vitamin A identified

Researchers at Lund University in Sweden have identified a previously unknown effect of vitamin A in human embryonic development. Their findings show that vitamin A affects the formation of blood cells.

The signal molecule, retinoic acid, is a product of vitamin A which helps to instruct how different types of tissue are to be formed in the growing embryo. For the first time, Professor Niels-Bjarne Woods’ laboratory, Lund Stem Cell Center in Sweden, has studied the effects of retinoic acid in relation to how blood cells develop from human stem cells. In the laboratory model, the stem cells are exposed to specific signal molecules, thereby developing into blood-producing cells.The researchers observed that increased levels of retinoic acid drastically reduced the number of blood cells that could be produced. A reduction in the retinoic acid instead increased the production of blood cells by 300 per cent. On the basis of these results, Niels-Bjarne Woods and his colleagues propose a new explanatory model of how retinoic acid affects the embryonic development of blood.Even if vitamin A is required for a normal pregnancy, it has long been known that too much vitamin A can be damaging to the foetus, with the risk of foetal malformation and miscarriage. Pregnant women have therefore been recommended to limit their consumption of foods that are high in vitamin A in the form of retinoids, such as liver.“Our results show that vitamin A in high doses has a negative effect on blood development. This suggests that there is an additional reason for pregnant women to avoid excessive intake of vitamin A during pregnancy,” says Niels-Bjarne Woods.While the concept that retinoic acid affects blood cell development has been demonstrated in animal models, this is the first time the experiments have been done using human cells.

Niels-Bjarne Woods’ research is about finding ways of artificially generating blood stem cells for use in blood stem cell transplants to patients with blood disorders and cancers, who do not have access to a suitable donor.

“The current research findings increase our understanding of the complexity of the process of blood formation during embryonic development. We hope that this, together with new future discoveries, will lead to the generation of blood stem cells in the laboratory, which in turn can be used to treat blood disorders and malignancies,” says Niels-Bjarne Woods.

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Gene sheds light on development of type 1 diabetes, autoimmune disease

Written by Catharine Paddock PhD

13 May 2015

Type 1 diabetes and multiple sclerosis are types of autoimmune disease – where the immune system attacks the body’s own tissue. Autoimmunity is a complex process, and scientists do not fully understand how it begins. Now, a new study finds an important clue in a gene called Clec16a that appears to control how immune system T cells are primed to attack targets.

When the study team, including Stephan Kissler, assistant professor of medicine at Harvard Medical School, Boston, MA, turned the gene off in mice genetically engineered to develop diabetes, the vast majority of the animals did not develop the disease.

The researchers believe the discovery brings closer the day when we will be able to prevent diabetes.

They report their findings in the journal Immunity.

Prof. Kissler, an immunology investigator at Harvard’s Joslin Diabetes Center, says they think the reason Clec16a is associated with so many different types of autoimmune disease is because it plays a key role in a process at the heart of the immune system. He explains:

“It’s nothing that’s specific for type 1 diabetes, it’s nothing that’s specific to multiple sclerosis. The way T cells are selected is something that’s common to all these diseases.”

CLEC16A IS INVOLVED IN THE DEVELOPMENT OF TYPE 1 DIABETES THROUGH AUTOPHAGY

Autophagy is a process that goes on in all cells. Literally it means “eat oneself,” and is the process through which cells digest their own waste proteins and put the recycled material on their cell surfaces – like putting out the trash.Autophagy can be activated for different reasons. For instance, if there is a shortage of nutrients or if cells are infected with a virus.

However, epithelial cells in the thymus – a specialized immune system organ that resides behind the breastbone and above the heart – use autophagy in a different way. They use it to show T cells which proteins belong in the body and which should be eliminated.

The researchers showed that the Clec16a gene is involved in the development of type 1 diabetes through the process of autophagy.

Prof. Kissler explains:

“By changing autophagy in TECs [thymic epithelial cells] you change T cell selection, and by changing T cell selection you change the risk of autoimmune disease.”

