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  • richardmitnick 4:13 pm on December 7, 2016 Permalink | Reply
    Tags: , Medicine, Southampton   

    From Southampton: “New cancer drug shows promise in helping patients with blood cancer” 

    U Southampton bloc

    University of Southampton

    5 December 2016
    No writer credit found

    New cancer drug shows promise in helping patients with blood cancer. No image credit.

    A drug, which has been developed from the results of cancer immunology research at the University of Southampton, has been showed to reduce the risk of follicular lymphoma progression.

    Results from the phase III GALLIUM study, being presented at the American Society of Hematology (ASH) congress, showed combining obinutuzumab (Gazyva) with chemotherapy in the first-line setting reduced the risk of disease progression or death by 34 per cent versus rituximab (Rituxan) plus chemotherapy in patients with follicular lymphoma.

    Results also showed that time to relapse extended by 32 per cent in patients receiving obinutuzumab plus chemotherapy compared to rituximab plus chemotherapy.

    Peter Johnson, Professor of Medical Oncology at the University of Southampton added: “This new type of antibody treatment for lymphoma has been developed from immunology research in Southampton which started more than 10 years ago, when we started to find out how these antibodies work. We have much more to do in many different types of cancer, but this is a great example of how discovery science can work through into better treatments for our patients”

    It is this detailed research to better understand new drugs and combinations with immunotherapy, that will be taking place in the University of Southampton’s new Centre for Cancer Immunology.

    The Centre, which is being built at Southampton General Hospital and due to open in 2017, will be the first of its kind in the UK to focus exclusively on immunotherapy, a revolutionary new treatment that supercharges the body’s natural defences to find and destroy cancer. The Centre will bring together world-leading specialists and its aim is to accelerate research progress and conduct more clinical trials.

    See the full article here .

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    U Southampton campus

    The University of Southampton is a world-class university built on the quality and diversity of our community. Our staff place a high value on excellence and creativity, supporting independence of thought, and the freedom to challenge existing knowledge and beliefs through critical research and scholarship. Through our education and research we transform people’s lives and change the world for the better.

    Vision 2020 is the basis of our strategy.

    Since publication of the previous University Strategy in 2010 we have achieved much of what we set out to do against a backdrop of a major economic downturn and radical change in higher education in the UK.

    Vision 2020 builds on these foundations, describing our future ambition and priorities. It presents a vision of the University as a confident, growing, outwardly-focused institution that has global impact. It describes a connected institution equally committed to education and research, providing a distinctive educational experience for its students, and confident in its place as a leading international research university, achieving world-wide impact.

  • richardmitnick 3:38 pm on December 7, 2016 Permalink | Reply
    Tags: , , Medicine,   

    From MIT Tech Review: “Personalized Cancer Vaccine Prevents Leukemia Relapse in Patients” 

    MIT Technology Review
    M.I.T Technology Review

    December 7, 2016
    Emily Mullin

    Shortly after Ernest Levy of Cooperstown, New York, returned from a trip to South Africa with his son for the 2010 World Cup, he was diagnosed with acute myeloid leukemia. The prognosis didn’t look good for Levy, now 76. Just over a quarter of adult patients survive five years after developing the disease, a type of cancer that affects bone marrow.

    Levy joined a clinical trial led by the Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School in Boston, testing a cancer vaccine for acute myeloid leukemia. After an initial round of chemotherapy, he and the other trial participants received the experimental vaccine, a type of immunotherapy intended to “reëducate” the immune cells to see cancer cells as foreign and attack them, explains David Avigan, chief of Hematological Malignancies and director of the Cancer Vaccine Program at Beth Israel.

    Now results from the trial suggest that the vaccine was able to stimulate powerful immune responses against cancer cells and protect a majority of patients from relapse—including Levy. Out of 17 patients with an average age of 63 who received the vaccine, 12 are still in remission four years or more after receiving the vaccine, Avigan and his co-authors at the Dana-Farber Cancer Institute report. The researchers found expanded levels of immune cells that recognize acute myeloid leukemia cells after vaccination. The results appear today in the journal Science Translational Medicine.

    Acute myeloid leukemia is typically treated with a combination of chemotherapies, but the cancer often relapses after initial treatment, with older patients having a higher chance of relapse.

    Therapeutic cancer vaccines are designed to work by activating immune cells called T cells and directing them to recognize and act against cancer cells, or by spurring the production of antibodies that bind to certain molecules on the surface of cancer cells. But producing effective therapeutic vaccines has proved challenging, with many of these vaccines either failing outright or showing only marginal increases in survival rates in clinical trials.

    Avigan and his colleagues created a personalized vaccine by taking leukemia cells from patients and then freezing them for preservation while they received a traditional chemotherapy. Then scientists thawed the cancer cells and combined them with dendritic cells, immune cells that unleash tumor-fighting T cells. The vaccine took about 10 days to manufacture and another three to four weeks before it was ready for administration.

