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  • richardmitnick 10:00 am on July 10, 2017 Permalink | Reply
    Tags: All NF2 patients develop multiple schwannomas, , Involvement in glioblastoma breast cancer prostate and gastric cancer, MedicalXpress, , Merlin deficiency, New research offers hope to neuro-tumor patients, NF2-Neurofibromatosis 2, Schwannomas meningiomas and ependymomas, the role of the normal cellular form of prion protein (PrPC) in the development of NF2-related tumours, University of Plymouth and Plymouth Hospitals NHS Trust   

    From MedicalXpress: “New research offers hope to neuro-tumor patients” 

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    MedicalXpress

    July 9, 2017
    No writer credit

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    Schwannoma tumor cell. Credit: University of Plymouth

    New research published today, 10th July 2017, online in the journal Oncogene could offer hope to the thousands of, mainly young, people affected by the hereditary condition Neurofibromatosis 2 (NF2). This condition is characterised by the development of multiple tumours of the nervous system such as schwannomas, meningiomas and ependymomas, each associated with mutations in a gene coding for a tumour suppressor called Merlin.

    In addition to NF2 disease there could be potential benefit for other cancers with the same mutations, including mesothelioma (usually linked to exposure to asbestos), breast cancer, colorectal carcinoma, melanoma, glioblastoma and spontaneous schwannomas and meningiomas occurring independently of NF2.

    Scientists from the University of Plymouth and Plymouth Hospitals NHS Trust, supported by The Laura Crane Youth Cancer Trust and Brain Tumour Research, have revealed the role of the normal, cellular form of prion protein (PrPC) in the development of NF2-related tumours.

    PrPC is normally present in the nervous system of healthy individuals and is absent in Creutzfeldt-Jakob prion disease patients who have a pathological form of prion protein called scrapie prion protein (PrPSc). While physiological levels of PrPC are important during embryogenesis (the process by which the embryo develops and forms), and are neuro-protective in adults, highly increased concentrations were found in several cancers such as glioblastoma, breast cancer, prostate and gastric cancer.

    Since all NF2 patients develop multiple schwannomas, the scientists have developed a human cell culture model for schwannoma, comprising of human schwannoma cells isolated from both patients and control normal healthy Schwann cells (which form the sheath that protects nerves). Using this model, the research team found for the first time that PrPC is over-produced in schwannoma compared with healthy Schwann cells. This overproduction is due to Merlin deficiency and strongly contributes to tumour growth and patient prognosis.

    The research team have already identified a range of existing drugs which could manage this protein overproduction and that are used currently for other non-NF2-related conditions, such as Creutzfeldt-Jakob disease, multiple myeloma (a type of bone marrow cancer) and Acute Myeloid Leukaemia (AML). By repurposing existing drugs, an effective therapy could be made available to NF2 patients, based on the failure of Merlin tumour suppressor expression, relatively quickly. The safety testing process for human use has already taken place for the original purpose of these drugs, which means they could be fast-tracked into clinical studies for NF2.

    Director of the study was Dr Sylwia Ammoun, Senior Research Fellow in Clinical Neurobiology, who had crucial support from PhD student Lucy Provenzano. Both are members of Professor Oliver Hanemann’s internationally-recognised brain and nervous system cancer research team at Plymouth University Peninsula Schools of Medicine and Dentistry.

    Dr Ammoun commented: “By understanding the relationship between overproduction of PrPC and Merlin deficiency in the development of schwannoma and meningioma, we have made a significant stride forward in the search for a drug treatment for NF2. This is a life-changing condition usually striking the young. That our discovery could also lead to hope for thousands of patients affected by other Merlin-deficient tumours, adds yet more to the significance and excitement of our findings.”

    Pam Thornes, Trust Manager at The Laura Crane Youth Cancer Trust, said: “We are extremely proud to have funded such pioneering cancer research as carried out by Dr Ammoun and PhD student Lucy Provenzano and collaborators in the Professor Hanemann laboratory. Their fantastic work is going to make a life-changing difference to the lives of so many young cancer patients and that their discovery could also lead to hope for thousands of patients affected by other Merlin-deficient tumours adds yet more to the significance and excitement of their finding. The Laura Crane Youth Cancer Trust is delighted to have been able to play a part in making this research a reality.”

