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  • richardmitnick 12:27 pm on May 20, 2017 Permalink | Reply
    Tags: Antibody for fighting cancer emerges, , , , LAP+ cells are increased in human cancer and predict a poor prognosis, MedicalXpress, , T cells   

    From MedicalXpress: “Antibody for fighting cancer emerges” 

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    MedicalXpress

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    Brigham and Women’s Hospital

    May 19, 2017
    No writer credit found

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    Killer T cells surround a cancer cell. Credit: NIH

    While studying the underpinnings of multiple sclerosis, investigators at Brigham and Women’s Hospital came across important clues for how to treat a very different disease: cancer. In a paper published in Science Immunology, a group of researchers led by neurologist Howard Weiner, MD, describe an antibody that can precisely target regulatory T cells which in turn unleashes the immune system to kill cancer cells. The team reports that the antibody decreased tumor growth in models of melanoma, glioblastoma and colorectal carcinoma, making it an attractive candidate for cancer immunotherapy.

    “As a neurologist, I never expected I would be publishing a paper about cancer immunotherapy, but as my team studied a subpopulation of T cells that are supposed to prevent autoimmune disease, we had an idea: if cancer is the opposite of an autoimmune disease, we could turn our investigations around and think about how to restore the immune system’s ability to prevent cancer’s growth,” said Weiner, co-director the Ann Romney Center for Neurologic Diseases at BWH.v

    The Weiner lab has been studying regulatory T cells (Tregs) for many years. Tregs, which help maintain the immune system’s tolerance of “self,” can, inadvertently, promote cancer’s growth by preventing the body’s immune system from detecting and attacking cancer cells. The researchers found that they could precisely target Tregs using an antibody that locks in on a molecular complex that’s uniquely expressed on the cell surface of Tregs. The team developed these so-called anti-LAP antibodies initially to investigate the development of multiple sclerosis, but realized their work had implications for the study of cancer.

    Previous studies have shown that LAP+ cells are increased in human cancer and predict a poor prognosis. Being able to target these cells could offer a new way to treat the disease.

    In the current study, the team used preclinical models to investigate how well anti-LAP antibodies could work in blocking the essential mechanisms of Tregs and restoring the immune system’s ability to fight cancer. They found that anti-LAP acts on multiple cell populations to promote the immune system’s ability to fight cancer, including increasing the activity of certain types of T cells and enhancing immune memory.

    “In addition to studying its therapeutic effect, we wanted to characterize the mechanism by which the anti-LAP antibody can activate the immune system,” said lead author Galina Gabriely, PhD, a scientist in the Weiner laboratory. “We found that it affects multiple arms of the immune system.”

    The current study has been conducted in preclinical models of cancer. In order to move this work toward the clinic, Tilos Therapeutics will be expanding on the Weiner lab’s research to modify the antibody for use in humans, a process that usually takes several years.

    “I see this work as the perfect example of how research in all branches of immunology into the mechanistic underpinnings of disease can have a huge impact on other fields, such as oncology,” said Barbara Fox, PhD, CEO of Tilos Therapeutics.

    See the full article here .

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  • richardmitnick 11:11 am on March 22, 2016 Permalink | Reply
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    From MedicalXpress: “FOXA1 found to control specificity of cancer cells” 

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    MedicalXpress

    March 21, 2016
    Bob Yirka

    1
    Electron microscopic image of a single human lymphocyte. Credit: Dr. Triche, National Cancer Institute

    A team of researchers with the Mayo Clinic has learned more about how a transcription factor known as FOXA1 forms cancer-specific genomic identifiers and how it regulates gene expression differently among four very different types of human cancer cell lines. In their paper published in the journal Science Advances, the team describes how they used gene editing techniques and other tools to learn more about the unique binding process that allows the protein to regulate gene expression in the different types of cancers.