Switching Clec16a off in diabetes-prone mice significantly reduced risk of disease

For their study, he and his colleagues turned the gene off in 40 mice engineered to develop type 1 diabetes. Only 2 mice developed diabetes compared to 60% in another group of similar mice that were left to develop naturally. While the team could see that switching off Clec16a made a big difference, they could not see which organ was involved or how the effect came about.

Through a series of transplant experiments, they found that the gene regulates T cell education indirectly in the thymus.

The team has achieved similar results with other genes before, but nothing as dramatic as with Clec16a, says Prof. Kissler. In a further investigation, the team found that Clec16a is also involved in of human cell autophagy.They now plan to find out if Clec16a affects T cell education in the human thymus. Prof. Kissler concludes:

“All we know for now is the gene has an effect on human autophagy. Is the same true in human thymus? How does that compare to what we’ve described in the mouse?”

Discovering that Clec16a plays the same role in the human thymus as in the mouse, would be a big step toward solving the mystery of how a complicated diseases like type 1 diabetes, multiple sclerosis and other autoimmune disorders develop.

Earlier this year, Medical News Today learned of another study that found women with multiple sclerosis may have a lower intake of anti-inflammatory and antioxidant nutrients, such as folate, vitamin E and magnesium. However, the researchers could not say if this is a cause or an effect of the disease.

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Major clinical trial supports early treatment for all HIV patients

It is estimated that around 35 million people worldwide are living with HIV – the virus that can progress to deadly AIDS. Now, an international randomized clinical trial funded by the National Institutes of Health finds that antiretroviral therapy is much more likely to be successful in halting HIV progression the sooner treatment is started.

The findings come from the Strategic Timing of AntiRetroviral Treatment (START) study, initiated in 2011 to determine the effects of earlier antiretroviral therapy (ART) for people withHIV (human immunodeficiency virus).The study reveals that HIV-infected people are much more likely to benefit from the treatment when they have higher levels of CD4+ T cells – immune cells that fight infection and disease – than lower levels. Since higher levels of these cells occur early in HIV infection, the findings indicate ART should be started early.The benefits of earlier ART for people with HIV were so clear in the clinical trial that an independent data safety and monitoring board (DSMB) recommended that the results be released early – the study was expected to cease at the end of next year.

The research team, including Dr. Jens Lundgren of the University of Copenhagen in Denmark, says combined with previous data showing ART lowers the risk of transmitting HIV to sexual partners, their findings suggest the treatment should be offered to all individuals with the virus.

“This is an important milestone in HIV research,” says Dr. Lundgren. “We now have strong evidence that early treatment is beneficial to the HIV-positive person. These results support treating everyone irrespective of CD4+ T-cell count.”

RISK OF SERIOUS ILLNESS, DEATH MORE THAN HALVED WITH EARLY ART

For the trial, 4,685 HIV-infected men and women aged 18 and older from 215 regions over 35 countries were enrolled. Prior to the study, none of the participants had received ART.At the time of enrollment, all participants had a normal CD4+ cell count – defined as 500 cells per cubic millimeter (cells/mm3) or higher.Half of the participants were randomized to receive ART immediately, while the remaining participants started ART when their CD4+ cell count fell to 350 cells/mm3.All individuals were followed for an average of 3 years. During this time, the researchers monitored the development of both serious AIDS (acquired immunodeficiency virus) events (such as AIDS-related cancer) and serious non-AIDS events (such as cardiovascular diseases, cancer and renal and liver disease), as well as death rates among all participants.

A DSMB analysis of the data conducted in March this year identified 86 cases of AIDS, serious non-AIDS events and deaths among participants whose ART was deferred, while there were 41 such cases among participants who received immediate treatment with ART.

What is more, the analysis revealed the risk of death or development of serious illness was 53% lower among participants treated with ART early, compared with those whose treatment was deferred.

The results revealed that the risk of both serious AIDS and serious non-AIDS events was lower among participants who received early ART than those who received deferred ART, and this reduced risk was strongest for AIDS events.The study findings were consistent across all regions, according to the analysis, and participants from low-, middle- and high-income countries showed similar benefits from early ART.Commenting on the findings, Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), says:

“We now have clear-cut proof that it is of significantly greater health benefit to an HIV-infected person to start antiretroviral therapy sooner rather than later.