    Dr Kieran Breen, Director of Research at Brain Tumour Research said: “Identifying a range of existing drugs which could be repurposed is an exciting approach by which we can speed up the progress of scientific discovery from the lab to the clinic, without compromising safety. Brain tumours kill more children and adults under the age of 40 than any other cancer, but lack of research funding over decades has meant that current treatments lag well behind those of leukaemia and many other cancers. We are having to play catch up to improve outcomes for patients and this study will bring us closer to identifying new and effective therapies”.

    See the full article here .

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  • richardmitnick 2:22 pm on July 7, 2017 Permalink | Reply
    Tags: , , Dendritic cells 'divide and conquer' to elude viral infection while promoting immunity, MedicalXpress,   

    From MedicalXpress: “Dendritic cells ‘divide and conquer’ to elude viral infection while promoting immunity” 

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    MedicalXpress

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    Infographic depicting a “division of labor” among DC subsets, which protects the body during viral infection. Credit: Carla Schaffer / AAAS

    A research team led by Jackson Laboratory (JAX) Professor Karolina Palucka, M.D., Ph.D., in collaboration with a research team at Institut Curie in France led by Dr. Nicolas Manel, have addressed a long-standing puzzle of immunology: How do dendritic cells (DCs) do their job of promoting adaptive immunity to a virus while avoiding getting infected themselves?

    DCs are the “beat cops” of the immune system. They round up viral antigens (proteins specific to a given virus), and present them to the receptors on T cells, which in turn promote an adaptive immune response to that virus. But along the way the DCs are vulnerable to infection by the virus, presumably compromising their protective powers.

    The research team reports in Science Immunology that two subsets of DCs work together to activate T cells against a virus: one dies and produces the viral antigens that the other then sweeps up and presents to the T cells.

    “We show that one DC subset (CD1c+ DCs) is susceptible to viral infection and produces viral fragments,” Palucka says. “Another DC subset (CD141+ DCs) uses these viral fragments to activate T cells against the virus. This paradigm may allow a better understanding of the induction of protective immunity against viruses and live-attenuated vaccines against viral infections.”

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    Silvin et al. found that a molecule called RAB15 can help limit viral infection in DCs, and examined its localization in human monocytes growing in culture. Credit: Silvin et al., Sci. Immunol. 2, eaai8071

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    CD141+ DCs are dependent on the productive infection of “bystander” CD1c+ DCs, to effectively activate T cells. Credit: Silvin et al., Sci. Immunol. 2, eaai8071

    See the full article here .

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  • richardmitnick 5:20 pm on July 2, 2017 Permalink | Reply
    Tags: , , Cancer hides in plain sight of the immune system, MedicalXpress,   

    From MedicalXpress: “New insights into why the immune system fails to see cancer” 

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    MedicalXpress

    June 29, 2017
    No writer credit found

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    Killer T cells surround a cancer cell. Credit: NIH.

    Cancer hides in plain sight of the immune system. The body’s natural tumor surveillance programs should be able to detect and attack rogue cancer cells when they arise, and yet when cancer thrives, it does so because these defense systems have failed. A team of investigators led by Niroshana Anandasabapathy, MD, PhD, at Brigham and Women’s Hospital have uncovered a critical strategy that some cancers may be using to cloak themselves – they find evidence of this genetic program across 30 human cancers of the peripheral tissue, including melanoma skin cancer. Their results are published June 29 in Cell.

    “Our study reveals a new immunotherapy target and provides an evolutionary basis for why the immune system may fail to detect cancers arising in tissues,” said corresponding author Anandasabapathy, of BWH’s Department of Dermatology. “The genetic program we report on helps the immune system balance itself. Parts of this program prevent the immune system from destroying healthy organs or tissues, but might also leave a blind spot for detecting and fighting cancer.”

    The authors studied immune mononuclear phagocytes – a group of disparate cells that act as the “Pac man” of the immune system. When these cells detect foreign invaders and dying normal tissues, they devour or engulf their components. These cells then present these components on their surface teach T cells to maintain tolerance to healthy tissues, or to fight infections and pathogens. Despite differences in function, all immune mononuclear phagocytes found in the skin- (a peripheral tissue like lung and gut) share a common set of genetic programming, which is further enhanced when they enter the tissue. This program is conserved in fetal and adult development, and across species. And, the research team reports, is co-opted by multiple human cancers of tissue.