    Many cancer vaccine strategies have homed in on a single target, or antigen. When the antigen is introduced in the body via injection, it causes an immune response. The body begins to produce T cells that recognize and attack the same antigen on the surface of cancer cells. The vaccine Avigan and his team created uses a mixture of cells that contain many antigens in an attempt to generate a more potent approach.

    Though the number of patients in the trial was small, Avigan says, “this was enough of a provocative finding” that the researchers will be expanding the trial to include more patients. At the same time, the personalized vaccine approach is already being tested in other types of cancers.

    See the full article here .

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  • richardmitnick 9:09 am on December 7, 2016 Permalink | Reply
    Tags: , Medicine, Prostate cancer study,   

    From UCLA: “New evidence links inflammation and increased prostate cancer risk” 

    UCLA bloc


    December 06, 2016
    Peter Bracke

    Access mp4 video here .
    Dr. Andrew Goldstein of UCLA uses walnuts to explain his latest research about chronic inflammation and it’s link to increased risk for prostate cancer.


    UCLA researchers have discovered a previously unrecognized type of progenitor cell that, though rare in most regions of the human prostate, is found in uncommonly high numbers in inflamed areas of the gland. These progenitor cells have the ability to initiate prostate cancer in response to genetic changes. The study results suggest inflammation increases overall risk for the disease by increasing the available pool of progenitor cells that can develop into prostate cancer.


    Scientists have known that one of the risk factors for high-grade prostate cancer is chronic inflammation of the prostate (a process in which cells from the immune system have taken up residence in the gland), but they have been unsure how this process led to cancer. UCLA-led research previously showed that two different types of cells, known as basal and luminal, represented potential progenitor cells and, with varying degrees of aggressiveness, could initiate prostate cancer. Further research by colleagues at Johns Hopkins Medical Center observed that prostate cells in the proximity of inflammation appeared different under the microscope and expressed different genes, leading to the hypothesis that they were more likely to proliferate than prostate cells from areas without inflammation. The UCLA-led team was able to test this hypothesis in human cells and found that cells from areas with inflammation are progenitor cells that can initiate aggressive tumors, validating their previous hypothesis and laying the foundation for the new study.


    Led by Dr. Andrew Goldstein, an assistant professor of molecular biology, the UCLA researchers investigated the CD38 gene, which is expressed by most (but not all) luminal cells in the human prostate. By comparing luminal cells that express CD38 with those that do not, they found that a greater proportion of luminal cells without CD38 had the potential to expand and grow. Results also showed that these CD38-negative luminal progenitor cells are rare in regions without inflammation but are significantly more common in regions of inflammation.

    The UCLA team then discovered that prostate tumors without CD38 were also more likely to be aggressive, to recur after initial treatment and to metastasize. The scientists hypothesized that the aggressive cancers that do not express CD38 may also arise in luminal cells that do not express CD38. These luminal progenitor cells without CD38 were found to be target cells for transformation, meaning that they can initiate cancer.


    Prostate cancer is the second leading cause of cancer death in American men, behind only lung cancer. About 1 man in 39 will die of prostate cancer each year, and an estimated 180,000 new cases of the disease are reported annually in the United States. The study furthers researchers’ understanding of the role that inflammation, progenitor cells and the CD38 gene play in the development of prostate cancer, and these findings can help lead to the development of improved treatments and screening methods for the disease.


    Goldstein is senior author of the study. The study’s first author is Xian Liu, a former member of Goldstein’s laboratory. Additional co-authors include Dr. Haley Hieronymus and Dr. Charles Sawyers of the Memorial Sloan-Kettering Cancer Center, and Dr. Tristan Grogan, Dr. Takao Hashimoto, Dr. Jack Mottahedeh, Dr. Donghui Cheng, Dr. Lijun Zhang, Dr. Kevin Huang, Dr. Tanya Stoyanova, Dr. Jung Wook Park, Dr. Ruzanna Shkhyan, Dr. Behdokht Nowroozizadeh, Dr. Matthew Rettig, Dr. David Elashoff, Dr. Steve Horvath, Dr. Jiaoti Huang and Dr. Owen Witte of UCLA. Goldstein, Rettig, Elashoff, Horvath and Witte are members of UCLA’s Jonsson Comprehensive Cancer Center.


    The study was published online today in Cell Reports.

    The study was funded by the U.S. Department of Defense and the Prostate Cancer Foundation. The research was additionally supported by UCLA’s Broad Stem Cell Research Center and SPORE in Prostate Cancer.

    See the full article here .