Moreover, early therapy conveys a double benefit, not only improving the health of individuals but at the same time, by lowering their viral load, reducing the risk they will transmit HIV to others. These findings have global implications for the treatment of HIV.”

FINDINGS STRONGLY SUPPORT US HIV TREATMENT GUIDELINES

While HIV treatment guidelines in the US recommend that all individuals with HIV undergo ART regardless of their CD4 count, guidelines from the World Health Organization (WHO) state that HIV-infected individuals should begin ART when their CD4 count falls to 500 cells/mm3 or lower.

The START findings are strongly in support of the US guidelines – with researchers claiming they provide “concrete scientific evidence” that all people with HIV should receive early ART.

“The study was rigorous and the results are clear,” say principal investigator James D. Neaton, PhD, a professor of biostatistics at the University of Minnesota. “The definitive findings from a randomized trial like START are likely to influence how care is delivered to millions of HIV-positive individuals around the world.”

The trial findings have been welcomed by UNAIDS – a joint United Nations program working to tackle the global AIDS crisis.”This is a further demonstration of the importance of science and research that enables an evidence-based, people-centered response to HIV that leaves no one behind,” says UNAIDS Executive Director Michel Sidibé.”Every person living with HIV should have immediate access to life-saving antiretroviral therapy,” he adds. “Delaying access to HIV treatment under any pretext is denying the right to health.”

Earlier this month, pharmaceutical giant GlaxoSmithKline (GSK) and the University of North Carolina at Chapel Hill announced they are teaming up to created a HIV Cure center dedicated to finding a way to eradicate the virus.GSK will be investing $20 million into the center – $4 million each year for a period of 5 years – which will be used to advance recent scientific approaches for combatting HIV, such as the “shock and kill” approach. This involves uncovering dormant HIV in immune cells and triggering the patient’s immune system to destroy the virus.

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RESEARCHERS HAVE DISCOVERED TWO NEW GROUPS OF VIRUSES.

Researchers at the University of Bonn and the German Center for Infection Research (DZIF) have discovered two new groups of viruses within the Bunyavirus family in the tropical forest of the Ivory Coast. Previously only five groups responsible for serious illnesses in humans and animals were known with previous studies stating that most are spread through blood-feeding insects. Based on the discovered viruses researchers conclude that the ancester to all bunyaviruses must have existed in arthropods such as insects. The study is published in the journal Proceedings of the National Academy of Sciences (PNAS).

The team state that the bunyavirus family includes five different groups of viruses which trigger serious illnesses in humans and animals and which can also cause significant damage to vegetables, such as tomatoes. The first viruses of this family were discovered in a place known as Bunyamwera in Uganda, from which they derive their name.

Previous studies report that the most well-known bunyaviruses include, for example, the Rift Valley fever virus, which can cause febrile illnesses with severe bleeding in humans. In 2011 the ‘Schmallenberg virus’, also a part of the Bunyavirus family and transmitted by gnats, gained much attention when it caused severe fetal malformations in ruminant animals including sheep in the German Sauerland region.

The current study focused on the African tropical forest of the Ivory Coast where the team has been conducting research for more than ten years. Because most bunyaviruses are transmitted by blood-sucking insects the researchers caught more than 7500 mosquitoes. Sorted according to species and sites of capture, the mosquitoes were combined into 432 mixed samples. In 26 of these samples, the researchers discovered particles of unknown bunyaviruses.

The data findings showed that there were two groups of as-yet-unknown viruses that the team named Jonchet virus and Ferak virus. The group then obtained fragments of the viral genetic material from the insect samples and joined these fragments together like a puzzle, reconstructing the entire genome sequence over four years. During the comparison of the genetic information with other viruses, it was found that Jonchet and Ferak viruses are two phylogenetically independent bunyavirus lineages.