    Scientists know that cancer doesn’t grow in isolation, tumors, like other parts of the body are made of cells which depend on the same biological processes to regulate organogenesis as other tissues or organs. One of those processes is transcriptional regulation, where cells regulate the conversion of DNA sequences to RNA. In this new effort, the researchers looked at the protein coding gene FOXA1, which has been associated with several types of human cancers. More specifically, they looked into how just one transcription factor is able to form cancer-specific genomic changes to different types of cells, because it is important when trying to understand how tumors grow and because to date, it is still not very well understood.

    The researchers started with a type of sequencing technology that allows for processing large numbers of genomes, which allowed them to see how FOXA1 targets genes in two different kinds of breast cancer cells as well as liver and prostate cancer cells—and that allowed them to see a previously unknown feature of the protein; tailored targeting and binding to DNA. The team then used the CRISPR- Cas9 genome editing technique to look deeper and found that cell-specific FOXA1 regulation was due to unique binding, genetic variations and/or possible non-genetic regulation, which added more evidence of FOXA1 controlling the process by which specific types of cancer cells develop.

    After analyzing their work, the team developed a hypothesis to describe how they believe the process works, describing it as a progression that looks rather like what happens when a flower blooms. They suggest that the ‘blooming’ of certain transcription factors may be managed by the uniqueness of its genetic variations, its unique binding abilities and likely some other possible factors which may include other regulators and/or chromatin remodeling. The net result is more information regarding the mechanism behind the growth of cancer cells, which adds to an ever growing body of data that may one day reveal a means for controlling such growth and thus preventing cancer from causing harm.

    More information: G. Zhang et al. FOXA1 defines cancer cell specificity, Science Advances (2016). DOI: 10.1126/sciadv.1501473

    See the full article here .

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  • richardmitnick 5:14 pm on March 21, 2016 Permalink | Reply
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    From MedicalXpress: ” ‘Silencer molecules’ switch off cancer’s ability to spread around body” 

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    MedicalXpress

    March 21, 2016
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    Scientists have revealed that a key molecule in breast and lung cancer cells can help switch off the cancers’ ability to spread around the body.

    The findings by researchers at Imperial College London, published in the journal EMBO Reports, may help scientists develop treatments that prevent cancer travelling around the body—or produce some kind of test that allows doctors to gauge how likely a cancer is to spread.

    During tumour growth, cancer cells can break off and travel in the bloodstream or lymph system to other parts of the body, in a process called metastasis.

    Patients whose cancers spread tend to have a worse prognosis, explains Professor Justin Stebbing, senior author of the study from the Department of Surgery and Cancer at Imperial: “The ability of a cancer to spread around the body has a large impact on a patient’s survival. However, at the moment we are still in the dark about why some cancers spread around the body—while others stay in one place. This study has given important insights into this process.”

    The researchers were looking at breast and lung cancer cells and they found that a protein called MARK4 enables the cells to break free and move around to other parts of the body, such as the brain and liver. Although scientist are still unsure how it does this, one theory is it affects the cell’s internal scaffolding, enabling it to move more easily around the body.

    The team found that a molecule called miR-515-5p helps to silence, or switch off, the gene that produces MARK4.

    In the study, the team used human breast cancer and lung cancer cells to show that the miR-515-5p molecule silences the gene MARK4. They then confirmed this in mouse models, which showed that increasing the amount of miR-515-5p prevents the spread of cancer cells. The findings also revealed that the silencer molecule was found in lower levels in human tumours that had spread around the body.

    The team then also established that patients with breast and lung cancers whose tumours had low amounts of these silencer molecules—or high amounts of MARK4—had lower survival rates.

    Researchers are now investigating whether either the MARK4 gene or the silencer molecule could be targeted with drugs. They are also investigating whether these molecules could be used to develop a test to indicate whether a patient’s cancer is likely to spread.

    Professor Stebbing said: “In our work we have shown that this silencer molecule is important in the spread of cancer. This is very early stage research, so we now need more studies to find out more about this molecule, and if it is present in other types of cancer.”

    Dr Olivier Pardo, lead author of the paper, also from the Department of Surgery and Cancer at Imperial, added: “Our work also identified that MARK4 enables breast and lung cancer cells to both divide and invade other parts of the body. These findings could have profound implications for treating breast and lung cancers, two of the biggest cancer killers worldwide.”