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    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

  • richardmitnick 1:08 pm on December 6, 2016 Permalink | Reply
    Tags: , , Medicine,   

    From UCLA: “Brains of people with autism spectrum disorder share similar molecular abnormalities” 

    UCLA bloc


    December 05, 2016
    Jim Schnabel

    Brains typically have a standard pattern for which genes are active and which are inactive (left). In the brains of people with autism (right), genes don’t follow that pattern, but they do have their own consistent patterns from one brain to the next. Neelroop Parikshak/UCLA Health

    Autism spectrum disorder is caused by a variety of factors, both genetic and environmental. But a new study led by UCLA scientists provides further evidence that the brains of people with the disorder tend to have the same “signature” of abnormalities at the molecular level.

    The scientists analyzed 251 brain tissue samples from nearly 100 deceased people — 48 who had autism and 49 who didn’t. Most of the samples from people with autism showed a distinctive pattern of unusual gene activity.

    The findings, published Dec. 5 in Nature, confirm and extend the results of earlier, smaller studies, and provide a clearer picture of what goes awry, at the molecular level, in the brains of people with autism.

    “This pattern of unusual gene activity suggests some possible targets for future autism drugs,” said Dr. Daniel Geschwind, the paper’s senior author and UCLA’s Gordon and Virginia MacDonald Distinguished Professor of Human Genetics. “In principle, we can use the abnormal patterns we’ve found to screen for drugs that reverse them — and thereby hopefully treat this disorder.”

    According to the Centers for Disease Control and Prevention, about 1.5 percent of children in the U.S. have autism; the disorder is characterized by impaired social interactions and other cognitive and behavioral problems. In rare cases, the disorder has been tied to specific DNA mutations, maternal infections during pregnancy or exposures to certain chemicals in the womb. But in most cases, the causes are unknown.

    In a much-cited study in Nature in 2011, Geschwind and colleagues found that key regions of the brain in people with different kinds of autism had the same broad pattern of abnormal gene activity. More specifically, researchers noticed that the brains of people with autism didn’t have the “normal” pattern for which genes are active or inactive that they found in the brains of people without the disorder. What’s more, the genes in brains with autism weren’t randomly active or inactive in these key regions, but rather had their own consistent patterns from one brain to the next — even when the causes of the autism appear to be very different.

    The discovery suggested that different genetic and environmental triggers of autism disorders mostly lead to disease via the same biological pathways in brain cells.

    In the new study, Geschwind and his team analyzed a larger number of brain tissue samples and found the same broad pattern of abnormal gene activity in areas of the brain that are affected by autism.

    “Traditionally, few genetic studies of psychiatric diseases have been replicated, so being able to confirm those initial findings in a new set of patients is very important,” said Geschwind, who also is a professor of neurology and psychiatry at the David Geffen School of Medicine at UCLA. “It strongly suggests that the pattern we found applies to most people with autism disorders.”

    The team also looked at other aspects of cell biology, including brain cells’ production of molecules called long non-coding RNAs, which can suppress or enhance the activity of many genes at once. Again, the researchers found a distinctive abnormal pattern in the autism disorder samples.

    Further studies may determine which abnormalities are drivers of autism, and which are merely the brain’s responses to the disease process. But the findings offer some intriguing leads about how the brains of people with autism develop during the first 10 years of their lives. One is that, in people with the disorder, genes that control the formation of synapses — the ports through which neurons send signals to each other — are abnormally quiet in key regions of the brain. During the same time frame, genes that promote the activity of microglial cells, the brain’s principal immune cells, are abnormally busy.

    This could mean that the first decade of life could be a critical time for interventions to prevent autism.

    The study also confirmed a previous finding that in the brains of people with autism, the patterns of gene activity in the frontal and temporal lobes are almost the same. In people who don’t have autism, the two regions develop distinctly different patterns during childhood. The new study suggests that SOX5, a gene with a known role in early brain development, contributes to the failure of the two regions to diverge in people with autism.

    The study’s lead authors are Neelroop Parikshak, Vivek Swarup and Grant Belgard of UCLA; other co-authors are Gokul Ramaswami, Michael Gandal, Christopher Hartl, Virpi Leppa, Luis de la Torre Ubieta, Jerry Huang, Jennifer Lowe and Steve Horvath of UCLA; Manuel Irimia of the Barcelona Institute of Science and Technology; and Benjamin Blencowe of the University of Toronto.

    The research was funded in part by the National Institutes of Health.

    See the full article here .

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    UC LA Campus

    For nearly 100 years, UCLA has been a pioneer, persevering through impossibility, turning the futile into the attainable.

    We doubt the critics, reject the status quo and see opportunity in dissatisfaction. Our campus, faculty and students are driven by optimism. It is not naïve; it is essential. And it has fueled every accomplishment, allowing us to redefine what’s possible, time after time.

    This can-do perspective has brought us 12 Nobel Prizes, 12 Rhodes Scholarships, more NCAA titles than any university and more Olympic medals than most nations. Our faculty and alumni helped create the Internet and pioneered reverse osmosis. And more than 100 companies have been created based on technology developed at UCLA.