The team then investigated how dangerous the two new groups of viruses are and how easily they can be transmitted to humans and animals.  They performed infection trials in a large number of cell cultures at different temperature levels. While pathogenic bunyaviruses can multiply at temperatures that include the human body temperature, growth of Jonchet and Ferak viruses ceases above 32 degrees Celsius, making it unlikely that the viruses infect humans or other vertebrates.  In addition, they reconstructed the evolutionary history of host associations of the entire family of viruses, demonstrating for the first time that viruses affecting vertebrates developed from arthropod-specific viruses.

The team surmise that virologists are now reaching out to discover the plethora of unknown viruses lurking in natural reservoirs such as insects, in an attempt to forecast pandemic risks.  The researchers hope that their temperature test for estimating the risk of vertebrate infection can be useful for assessing other viruses that are currently being discovered.

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Source:  University of Bonn Medical Centre

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NEW BIOMARKER FOR LUNG CANCER.

RESEARCHERS DISCOVER ‘HIGHLY EFFECTIVE’ NEW BIOMARKER FOR LUNG CANCER IN HUMAN TRIALS.

Survival rates for patients with lung cancer increase dramatically the earlier the disease is diagnosed, underscoring the need for effective biomarkers that can be used for detection. Now, scientists at The Wistar Institute have found a protein that circulates in the blood that appears to be more accurate at detecting non-small cell lung cancer (NSCLC) than currently available methods used for screening.  The opensource study is published in the journal Oncotarget.

The team state that if the accuracy of this biomarker can be confirmed in a larger trial, this could lead to the development of a simple blood test that could be used for annual screening. They believe that this blood test would be easier to use, more accurate and less invasive than low-dose computed tomography (LDCT) scans, the method for lung cancer screening currently recommended by the U.S. Preventive Services Task Force (USPSTF). They go on to add that because of its accuracy, it could also better distinguish between benign lung tumours that do not pose a threat and malignant tumours that have the potential to grow and spread.

The team state that lung cancer is the leading cause of cancer deaths in both men and women in the United States. However, the five-year survival rate increases dramatically if the disease is caught and treated early. According to the American Cancer Society, if NSCLC is caught in its earliest stage, the five-year survival rate is 49 percent. However, patients who are diagnosed when the disease has metastasized, meaning that it has spread to other organs, have only about a 1 percent chance of achieving survival after five years.

In 2013, the USPSTF recommended annual screening to patients at least 55 years old who had a history of smoking and are therefore considered at high risk for developing lung cancer. Previous studies have shown that this method of screening is considered invasive and relatively expensive while not being highly accurate or widely available on a global scale.  The team state that there are many people who stand to benefit from a better diagnostic test for lung cancer and if a simple blood test can be developed that’s more accurate than low-dose CT scans, which can detect the cancer earlier with a less expensive, less invasive and more accurate blood test. Everyone stands to gain from such a test becoming available.

In the current study the team focused on cancer testis antigens (CTAs), since they are often found in tumour cells that circulate in the blood. After analyzing 116 different CTAs, the researchers identified the protein AKAP4 as a potential biomarker that could effectively distinguish between patients with and without NSCLC.

The researchers then tested AKAP4 as a biomarker in a pilot cohort that contained 264 blood samples from patients with NSCLC and 135 control samples. Of the 264 NSCLC samples, 136 samples were from patients who received a stage I diagnosis. The researchers analyzed the effectiveness of the biomarker by looking at the area under the curve (AUC), a method that calculates the ability of the test to distinguish those with disease from those without it. An AUC value of 1 means that the test perfectly distinguishes between the patients who have and don’t have a particular disease.

When the researchers compared all 264 of the NSCLC samples with the 135 control samples, the AUC was 0.9714. When the researchers looked at only the 136 samples with known stage I disease, the AUC was 0.9795. While the researchers noted that the presence of AKAP4 increased with the stage of the disease, AKAP4 was still detectable in the samples with early stage disease.