    The team finds that this program is prompted by an “instructive cue” from interferon gamma – a molecule that plays a critical role in regulating immunity. The authors find IFN-gamma for mononuclear phagocytes in development but that IFN-gamma and tissue immune signatures are much higher in skin cancer than in healthy skin. Having an immune response measured by IFN-gamma and tissue signatures correlated with improved metastatic melanoma survival outcomes, making these signatures potential biomarkers for cancer survival.

    The authors reasoned such a program might contain key molecules that help the immune system reduce inflammation, but that might also leave a blind spot to cancer detection. One of the key genes the researchers detected is suppressor of cytokine signaling 2 (SOCS2). When this gene was turned off in a mouse model, the immune system was able to robustly detect and reject cancer in models of melanoma and thymoma (cancer of the thymus). They also observed improved vaccination responses, and heightened auto-inflammation suggesting this gene normally dampens auto-inflammatory responses and contracts protective immunity.

    “Our research suggests that these cancers are co-opting tissue-specific immune development to escape detection, but we see that turning off SOCS2 unmasks them,” said Anandasabapathy. “This sheds new light on our understanding of how the immune system is programed to see cancers and also points the way toward new therapeutic targets for treating cancers that have these signatures.”

    See the full article here .

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  • richardmitnick 10:08 pm on July 1, 2017 Permalink | Reply
    Tags: MedicalXpress, Patients with multiple sclerosis may benefit from over-the-counter therapy   

    From MedicalXpress: “Patients with multiple sclerosis may benefit from over-the-counter therapy” 

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    MedicalXpress

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    Demyelination by MS. The CD68 colored tissue shows several macrophages in the area of the lesion. Original scale 1:100. Credit: Marvin 101/Wikipedia

    Treatment options currently are limited for people suffering from secondary progressive multiple sclerosis. However, an OHSU pilot study suggests over-the-counter antioxidant lipoic acid holds promise in improving patients’ lives.

    The research was published June 28 in the journal Neuroimmunology & Neuroinflammation.

    The randomized double-blind study involved 51 participants who completed the two-year trial. Twenty-seven people were given a 1,200-milogram daily dose of lipoic acid, with the remaining 24 participants given a placebo. Researchers are using the findings from the pilot trial to design the expanded multi-site clinical trial to begin later this year in Portland and other sites that have yet to be finalized.

    “These are high doses,” said lead author Rebecca Spain, M.D., M.S.P.H., an assistant professor of neurology in the OHSU School of Medicine. “And while it seems safe, we won’t know whether it actually improves the lives of people with MS until we can replicate the results in the pilot study through a much bigger clinical trial. Fortunately, we’re going to be able to answer that question with the participation of kind volunteers.”

    MS is a chronic condition that affects an estimated 2.3 million people worldwide. In MS, the sheath covering nerve fibers in the brain and spinal cord becomes damaged, slowing or blocking electrical signals from the brain reaching the eyes, muscles and other parts of the body.

    The major finding of the pilot study involved measuring the degree to which lipoic acid arrested the rate of whole brain atrophy, as measured through magnetic resonance imaging.

    The study revealed a 68 percent improvement over the placebo in slowing the rate of whole brain atrophy in patients with secondary progressive MS. For the sake of comparison, a clinical trial involving the recent FDA-approved pharmaceutical Ocrevus showed an 18 percent improvement over a placebo in slowing the rate of whole brain atrophy for patients with primary progressive forms of the disease.

    In addition, the pilot study suggested improved walking times and fewer falls among study participants who took a daily dose of lipoic acid compared with those who received the placebo. Researchers are eager to test those outcomes in the larger clinical trial.

    A companion study, published concurrently by Neuroimmunology & Neuroinflammation [link requested], measured the rate of absorption and clearance of lipoic acid through periodic blood tests of pilot study participants. The results will help to inform the design of additional clinical trials.

    Lipoic acid was determined to be safe and well-tolerated by pilot study participants. Stomach upset was the most frequent side effect.

    See the full article here .