  • richardmitnick 2:43 pm on December 5, 2016 Permalink | Reply
    Tags: , , Chemotherapy can cause metastasis, Medicine, Prof. Yuval Shaked,   

    From Technion via Globes: “Research: Chemotherapy can cause metastasis” 

    Technion bloc




    5 Dec, 2016
    Gali Weinreb

    Prof. Yuval Shaked

    New research at Israel’s Technion alarmingly reveals that the body acts to assist the tumor because it wrongly identifies chemotherapy as damaging.

    New research at Israel’s Technion alarmingly reveals that the body acts to assist the tumor because it wrongly identifies chemotherapy as damaging.

    As if the pressure caused by chemotherapy treatment was not enough, the results of the research conducted by Prof. Yuval Shaked may provide a new cause for alarm: in a series of research studies on animals, human cancer tumor cultures and indirectly also on cancer patients themselves, Shaked and his team found that while chemotherapy destroys the tumor, it encourages the development of metastasis tumors. This takes place since the body identifies chemotherapy as an attack on the body itself and mobilizes all systems for the least desirable cause – saving the tumor. At the same time, Shaked, a researcher at the new Technion Integrative Cancer Research Center, is quick to clarify: “Our research studies do not imply that chemotherapy treatments should be stopped. Chemotherapy still does more good than harm.”

    What does this series of research studies say? It identifies a real need to find a new solution, in which chemotherapy is applied in a way that reduces the damage caused as much as possible, while preserving its benefits. And Shaked also has some relevant ideas, presented in his research.

    “This series of research studies began years ago. It has been known and evident for years that cancer tumors become resistant to chemotherapy and turn ever more aggressive over time, but estimates had been that this entire development takes place inside the cancer cells themselves, the cells that remained in the body despite the damage of chemotherapy,” Shaked explains. “Following our research, it appears that the reality is somewhat more complex. It seems that resistance is developed not only by tumor cells, but by the patient’s entire body. Resistance to the treatment is directed by the body.”

    When the tumor sustains damage, body systems wrongly identify it as undesired damage to the body and act to assist the tumor. And there is even worse news: “This is true not only for chemotherapy, but for any intervention aimed at damaging the tumor. Once the tumor is harmed, the body tries to help,” Shaked says.

    The mechanisms to treat this damage do not only cause renewed multiplication in cancer tumor cells, after chemotherapy has caused it to shrink, they also turn it more violent and aggressive and encourage the formation of metastasis tumors. Animal trials have shown that even if there are no tumors, the provision of chemotherapy or anticancer drugs that kill cells activate damage treatment mechanisms that could stir cancerous processes in a mouse, if they already existed.

    In order to further support their conclusion, Shaked and his team conducted a third test in which they first treated healthy mice with an anticancer drug (not chemotherapy, but a new generation drug) such as Velcade, and only later infected the mice with cancer, without treating them. The mice treated with Velcade before infection died earlier than mice that had not been treated.

    So, the resistance of cancer to treatment, the fact that treatment becomes less effective over time, is caused by the body and not the cancer cells themselves.

    “The cancer cell and the tumor probably also have some resistance, but articles have been published saying that this resistance alone does not always explain the tumor returning after the treatment; that is, this cannot happen so rapidly only via evolution and selection of tumor cells, and there is another explanation.”

    After their research on animals, in which Shaked and his team have shown that mice treated with chemotherapy developed more metastasis tumors, with tumors becoming more aggressive, and following the research indicating that treatment alone is harmful to an animal that had no cancer to begin with, further human research studies have been conducted.

    “We took blood samples from a patient before and after chemotherapy treatment and dripped it on cancer cells in a dish. The cells that encountered the blood of a patient who had been treated with chemotherapy turned more aggressive. The blood contained materials that encouraged the development of the main tumor, and probably also of metastasis tumors.”

    Then why continue with chemotherapy anyway?

    “Despite our findings, these are the best treatments available today. The advantages of destroying the tumor using chemotherapy, which extends the patient’s life, at present outweigh the harm caused by bolstered resistance and metastasis tumors. As mentioned, this is true not only for chemotherapy treatment, but for any treatment that damages the tumor and causes it to develop resistance.”

    But what about the test you have presented, in which mice that received Velcade and were infected with cancer had lived for a shorter period than mice only infected with cancer?

    “These were mice that first received Velcade, and only after the body started secreting materials encouraging damage repair, which we already know also encourage metastasis and make the tumor more aggressive – only then were they infected with cancer, without receiving any treatment. If, after infection, we would have continued treating the mouse with Velcade, I believe that it would have still lived longer than the mice that received no treatment.”

    Does this mean that drug treatment should be continued – always and without any reservations?