The results show that AKAP4 appears to be a highly effective biomarker for the detection of non-small cell lung cancer. If the team are able to confirm these results in a more robust study, then there is the potential for a new, more accurate screening method that could help save many, many lives.

With the positive results of this study the team will conduct a larger study with a goal of analyzing at least 800 samples. Multiple hospitals have agreed to provide blood samples for analysis to Wistar for this next study.

The team surmise that they have found a target that could result in a more accurate test than any method that’s been used to screen for non-small cell lung cancer to date.  They go on to add that with the government recommending annual screening for high-risk populations, the identification of a promising target like AKAP4 comes at a critical time. Early detection is needed in order to have a meaningful impact on this devastating disease.

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Source:  The Wistar Institute 

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NEW WHOLE BLOOD ASSAY IS THE FIRST TO IDENTIFY LATENT TB INFECTIONS.

A study by researchers at UT Southwestern Medical Center has identified how an enzyme involved in protecting the body from pathogens senses Mycobacterium tuberculosis (TB), a bacterial pathogen that infects millions of people worldwide and causes about 1.5 million deaths annually.  The team state that the new finding has potential implications for the development of immunity-based therapies to treat tuberculosis, which typically takes months to eradicate and has become increasingly resistant to antibiotics.  The opensource study is published in the journal Cell Host & Microbe.

The researchers explain that the enzyme, called cyclic GMP-AMP synthase (cGAS), acts as a sensor in the immune system and is essential for defense against the tuberculosis bacteria. When infected with TB, mice lacking this enzyme succumbed much quicker than mice with normal cGAS activity in the current study.  Based on the data finding the team believe that modulating cGAS activity could be a novel approach to therapy. They go on to state that there remains a dire need for new therapies against tuberculosis, and thus identifying pathways to stop the pathogen is of vital importance.

TB is a bacterial infection with widespread global reach, state the team. About one-third of the world’s population is infected with the bacterium, though most infected people have no symptoms and may not know they have it. Tuberculosis is the No. 1 cause of bacteria-related death and also the leading cause of death for people infected with HIV. TB is spread by airborne personal contact with an infected individual.  While TB is prevalent in underdeveloped countries, about 12,000 to 15,000 new cases arise in the U.S. annually, mainly in people who are immigrants from counties where TB is more endemic.

The researchers discovered the cGAS enzyme and how it orchestrates immune responses to DNA in 2012 .  They hypothesize that the current study finding that the cGAS pathway is important for sensing and defending against TB infection suggests that this pathway may be harnessed to develop better vaccines and therapeutics to protect people from this dreaded disease.

The current study showed that when tuberculosis is detected by cGAS, a compound called cyclic GMP-AMP (cGAMP) is produced. cGAMP then initiates a cell signaling cascade that triggers production of interferons and cytokines and activation of autophagy, an important host-defense mechanism. Thus, cGAMP could possibly be leveraged as a biomarker for active disease and therapy response, and could be used as an adjuvant for developing an effective TB vaccine or therapy.

The team surmise that the work and two similar studies also reported in Cell Host & Microbe point to cGAS as having strong potential for immunity-based therapeutics to combat TB, and potentially other infectious diseases.

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Activation of the DNA-dependent cytosolic surveillance pathway in response to Mycobacterium tuberculosis infection stimulates ubiquitin-dependent autophagy and inflammatory cytokine production, and plays an important role in host defense against M. tuberculosis. However, the identity of the host sensor for M. tuberculosis DNA is unknown. Here we show that M. tuberculosis activated cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) in macrophages to produce cGAMP, a second messenger that activates the adaptor protein stimulator of interferon genes (STING) to induce type I interferons and other cytokines. cGAS localized with M. tuberculosis in mouse and human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in human or mouse macrophages blocked cytokine production and induction of autophagy. Mice deficient in cGAS were more susceptible to lethality caused by infection with M. tuberculosis. These results demonstrate that cGAS is a vital innate immune sensor of M. tuberculosis infection. Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis. Shiloh et al 2015.

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Source:  UT Southwestern Medical Center

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Blood test for early stage pancreatic cancer looks promising!!!