    More information: O. E. Pardo et al. miR-515-5p controls cancer cell migration through MARK4 regulation, EMBO reports (2016). DOI: 10.15252/embr.201540970

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  • richardmitnick 11:14 am on March 19, 2016 Permalink | Reply
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    From MedicalXpress: “New gene identified as cause, early indicator of breast cancer” 

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    Medicalxpress

    March 18, 2016
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    When mutated, a gene known for its ability to repair DNA, appears to instead cause breast cancer, scientists report.

    The gene GT198, whether mutated by genetics and/or environmental factors, has strong potential as both as a way to diagnose breast cancer early and as a new treatment target, said Dr. Lan Ko, cancer biologist in the Department of Pathology at the Medical College of Georgia at Augusta University and at the Georgia Cancer Center at AU.

    Mutations of the gene are known to be present in both early onset breast and ovarian cancer. Now scientists have shown that the stem, or progenitor cells, which should ultimately make healthy breast tissue, can also have GT198 mutations that prompt them to instead make a perfect bed for breast cancer.

    Their studies, published in the American Journal of Pathology, were done on an international sampling from 254 cases of breast cancer in pre- and postmenopausal women.

    “This gene mutation can be in both the blood and the tumor tissue of patients, and in the tissue, it’s in high percentages,” said Ko, the study’s corresponding author. “We believe that once this gene is mutated, it induces the tumor to grow.”

    GT198, which is also a coactivator of receptors for steroid hormones such as estrogen, is normally regulated by estrogen, Ko said. But once mutated, GT198 can enable tumor production without estrogen. “Regardless of how much hormone you have, it’s out-of-control growth,” Ko said of the resulting classic, rapid growth of cancer.

    In a cancerous breast, scientists have seen the problems with the various components of breast tissue but could not fully explain why they happened. The tissue, called the stroma, includes fat cells, or adipocytes, that provide padding; fibroblasts, which make the framework for tissue; pericytes in blood vessels, which are contractile cells that help regulate blood pressure; as well as myoepithelial cells comprising the outer layer of the ductal system through which milk flows.

    The new study backs up a few steps and shows that mutated GT198 also directly affects stem cells found on blood vessels that make these various components of breast tissue. “This puts it together,” Ko said.

    “It’s a new target in cancer. It’s very exciting,” said Dr. Nita Maihle, MCG cancer biologist, associate center director for education at the university’s Cancer Center and a study co-author. “This tells you that all the different types of stromal cells in breast tissue are affected by the GT198 mutation because they all come from a common progenitor cell.”

    The net effect is a tumorigenic environment filled with what Ko calls inappropriate offspring. “Here is a cause-consequence relationship,” she said.

    Next steps include pursuing therapies, including antibodies and herb-derived treatments, that target the misguided progenitor cells, instead of only targeting the cancerous breast tissue they produce, Ko said. “We think the way to treat breast cancer is to target the progenitor cells. We want to kill these cells that are feeding the tumor rather than just killing the tumor cells, which is less effective.”

    In a 2013 study in The Journal of Biological Chemistry, Ko and her colleagues showed tumor cells containing mutated GT198 protein in the stroma in various types of ovarian cancer, indicating the gene could also be a source for ovarian cancer.

    Ko first cloned the human GT198 gene while a postdoctoral fellow at Harvard Medical School, and subsequent studies by her and others have shown it has multiple roles that also include regulating stem cells, cell suicide and turning other genes off and on.

    All cells have the GT198 gene but most adult cells don’t express it. In the breast, for example, it may be transiently expressed in a pregnant woman preparing for milk production and, potentially, in the case of breast injury. Males express it in the testes.

    Ductal breast cancer, which is in the ducts that carry milk, is the most common type of breast cancer and lobular carcinoma, which begins in the milk-producing glands, is the second most common. Most breast cancer comes from the cells that line those ducts, Maihle said.