    “This is not something I can answer in a sweeping manner. Every patient should consult their doctor. In the future, we might be able to predict which patients will develop a strong bodily reaction to the treatment, which will encourage the tumor to a greater extent, and for whom chemotherapy is not advisable, and who will have a weak reaction, turning this into a worthwhile treatment.”

    A cause for optimism

    After Shaked has shown the potential damage (as well as the usefulness) of cancer treatments, he has started examining ways of reducing this damage and turning the treatments more effective.

    In order to do this, you need to first understand how exactly the treatment affects the body.

    “We have estimated that the mechanism also involves the immune system, and therefore conducted another experiment: we took cells from the immune system of an animal and subjected them to chemotherapy. We have discovered that the process does pass through immune system cells. When we returned these immune cells to a mouse that did not undergo the treatment but has cancer, it was as if the mouse himself received the treatment – the increased aggressiveness of the tumor of the mouse that did not undergo the treatment but was injected with cells from the immune system of a mouse that did undergo the treatment resembled that of a mouse that did undergo the treatment.

    “So what is the cause for optimism? The next test: we took immune system cells, exposed them to chemotherapy, but this time with a drug that prevents the learning process that helps repair the damage. This time, when we injected the cells back to a mouse sick with cancer, his condition did not deteriorate.

    “Looking 800 steps ahead, if we could provide a person undergoing chemotherapy with a drug that could prevent his immune system from becoming accustomed to chemotherapy, the body may not develop the response which assists the tumor, and the tumor may not become so resilient or aggressive, which would make chemotherapy significantly more effective. Some of the drugs preventing the immune system from becoming accustomed to chemotherapy already exist and are sometimes given to patients with various illnesses (not necessarily cancer); they can be converted into cancer treatment quite easily.”

    You have mentioned the body’s reaction to chemotherapy can differ between patients.

    “We have so far discovered about 60 different factors in the body which are affected by chemotherapy; their combination affects the tumor and the metastasis reaction. These 60 factors are in fact 60 new targets for anti-cancer drugs, 60 factors that can be affected by drugs to reduce the reaction. There are already drugs on the market that could affect some of these factors. For example, we found an arthritis drug which reduces one of these harmful factors (that is, factors helping the tumor), and we have indeed shown that if it is provided with chemotherapy to mice with cancer, some of them have a longer life expectancy.

    “We could theoretically, create a combination matched to every patient, which depends on which of these 60 factors are affected by chemotherapy for that specific patient. These combinations could reduce pro-cancer reactions and thereby extend the patient’s life.”

    In the search for a cure for cancer, the body’s reaction to the cure is not even examined today, but only the treatment’s efficacy, right?

    “In principle, you are correct, other than one comment – in addition to testing the cure’s effectiveness in shrinking the tumor, the extent to which the drug is toxic to the body and the patient is also tested; but the body’s other reactions, which could eventually help the cancer cells are never examined. The main insight from our research is that the body does dictate the future of the tumor. The result of the treatment follows from the interaction between the treatment itself, the type of the treatment, and the specifics of the patient’s body.”

    One of the findings of Shaked’s research is that not only chemotherapy, but any damage to a cancerous cells creates a pro-cancerous counter-reaction in the body, but he says that there are also exceptions. “There is a certain type of chemotherapy, or more correctly a certain regimen, which we found does not result in a negative reaction in the body,” he says and explains: “At present, when administering chemotherapy, the principle is to bombard the body with the largest dosage of the material that can be administered without killing the patient. This method makes a lot of sense, since it provides for the most probable destruction of the tumor. Therefore, according to the logic that has guided the medical world so far, it verifies that nothing is left of the tumor, thereby reducing the chances of it recurring. However, our research indicates that it is exactly such chemotherapy treatment, a maximum-dosage ‘bombardment’, which creates the body’s counter-reaction that encourages tumor aggressiveness. This is of course not the only problem with high-dosage chemotherapy. It causes numerus side effectives and immense damage to the patient. After completing a high-dosage chemotherapy, the body must be given time to recover, which also gives the tumor time to recover.

    At present, with no relation to our research, they have begun testing a treatment method called metronomic chemotherapy on patients, a ‘continuously-administered’ treatment. The intention is to provide small doses of chemotherapy, but administer them on a daily basis. This dosage results in fewer side effects and enables the patient to continue with his daily life. As a result, the tumor does not shrink much, but also does not grow much, or at least, if it does grow, it does so slowly. A cancerous tumor that lives in the body and does not grow does not damage the patient. Only once it starts growing in a more significant manner does it damage other tissue and consume body resources in ways that are harmful. If a metronomic treatment enables patients to live with the same tumor for a long time, without completely killing it but exerting some control, as done with other chronic diseases, and while maintaining a good quality of life, it might be preferable to bombardment.