Blood test for early stage pancreatic cancer looks promising

 Thursday 25 June 2015 at 3am PST

by Catharine Paddock PhD

Atudy that successfully differentiated patients with pancreatic cancer from those with another pancreatic disease using a new biomarker, could lead to a blood test that detects pancreatic cancer early enough for curative surgery to be feasible.

Pancreatic cancer has a very poor survival rate and ranks fourth as a leading cause of cancer deaths in the US, where around 46,000 people a year are diagnosed with the disease.

One reason the disease is so deadly is because by the time it is diagnosed, the tumor is too advanced for surgery to be an option – only about 15% of patients qualify for curative surgery.

However, if pancreatic cancer is spotted early, surgery that boosts chance of survival is more feasible, say researchers from the University of Texas MD Anderson Cancer Center in Houston.

In their study the team shows how a protein released by cancer cells into the bloodstream could be used to screen for early pancreatic cancer.

Cancer cells release the protein – which is coded by the gene glypican-1 (GPC1) – in small virus-sized particles called exomes. The exomes contain a mixture of DNA, RNA and proteins.

Blood test looks for cancer exomes

For the study, the team devised a blood test that looks for exomes enriched with the glypican-1 protein – these cancer exomes are called GPC1+ crExos.

A blood test based on these cancer exomes was able successfully to differentiate patients with pancreatic cancer from patients with another chronic pancreatic disease.

It passed both measures of a successful diagnostic test with top marks: specificity (correctly identifying patients with a disease) and sensitivity (correctly ruling out those without the disease), as senior author Raghu Kalluri, a professor in cancer biology, explains:

“GPC1+ crExos were detected in small amounts of serum from about 250 patients with pancreatic cancer with absolute specificity and sensitivity, importantly distinguishing patients with chronic pancreatitis from those with early- and late-stage pancreatic cancer.”

Prof. Kalluri says levels of the cancer exomes were significantly lower in patients after they had their tumors removed.

CANCER EXOMES COULD BE A MORE RELIABLE SCREEN THAN CIRCULATING TUMOR CELLS

The study also examined samples from breast cancer patients and found – like the pancreatic cancer patients – they also showed high levels of the GPC1+ crExos.

Prof. Kalluri notes that these protein-enriched exomes can be detected in blood samples that have been kept frozen for nearly 30 years. You can’t do this with circulating tumor cells (CTCs) – they require large amounts of fresh blood, he says.

He explains that these cancer exomes could also be useful in other ways:

“DNA, RNA and proteins can be isolated from cancer exosomes isolated from stored specimen for further genetic and biological analyses. Therefore, cancer exosomes are not just a biomarker but isolating them provides a trove of cancer-specific information.”

The team suggests cancer exomes appear to be a more reliable way to screen for pancreatic cancer than using the more common CA 19-9 biomarker test. Using the cancer exome test, they found precancerous lesions in mice bred to develop pancreatic cancer before they could be spotted on magnetic resonance imaging (MRI).

Prof. Kalluri says because they carry cancer-specific genetic material, the protein-enriched exomes could potentially enhance the specificity of MRI or CT scans, and concludes:

“Studies comparing stage of disease with outcome following surgery suggest that death rates for pancreatic cancer would be reduced if the disease were diagnosed at an earlier stage. This presents an unprecedented opportunity for informative early detection of pancreatic cancer and in designing potential curative surgical options.”

As well as the MD Anderson Cancer Center, The Cancer Prevention and Research Institute of Texas, and the National Cancer Institute (part of the by the National Institutes of Health) provided funds for the study.

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Avocado compound holds promise for treating leukemia!!!!

AVOCADO COMPOUND HOLDS PROMISE FOR TREATING LEUKEMIA

 16 June 2015 at 8am PST

They are responsible for one of our favorite Mexican dips and can brighten up any salad, but a new study finds there may be much more to avocados; a compound found in the fruit could help tackle acute myeloid leukemia.

Prof. Paul Spagnuolo, of the University of Waterloo in Ontario, Canada, and colleagues publish their findings in the journalCancer Research.