    BRCA1 and 2, genes whose proteins are supposed to work as tumor suppressors and also repair DNA damage, were the first known risk factor genes for familial breast cancer as well as ovarian and other cancers. About 4 percent of familial breast cancers would include inherited mutations of GT198, which is also considered a causative gene in sporadic cases, Ko said.

    See the full article here .

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  • richardmitnick 5:31 am on April 11, 2015 Permalink | Reply
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    From MedicalXpress: “Telomeres and cancer mortality: The long and the short of it” 

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    MedicalXpress

    April 10, 2015
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    Human chromosomes (grey) capped by telomeres (white). Credit: PD-NASA; PD-USGOV-NASA

    Telomeres are short stretches of repeated nucleotides that protect the ends of chromosomes. In somatic cells, these protective sequences become shorter with each cellular replication until a critical length is reached, which can trigger cell death.

    In actively replicating cells such as germ cells, embryonic stem cells, and blood stem cells of the bone marrow, the enzyme telomerase replenishes these protective caps to ensure adequate replication. Cancer cells also seem to have the ability to activate telomerase, which allows them to keep dividing indefinitely, with dire consequences for the patient. However, according to a study published April 10 in the JNCI: Journal of the National Cancer Institute, the extent to which cancer cells can utilize telomerase may depend on which variants of the genes related to telomerase activity are expressed in an individual’s cells.

    Telomere shortening is an inevitable, age-related process, but it can also be exacerbated by lifestyle factors such as obesity and smoking. Thus, some previous studies have found an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association found between short telomeres and increased cancer mortality was correlational but other factors (age and lifestyle), not adjusted for in previous studies, were the real causes. Genetic variation in several genes associated with telomere length (TERC, TERT, OBFC1) is independent of age and lifestyle. Thus, a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow the presumably causal association of telomere length and cancer mortality to be studied.

    To perform this analysis, Line Rode, M.D., Ph.D., of the Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark, and colleagues, used data from two prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, including 64,637 individuals followed from 1991-2011. Participants completed a questionnaire and had a physical examination and blood drawn for biochemistry, genotyping, and telomere length assays.

    For each subject, the authors had information on physical characteristics such as body mass index, blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables. In addition to the measure of telomere length for each subject, three single nucleotide polymorphisms of TERC, TERT, and OBFC1 were used to construct a score for the presence of telomere shortening alleles.

    A total of 7607 individuals died during the study, 2420 of cancer. Overall, as expected, decreasing telomere length as measured in leukocytes was associated with age and other variables such as BMI and smoking and with death from all causes, including cancer. Surprisingly, and in contrast, a higher genetic score for telomere shortening was associated specifically with decreased cancer mortality, but not with any other causes of death, suggesting that the slightly shorter telomeres in the cancer patients with the higher genetic score for telomere shortening might be beneficial because the uncontrolled cancer cell replication that leads to tumor progression and death is reduced.

    The authors conclude, “We speculate that long telomeres may represent a survival advantage for cancer cells, allowing multiple cell divisions leading to high cancer mortality.”

    See the full article here.

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  • richardmitnick 2:08 pm on April 7, 2015 Permalink | Reply
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    From MedicalXpresss: “Food for thought: Master protein enhances learning and memory” 

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    MedicalXpress

    April 7, 2015
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    Salk researchers and collaborators discovered that physical and mentalactivities rely on a single metabolic protein, ERRγ, that controls theflow of blood and nutrients throughout the body. In this image, ERRγ isshown (stained red) in the hippocampus, the area of the brain largely responsible for memory. The new work could point to a way to enhance learning. Credit: Salk Institute

    Just as some people seem built to run marathons and have an easier time going for miles without tiring, others are born with a knack for memorizing things, from times tables to trivia facts. These two skills ― running and memorizing ― are not so different as it turns out.

    Salk scientists and collaborators have discovered that physical and mental activities rely on a single metabolic protein that controls the flow of blood and nutrients throughout the body, as reported in the journal Cell Metabolism. The new study could point to potential treatments in regenerative and developmental medicine as well as ways to address defects in learning and memory.