    “It is very important to remain cautious when discussing this possibility, since this is still an experimental treatment. It is currently undergoing phase III human trials. So far, the results show that with some patients, already subjected to many other treatments, who have developed resistance to everything and have had no other alternative, life expectancy has been extended using low-dosage chemotherapy treatment. This is a generic drug which is not at expensive.”

    Shaked says that the metronomic method raises concerns among most doctors, since it contradicts everything they have learned about proper chemotherapy, “but for patients with no proper treatment alternatives, this is certainly a possibility that should be examined.”

    Shaked adds that an initial examination run by him and his team raised the possibility that such a treatment, with a small daily dosage, causes the body to react less than a classic chemotherapy regimen, thereby keeping the tumor less aggressive for a longer period. But, for the time being, these are only assumptions. “We are currently running a test aimed at discovering the chemotherapy dosage that does not cause a negative body reaction,” he says.

    “One of the problems with such a treatment is that only a few chemotherapy drugs can be administered orally. A daily infusion is not a viable solution and producing a chemotherapy pump is impossible, which the agent will damage subdermal tissue in the place where the pump is injected. In order to make such a treatment succeed on the market, we will have to develop new chemotherapy formulas, which can be administered orally.

    “This is not necessarily a bad thing; while old-school chemotherapy is no longer patented and therefore drug companies have little motivation to research and develop it, such a drug, with an innovative drug administration mechanism, would be patented, making it more lucrative for drug companies.”

    See the full article here .

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  • richardmitnick 1:06 pm on December 5, 2016 Permalink | Reply
    Tags: , , Gene Therapies for Fatal Diseases, Medicine, Ronald G. Crystal   

    From Cornell: “Gene Therapies for Fatal Diseases” 

    Cornell Bloc

    Cornell University

    Caitlin Hayes

    Ronald Crystal is known for developing a treatment for a common, often-fatal hereditary disorder that causes emphysema and liver disease.

    Ronald Crystal. No image credit.

    In the 1980s, Ronald G. Crystal, Chairman, Department of Genetic Medicine, Weill Cornell Medicine, developed a treatment for one of the most common hereditary disorders in Caucasians: Alpha-1 Antitrypsin (A1AT) Deficiency. The inability to produce normal levels of the A1AT protein makes patients susceptible to emphysema and liver disease and is often fatal. Crystal and his team were able to purify the deficient protein from normal blood samples and deliver it back to patients with the disorder. More than 6,000 people around the world are using this treatment today, but Crystal says there’s a catch.

    “Proteins have a very short half-life,” he says. “For A1AT, they last about one week, so you have to administer the therapy with intravenous infusions every week.”

    n 1989 with prompting from a former postdoctoral student and collaborator, Crystal saw an opportunity to develop a one-time treatment for A1AT deficiency. By using a virus to deliver the gene that produces the protein, researchers could in theory give a patient the lifelong machinery to make their own A1AT. “It was this eureka moment of realizing that if we had the right virus, we might be able to take a hereditary disorder and use the virus one time to cure the disease,” says Crystal. “That’s what got me started on gene therapy.”

    Gene Therapies, Licensed and Ready for Clinical Trials

    Almost 30 years and many contributions later, Crystal may finally have the gene therapy for A1AT deficiency that would require just one dose. He licensed this technology, along with two other therapies, to a startup he co-founded in 2014, Annapurna Therapeutics. Annapurna recently merged with another company to form Adverum Biotechnologies, which will independently carry out a large clinical trial of Crystal’s gene therapy for A1AT deficiency. Crystal is an advisory board member and a paid consultant for Adverum.

    The Technology—How It Works

    Crystal’s lab focuses on in vivo gene therapy, whereby genes are delivered directly to the patient. “The problem and the challenge of the technology has been how do you get genes into human cells? How do you get them to go where you want them to go?”

    The answer is viruses. Viruses have evolved to transfer their genetic material to the cell, usually to the nucleus, and they can target certain organs or tissues. Once there, “they basically hijack the cell’s genetic machinery to reproduce themselves,” Crystal explains. In the gene therapy field, researchers essentially empty these viruses of their own genetic information and replace it with genes that a patient needs expressed.

    “We use the structure of the virus like a Trojan horse,” Crystal says. “The idea is then to directly administer the virus to the brain or heart or liver, and the virus will deliver the genetic information to the nucleus of the cell. There, it uses the cell’s genetic machinery to transcribe the gene, make a protein, and then that protein either functions within the cell or is secreted.”

    A good deal of the work in Crystal’s lab therefore involves finding and modifying viruses and genes for target organs, inserting therapeutic genes into viruses, and carrying out the studies in animal models and in small clinical trials. The therapies licensed to Adverum include the A1AT deficiency therapy as well as a therapy for another genetic disorder: hereditary angioedema. In patients with hereditary angioedema, blood vessels leak fluid and cause excessive swelling, which can lead to premature death. The third treatment is a gene therapy for severe allergy such as peanut allergy. “We can cure the diseases in mouse models in one dose,” says Crystal. “Whether they’ll work in humans, of course, we don’t know—yet.”