Acute myeloid leukemia (AML) is a cancer that begins in the bone marrow, where blood stem cells (immature cells) turn into mature blood cells. In AML, the blood stem cells in the bone marrow become abnormal myeloblasts – a form of white blood cell – red blood cells or platelets.

It is estimated that more than 20,000 people in the US will be diagnosed with AML this year, and more than 10,000 people will die from the cancer.

Most common among people aged 65 and older, AML has a poor survival rate, with around 90% of seniors with the cancer dying within 5 years of diagnosis.

But according to Prof. Spagnuolo and colleagues, there is a compound in avocados – called avocatin B – that holds promise for a new treatment for AML.

AVOCATIN B TARGETS AND DESTROYS LEUKEMIA STEM CELLS

Using a high-throughput cell-based screen to assess the effects of avocatin B on human leukemia stem cells, the researchers found the compound selectively targets and destroys them while leaving healthy blood cells unscathed.

“Not only does avocatin B eliminate the source of AML, but its targeted, selective effects make it less toxic to the body, too,” explains Prof. Spagnuolo.

While the researchers say it is many years before avocatin B can be used in clinical settings to treat AML, they have teamed up with Canada’s Centre for Commercialization of Regenerative Medicine (CCRM) to file a patent for the compound for this use.

“It’s an exciting time for our lab,” says Prof. Spagnuolo. “With the help of CCRM we are now pursuing commercial partnership that would take avocatin B into clinical trials.”

Avocatin B falls into a category of compounds known as nutraceuticals, defined as food-derived products that have potential clinical benefits.

Prof. Spagnuolo and colleagues say they are one of very few research teams globally who are applying the vigorous drug-investigation processes incorporated within the pharmaceutical industry to nutraceuticals.

While most researchers investigate food or plant extracts for their potential clinical use, Prof. Spagnuolo says using nutraceuticals offers a more clear-cut insight.

“Extracts are less refined,” he says. “The contents of an extract can vary from plant to plant and year to year, depending on lots of factors – on the soil, the location, the amount of sunlight, the rain.”

“Evaluating a nutraceutical as a potential clinical drug requires in-depth evaluation at the molecular level,” he adds. “This approach provides a clearer understanding of how the nutraceutical works, and it means we can reproduce the effects more accurately and consistently. This is critical to safely translating our lab work into a reliable drug that could be used in oncology clinics.”

This is not the first study to hail avocados for their potential health benefits. In January, Medical News Today reported on a study claiming that eating one avocado daily as a part of a moderate-fat diet could reduce levels of “bad” cholesterol among people who are overweight or obese.

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Immunotherapy heralds ‘new era’ for cancer treatment

by Honor Whiteman

A “whole new era” for cancer treatment is upon us, according to experts. Two new studies published in the New England Journal of Medicine provide further evidence that immunotherapy – the use of drugs to stimulate immune response – is highly effective against the disease.

Recently presented at the 2015 American Society for Clinical Oncology annual meeting, one study revealed that a drug combination of ipilimumab and nivolumab (an immune therapy drug) reduced tumor size in almost 60% of individuals with advanced melanoma – the deadliest form of skin cancer – compared with ipilimumab alone, while another study found nivolumab reduced the risk of lung cancer death by more than 40%.Nivolumab is a drug already approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma in patients who have not responded to ipilimumab or other medications. It is also approved for the treatment of non-small cell lung cancer (NSCLC) that has metastasized during or after chemotherapy.

According to cancer experts, however, the results of these latest studies indicate that nivolumab and other immune therapy drugs could one day become standard treatment for cancer, replacing chemotherapy.Prof. Roy Herbst, chief of medical oncology at Yale Cancer Center in New Haven, CT, believes this could happen in the next 5 years. “I think we are seeing a paradigm shift in the way oncology is being treated,” he told The Guardian. “The potential for long-term survival, effective cure, is definitely there.”