    “This is all about getting energy where it’s needed to ‘the power plants’ in the body,” says Ronald Evans, director of Salk’s Gene Expression Laboratory and senior author of the new paper, published April 7, 2015.”The heart and muscles need a surge of energy to carry out exercise and neurons need a surge of energy to form new memories.”

    Energy for muscles and brains, the scientists discovered, is controlled by a single protein called estrogen-related receptor gamma (ERRγ). Evans’research group has previously studied the role of ERRγ in the heart and skeletal muscles. In 2011, they discovered that promoting ERRγ activity int he muscle of sedentary mice increased blood supply to their muscles and doubled their running capacity. ERRγ, they went on to show, turns on a whole host of muscle genes that convert fat to energy.

    Thus, ERRγ became known as a master metabolic switch that energized muscle to enhance performance. Although studies had also shown that ERRγ was active in the brain, researchers didn’t understand why ― the brain burns sugar and ERRγ was previously shown to only burn fat. So the team decided to look more closely at what the protein was doing in brain cells.

    By first looking at isolated neurons, Liming Pei, lead and co-corresponding author of the paper, found that, as in muscle, ERRγactivates dozens of metabolic genes in brain cells. Unexpectedly, this activation related to sugar instead of fat. Neurons that lacked ERRγ could not ramp up energy production and thus had a compromised performance.

    “We assumed that ERRγ did the same thing throughout the body,” says Evans.”But we learned that it’s different in the brain.” ERRγ, they now conclude, turns on fat-burning pathways in muscles and sugar-burning pathways in the brain.

    Evans and his collaborators noticed that ERRγ in live mice was most active in the hippocampus ― an area of the brain that is active in producing new brain cells, is involved in learning and memory and is known to require lots of energy. They wondered whether ERRγ had a direct role in learning and memory. By studying mice lacking ERRγ in the brain, they found a link.

    While mice without the protein had normal vision, movement and balance,they were slower at learning how to swim through a water maze ― and poor at remembering the maze on subsequent trials ― compared to mice with normal levels of ERRγ.

    “What we found is that mice that missing ERRγ are basically very slow learners,” says Pei. Varying levels of ERRγ could also be at the root of differences between how individual humans learn, he hypothesizes.”Everyone can learn, but some people learn and memorize more efficiently than others, and we now think this could be linked to changes in brain metabolism.”

    A better understanding of the metabolism of neurons could help point the way to improved treatments for learning and attention disorders. And possibly, revving up levels of ERRγ could even enhance learning, just as it enhances muscle function.

    “What we’ve shown is that memories are really built on a metabolic scaffold,” says Evans. “And we think that if you want to understand learning and memory, you need to understand the circuits that underlie and power this process.”

    See the full article here.

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  • richardmitnick 7:54 am on March 22, 2015 Permalink | Reply
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    From MedicalXpress: “Vitamin D may keep low-grade prostate cancer from becoming aggressive” 

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    MedicalXpress

    Taking vitamin D supplements could slow or even reverse the progression of less aggressive, or low-grade, prostate tumors without the need for surgery or radiation, a scientist will report today.

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    His team will describe the approach in one of nearly 11,000 presentations at the 249th National Meeting & Exposition of the American Chemical Society (ACS).

    If a tumor is present in a prostate biopsy, a pathologist grades its aggressiveness on a scale known as the Gleason grading system.

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    Gleason grade Lower grades are associated with small, closely packed glands. Cells spread out and lose glandular architecture as grade increases.

    Tumors with Gleason scores of 7 and above are considered aggressive and likely to spread, requiring surgical removal of the prostate gland (prostatectomy) or radiation therapy. In contrast, prostate tumors with Gleason scores of 6 and below are less aggressive, and in some cases may cause no symptoms or health problems for the duration of the man’s life.