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  • richardmitnick 4:27 pm on June 20, 2017 Permalink | Reply
    Tags: , , Drynaria Rhizome, MedicalXpress, Naringenin and two naringenin metabolites   

    From MedicalXpress: “Plant reveals anti-Alzheimer’s compounds” 

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    MedicalXpress

    June 20, 2017
    No writer credit found

    1
    Diagram of the brain of a person with Alzheimer’s Disease. Credit: Wikipedia/public domain.

    Japanese scientists have developed a method to isolate and identify active compounds in plant medicines, which accurately accounts for drug behavior in the body. Using the technique, they have identified several active compounds from Drynaria Rhizome, a traditional plant medicine, which improve memory and reduce disease characteristics in a mouse model of Alzheimer’s disease.

    Traditional plant medicines have been used by humans for a long time, and these therapies are still popular in many countries. Plants typically contain a huge variety of compounds, many of which have no effect in the body, and some which can have significant effects. If a plant medicine shows a therapeutic effect, scientists are interested in isolating and identifying the compounds that cause the effect to see if they can be used as new drugs.

    In many cases, scientists repeatedly screen crude plant medicines in lab experiments to see if any compounds show a particular effect in cells grown in a dish or in cell-free assays. If a compound shows a positive effect in cells or test tubes, it could potentially be used as a drug, and the scientists go on to test it in animals. However, this process is a lot of work and doesn’t account for changes that can happen to drugs when they enter the body – enzymes in the blood and liver can metabolize drugs into various forms called metabolites. In addition, some areas of the body, such as the brain, are difficult to access for many drugs, and only certain drugs or their metabolites will enter these tissues.

    “The candidate compounds identified in traditional benchtop drug screens of plant medicines are not always true active compounds, because these assays ignore bio-metabolism and tissue distribution,” explains Chihiro Tohda, senior author on the recent study published in Frontiers in Pharmacology. “So, we aimed to develop more efficient methods to identify authentic active compounds that take these factors into account.”

    The scientists were interested in finding active compounds for Alzheimer’s disease in Drynaria Rhizome, a traditional plant medicine. They used mice with a genetic mutation as a model for Alzheimer’s disease. This mutation gives the mice some characteristics of Alzheimer’s disease, including reduced memory and a buildup of specific proteins in the brain, called amyloid and tau proteins. This means that the mice are a useful tool to test potential Alzheimer’s disease treatments.

    Initially, the researchers mashed the plant up and treated the mice orally using this crude plant extract. They found that the plant treatment reduced memory impairments and levels of amyloid and tau proteins in their brains. In a key step, the team then examined the mouse brain tissue, where the treatment is needed, 5 hours after they treated the mice with the extract. They found that three compounds from the plant had made it into the brain – these were a compound called naringenin and two naringenin metabolites.

    The researchers then treated the mice with pure naringenin and noticed the same improvements in memory deficits and reductions in amyloid and tau proteins, meaning that naringenin and its metabolites were likely the active compounds in the plant. They found a protein called CRMP2 that naringenin binds to in neurons, which causes them to grow, suggesting that this could be the mechanism by which naringenin can improve Alzheimer’s disease symptoms.

    The team hope that the technique can be used to identify other treatments. “We are applying this method to discover new drugs for other diseases such as spinal cord injury, depression and sarcopenia,” explains Tohda.

    See the full article here .

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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
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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

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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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    1

    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.

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    Medical Xpress is a web-based medical and health news service that is part of the renowned Science X network. Medical Xpress features the most comprehensive coverage in medical research and health news in the fields of neuroscience, cardiology, cancer, HIV/AIDS, psychology, psychiatry, dentistry, genetics, diseases and conditions, medications and more.

     
  • richardmitnick 5:31 am on April 11, 2015 Permalink | Reply
    Tags: , , MedicalXpress   

    From MedicalXpress: “Telomeres and cancer mortality: The long and the short of it” 

    Medicalxpress bloc

    MedicalXpress

    April 10, 2015
    No Writer Credit

    1
    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.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Medical Xpress is a web-based medical and health news service that is part of the renowned Science X network. Medical Xpress features the most comprehensive coverage in medical research and health news in the fields of neuroscience, cardiology, cancer, HIV/AIDS, psychology, psychiatry, dentistry, genetics, diseases and conditions, medications and more.

     
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