NIVOLUMAB PLUS IPILIMUMAB REDUCED TUMOR SIZE BY AT LEAST A THIRD FOR ALMOST 1 YEAR

Nivolumab belongs to a class of drugs known as “checkpoint inhibitors.” It works by blocking the activation of PD-L1 and PD-1 – proteins that help cancer cells hide from immune cells, avoiding attack.In a phase 3 trial, Dr. Rene Gonzalez, of the University of Colorado Cancer Center, and colleagues tested the effectiveness of nivolumab combined with ipilimumab – a drug that stimulates immune cells to help fight cancer – or ipilimumab alone in 945 patients with advanced melanoma (stage III or stage IV) who had received no prior treatment.

While 19% of patients who received ipilimumab alone experienced a reduction in tumor size for a period of 2.5 months, the tumors of 58% of patients who received nivolumab plus ipilimumab reduced by at least a third for almost a year.

Commenting on these findings, study co-leader Dr. James Larkin, of the Royal Marsden Hospital in the UK, told BBC News:

“By giving these drugs together you are effectively taking two brakes off the immune system rather than one, so the immune system is able to recognize tumors it wasn’t previously recognizing and react to that and destroy them.

For immunotherapies, we’ve never seen tumor shrinkage rates over 50% so that’s very significant to see. This is a treatment modality that I think is going to have a big future for the treatment of cancer.”

Dr. Gonzalez and colleagues also demonstrated the effectiveness of another immune therapy drug called pembrolizumab in patients with advanced melanoma.While 16% of 179 patients treated with chemotherapy alone experienced no disease progression after 6 months, the team found that disease progression was halted for 36% of 361 patients treated with pembrolizumab after 6 months.Dr. Gonzalez notes that while a combination of nivolumab and ipilimumab shows greater efficacy against advanced melanoma than pembrolizumab, it also presents greater toxicity. Around 55% of patients treated with nivolumab plus ipilimumab had severe side effects, such as fatigue and colitis, with around 36% of these patients discontinuing treatment.

Dr. Gonzalez says such treatment may be better for patients whose cancer does not involve overexpression of the PD-L1 protein.”Maybe PDL1-negative patients will benefit most from the combination, whereas PDL1-positive patients could use a drug targeting that protein with equal efficacy and less toxicity,” he adds. “In metastatic melanoma, all patients and not just those who are PD-L1-positive may benefit from pembrolizumab.”

NIVOLUMAB ALMOST DOUBLED PATIENT SURVIVAL FROM NSCLC

In another study, Dr. Julie Brahmer, director of the Thoracic Oncology Program at the Johns Hopkins Kimmel Cancer Center, and colleagues tested the effectiveness of nivolumab against standard chemotherapy with the drug docetaxel among 260 patients with NSCLC.

All patients had been treated for the disease previously, but the cancer had returned and spread.The team found that patients who received nivolumab had longer overall survival than those treated with standard chemotherapy, at 9.2 months versus 6 months.

At 1 year after treatment, the researchers found nivolumab almost doubled patient survival. Around 42% of patients who received nivolumab were alive after 1 year, compared with only 24% of patients who received chemotherapy.

The study results also demonstrated a longer period of halted disease progression for patients who received nivolumab compared with those who had chemotherapy, at 3.5 months versus 2.8 months.Overall, the researchers estimated that, compared with patients who received chemotherapy, those who received nivolumab were at 41% lower risk of death from NSCLC.

Commenting on these findings, Dr. Brahmer says:

“This solidifies immunotherapy as a treatment option in lung cancer. In the 20 years that I’ve been in practice, I consider this a major milestone.”

While both studies show promise for the use of immunotherapy in cancer treatment, experts note that such treatment would be expensive. The use of nivolumab plus ipilimumab for the treatment of advanced melanoma, for example, would cost at least $200,000 per patient.

As such, researchers say it is important that future research determines which cancer patients would be most likely to benefit from immunotherapy. Medical News Today recently reported on a study conducted by investigators from Cancer Research UK, which reveals a class of drugs called AKT inhibitors may boost the effect of radiotherapy against various cancers, including breast, kidney, melanoma and brain cancers.

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