    In cases of low-grade prostate cancer, many urologists do not treat the disease, but instead do what’s called “active surveillance,” says Bruce Hollis, Ph.D., who is at the Medical University of South Carolina. “The cure—meaning surgery or radiation—is probably worse than the disease, so they wait a year and then do another biopsy to see where the patient stands.”

    However, knowing that they have even low-grade prostate cancer can cause patients and their families excessive anxiety, which prompts some of the men to undergo an elective prostatectomy, despite the risk of complications such as infection, urinary incontinence and erectile dysfunction. But a man must wait 60 days from the time of his biopsy before he can undergo a prostatectomy, so that inflammation from the biopsy can subside.

    Hollis wondered if giving these men vitamin D supplements during the 60-day waiting period would affect their prostate cancer. His previous research had shown that when men with low-grade prostate cancer took vitamin D supplements for a year, 55 percent of them showed decreased Gleason scores or even complete disappearance of their tumors compared to their biopsies a year before (J. Clin. Endocrinol. Metab., 2012, DOI: 10.1210/jc.2012-1451).

    In a new randomized, controlled clinical trial, his team assigned 37 men undergoing elective prostatectomies either to a group that received 4,000 U of vitamin D per day, or to a placebo group that didn’t receive vitamin D. The men’s prostate glands were removed and examined 60 days later.

    Preliminary results from this study indicate that many of the men who received vitamin D showed improvements in their prostate tumors, whereas the tumors in the placebo group either stayed the same or got worse. Also, vitamin D caused dramatic changes in the expression levels of many cell lipids and proteins, particularly those involved in inflammation. “Cancer is associated with inflammation, especially in the prostate gland,” says Hollis. “Vitamin D is really fighting this inflammation within the gland.”

    The protein most strongly induced by vitamin D was one called growth differentiation factor 15 (GDF15). Previous studies by other groups showed that GDF15 dials down inflammation, and many aggressive prostate cancers make little or no GDF15.

    The new research suggests that vitamin D supplementation may improve low-grade prostate cancers by reducing inflammation, perhaps lessening the need for eventual surgery or radiation treatment. “We don’t know yet whether vitamin D treats or prevents prostate cancer,” says Hollis. “At the minimum, what it may do is keep lower-grade prostate cancers from going ballistic.”

    Hollis notes that the dosage of vitamin D administered in the study—4,000 U—is well below the 10,000-20,000 U that the human body can make from daily sun exposure. “We’re treating these guys with normal body levels of vitamin D,” he says. “We haven’t even moved into the pharmacological levels yet.”

    See the full article here.

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  • richardmitnick 4:04 am on March 11, 2015 Permalink | Reply
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    From Medicalxpress: “Researchers identify control mechanism for glutamine uptake in breast cancer cells” 

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    Medicalxpress

    March 10, 2015
    No Writer Credit

    1
    Electron microscopic image of a single human lymphocyte. Credit: Dr. Triche National Cancer Institute

    Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) have discovered a mechanism that explains why some breast cancer tumors respond to specific chemotherapies and others do not. The findings highlight the level of glutamine, an essential nutrient for cancer development, as a determinant of breast cancer response to select anticancer therapies, and identify a marker associated with glutamine uptake, for potential prognosis and stratification of breast cancer therapy.

    “Our study indicates that a protein called RNF5 determines breast cancer response to paclitaxel, one of the most common chemotherapy drugs,” said Ze’ev Ronai, Ph.D., scientific director of Sanford-Burnham’s La Jolla campus. “Paclitaxel belongs to a class of drugs called taxanes that work by triggering a stress response in cells that in turn promotes an interaction between RNF5 and glutamine uptake proteins. We found that this interaction causes degradation of the glutamine carrier proteins, leading to an insufficient supply of glutamine and the sensitization of breast cancer tumors to death.”

    The study results were published in today’s online edition of Cancer Cell.

    For some time researchers have known that many tumor cell types are dependent on glutamine for growth and survival, but didn’t know how glutamine uptake was regulated. The new findings demonstrate the importance of RNF5 in the control of glutamine uptake, and in antagonizing tumor development. The findings also suggest that testing tumors for RNF5 and glutamine carrier protein levels, such as SLC1A5, may be used to identify patients best suited to taxanes-based therapy.