    The Partnership of Academia and Industry for Conducting Large-Scale Clinical Trials

    When it comes to the kinds of large-scale clinical trials that are necessary for drug approval, academics often don’t have the resources, Crystal says. “In the academic world, we can carry out early phase I studies, studies in 20 or 30 patients, but we don’t have the infrastructure or the funds to carry out the large studies that are required.”

    One answer is to partner with biotech and pharmaceutical companies, Crystal continues. “In our lab, we’ve made the initial viruses, shown that they work in animal models, in some cases shown safety, in some cases not yet,” he explains. “The concept then is to partner the academic environment—with new ideas, new therapies, and early data—with industry. They will take it over and run the clinical trials, and turn it into a drug if it works.”

    To avoid conflicts, Crystal won’t be involved in the clinical trials. “I think it’s a very good paradigm, a good way that we in the academic world can get the ideas and the creativity that we have and move it towards curing patients.”

    Foresight: Linking Technologies to Clinical Problems

    As a pulmonary doctor by training, Crystal has always had an eye on clinical problems and how his research can address them. When he began working in the gene therapy field, he followed the technology to the problems that this technology could address.

    “It’s really a kind of opportunism, in terms of understanding how the technology can be married to a clinical problem,” he says. “It’s a combination of seeing the advantages and limitations to the technology and being lucky enough to have training in medicine—so we can see how to use this technology and where best to apply it.”

    While the technology has guided Crystal to certain problems, the underlying goal has always been to improve human health. At the National Institutes of Health, where he worked for 23 years before joining Weill Cornell Medicine, his group was the first to carry out a human gene therapy in vivo to treat cystic fibrosis. With his collaborators, he has also worked on therapies for cardiac ischemia, cancer, and central nervous system disorders, and he is developing vaccines for addictive substances such as cocaine as well as other projects.

    Fusing Basic Science and Clinical Medicine

    “I decided a long time ago to focus my career on that interface between basic science and clinical medicine,” Crystal says. “I think if you ask my colleagues, physician-scientists who do similar kinds of things, probably the most satisfying thing is to at least have the opportunity to develop therapies for human disease. When we can do something and play a role in its success, that’s very satisfying.”

    Weill Cornell Medicine, Crystal continues, is a great place for the kind of work that brings basic science to clinical problems. “As a clinical scientist, it’s very important to have access to individuals who are willing to participate in clinical trials, and 10 percent of the population lives within 50 miles of Weill Cornell Medicine,” he explains, “and we have Weill Cornell Medicine, The Rockefeller University, Memorial Sloan Kettering Cancer Center, Hospital for Special Surgery—it’s a very high density of clinical and scientific talent. That’s a wonderful milieu to be in.”

    See the full article here .

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    Once called “the first American university” by educational historian Frederick Rudolph, Cornell University represents a distinctive mix of eminent scholarship and democratic ideals. Adding practical subjects to the classics and admitting qualified students regardless of nationality, race, social circumstance, gender, or religion was quite a departure when Cornell was founded in 1865.

    Today’s Cornell reflects this heritage of egalitarian excellence. It is home to the nation’s first colleges devoted to hotel administration, industrial and labor relations, and veterinary medicine. Both a private university and the land-grant institution of New York State, Cornell University is the most educationally diverse member of the Ivy League.

    On the Ithaca campus alone nearly 20,000 students representing every state and 120 countries choose from among 4,000 courses in 11 undergraduate, graduate, and professional schools. Many undergraduates participate in a wide range of interdisciplinary programs, play meaningful roles in original research, and study in Cornell programs in Washington, New York City, and the world over.

  • richardmitnick 12:19 pm on December 5, 2016 Permalink | Reply
    Tags: , , Medicine, ,   

    From Harvard Medical School: “Zika’s Entry Points” 

    Harvard University
    Harvard University


    Harvard Medical School

    December 1, 2016

    Fast-spreading virus can take multiple routes into the growing brain.

    Zika virus (light blue) spreads through a three-dimensional model of a developing brain. Image: Max Salick and Nathaniel Kirkpatrick/Novartis

    Around the world, hundreds of women infected with the Zika virus have given birth to children suffering from microcephaly or other brain defects, as the virus attacks key cells responsible for generating neurons and building the brain as the embryo develops.

    Studies have suggested that Zika enters these cells, called neural progenitor cells or NPCs, by grabbing onto a specific protein called AXL on the cell surface. Now scientists at the Harvard Stem Cell Institute (HSCI) and Novartis have shown that this is not the only route of infection for NPCs.