    “Not all tumors are equipped to respond to paclitaxel therapy,” said Ronai. “Using a cohort of more than 500 breast cancer patient samples, we found that only 30 percent of tumors exhibit high levels of RNF5 and low levels of glutamine carrier proteins—the optimal profile for response to paclitaxel.”

    “Understanding these types of cell mechanisms and tumor characteristics that determine the response to anticancer drugs can lead to better patient stratification as well as improved therapy approaches,” said Gordon Mills, M.D., Ph.D., chairman of the Department of Systems Biology at MD Anderson Cancer Center, 2013 recipient of the Susan B. Komen Brinker Award for contributions to breast cancer research, and co-author of the study. “The opportunity to identify and target key pathways involved in the behavior of breast cancer cells has the potential to both increase efficacy and decrease toxicity of therapy.”

    “We also used this patient cohort to test the predictive value of measuring levels of glutamine carrier proteins as a prognostic marker,” said Ronai. Our results indicate that these proteins are an outstanding marker of patient outcome, as good as currently used markers.”

    “We have started screening for inhibitors of glutamine carrier proteins as a potential new target for breast cancer treatment,” said Ronai, who is also examining the mechanism for glutamine control in other tumor types.

    See the full article here.

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  • richardmitnick 4:37 am on March 10, 2015 Permalink | Reply
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    From Medical Xpress: “Scientists find class of drugs that boosts healthy lifespan” 

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    Medicalxpress

    March 9, 2015
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    A research team from The Scripps Research Institute (TSRI), Mayo Clinic and other institutions has identified a new class of drugs that in animal models dramatically slows the aging process—alleviating symptoms of frailty, improving cardiac function and extending a healthy lifespan.

    The new research was published March 9 online ahead of print by the journal Aging Cell.

    The scientists coined the term “senolytics” for the new class of drugs.

    “We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders,” said TSRI Professor Paul Robbins, PhD, who with Associate Professor Laura Niedernhofer, MD, PhD, led the research efforts for the paper at Scripps Florida. “When senolytic agents, like the combination we identified, are used clinically, the results could be transformative.”

    “The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging,” said Mayo Clinic Professor James Kirkland, MD, PhD, senior author of the new study. “It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time.”

    Finding the Target

    Senescent cells—cells that have stopped dividing—accumulate with age and accelerate the aging process. Since the “healthspan” (time free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that finding treatments that accomplish this in humans could have tremendous potential.

    The scientists were faced with the question, though, of how to identify and target senescent cells without damaging other cells.

    The team suspected that senescent cells’ resistance to death by stress and damage could provide a clue. Indeed, using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of “pro-survival networks” that help them resist apoptosis or programmed cell death. This finding provided key criteria to search for potential drug candidates.

    Using these criteria, the team homed in on two available compounds—the cancer drug dasatinib (sold under the trade name Sprycel) and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory.

    Further testing in cell culture showed these compounds do indeed selectively induce death of senescent cells. The two compounds had different strong points. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.

    Remarkable Results

    Next, the team looked at how these drugs affected health and aging in mice.

    “In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan,” said Niedernhofer, whose animal models of accelerated aging were used extensively in the study. “Remarkably, in some cases, these drugs did so with only a single course of treatment.”

    In old mice, cardiovascular function was improved within five days of a single dose of the drugs. A single dose of a combination of the drugs led to improved exercise capacity in animals weakened by radiation therapy used for cancer. The effect lasted for at least seven months following treatment with the drugs. Periodic drug administration of mice with accelerated aging extended the healthspan in the animals, delaying age-related symptoms, spine degeneration and osteoporosis.

    The authors caution that more testing is needed before use in humans. They also note both drugs in the study have possible side effects, at least with long-term treatment.

    The researchers, however, remain upbeat about their findings’ potential. “Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds,” Robbins said. “Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects.”

    See the full article here.

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