    The scientists demonstrated that the Zika virus infected NPCs even when the cells did not produce the AXL surface receptor protein that is widely thought to be the main vehicle of entry for the virus.

    “Our finding really recalibrates this field of research, because it tells us we still have to go and find out how Zika is getting into these cells,” said Kevin Eggan, principal faculty member at HSCI, professor of stem cell and regenerative biology at Harvard University’s Faculty of Arts and Sciences and Harvard Medical School, and co-corresponding author on a paper reporting the research in Cell Stem Cell.

    “It’s very important for the research community to learn that targeting the AXL protein alone will not defend against Zika,” agreed Ajamete Kaykas, co-corresponding author and a senior investigator in neuroscience at the Novartis Institutes for Biomedical Research (NIBR).

    Previous studies have shown that blocking expression of the AXL receptor protein does defend against the virus in a number of human cell types. Given that the protein is highly expressed on the surface of NPCs, many labs have been working on the hypothesis that AXL is the entry point for Zika in the developing brain.

    “We were thinking that the knocked-out NPCs devoid of AXL wouldn’t get infected,” said Max Salick, a NIBR postdoctoral researcher and co-first author on the paper. “But we saw these cells getting infected just as much as normal cells.”

    Working in a facility dedicated to infectious disease research, the scientists exposed two-dimensional cell cultures of AXL-knockout human NPCs to the Zika virus. They followed up by exposing three-dimensional mini-brain “organoids” containing such NPCs to the virus. In both cases, cells clearly displayed Zika infection. This finding was supported by an earlier study that knocked out AXL in the brains of mice.

    “We knew that organoids are great models for microcephaly and other conditions that show up very early in development and have a very pronounced effect,” said Kaykas. “For the first few months, the organoids do a really good job in recapitulating normal brain development.”

    Historically, human NPCs have been difficult to study in the lab because it would be impossible to obtain samples without damaging brain tissue. With the advancements in induced pluripotent stem cell (iPS cell) technology, a cell reprogramming process that allows researchers to coax any cell in the body back into a stem cell-like state, researchers can now generate these previously inaccessible human tissues in a petri dish.

    The team was able to produce human iPS cells and then, using gene-editing technology, modify the cells to knock out AXL expression, said Michael Wells, a Harvard postdoctoral researcher in the Eggan Lab and co-first author. The scientists pushed the iPS cells to become NPCs, building the two-dimensional and three-dimensional models that were infected with Zika.

    The Harvard and NIBR collaborators started working with the virus in mid-April 2016, only six months before they published their findings. This unusual speed of research reflects the urgency of Zika’s global challenge, as the virus has spread to more than 70 countries and territories.

    “At the genesis of the project, my wife was pregnant,” Eggan remarked. “One can’t read the newspapers without being concerned.”

    The collaboration grew out of interactions at the Broad Institute of Harvard and MIT’s Stanley Center for Psychiatric Research, where Eggan directs the stem cell program. His lab already had developed cell culture systems for studying NPCs in motor neuron and psychiatric diseases. The team at Novartis had created brain organoids for research on tuberous sclerosis complex and other genetic neural disorders.

    “Zika seemed to be a big issue where we could have an impact, and we all shared that interest,” Eggan said. “It’s been great to have this public/private collaboration.”

    The researchers are studying other receptor proteins that may be open to Zika infection in hopes that their basic research eventually will help in the quest to develop vaccines or other drugs that defend against the virus.

    See the full article here .


    There is a new project at World Community Grid [WCG] called OpenZika.
    Zika depiction. Image copyright John Liebler, http://www.ArtoftheCell.com
    Rutgers Open Zika

    WCG runs on your home computer or tablet on software from Berkeley Open Infrastructure for Network Computing [BOINC]. Many other scientific projects run on BOINC software.Visit WCG or BOINC, download and install the software, then at WCG attach to the OpenZika project. You will be joining tens of thousands of other “crunchers” processing computational data and saving the scientists literally thousands of hours of work at no real cost to you.

    This project is directed by Dr. Alexander Perryman a senior researcher in the Freundlich lab, with extensive training in developing and applying computational methods in drug discovery and in the biochemical mechanisms of multi-drug-resistance in infectious diseases. He is a member of the Center for Emerging & Re-emerging Pathogens, in the Department of Pharmacology, Physiology, and Neuroscience, at the Rutgers University, New Jersey Medical School. Previously, he was a Research Associate in Prof. Arthur J. Olson’s lab at The Scripps Research Institute (TSRI), where he ran the day-to-day operations of the FightAIDS@Home project, the largest computational drug discovery project devoted to HIV/AIDS, which also runs on WCG. While in the Olson lab, he also designed, led, and ran the largest computational drug discovery project ever performed against malaria, the GO Fight Against Malaria project, also on WCG.

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    The Harvard Medical School community is dedicated to excellence and leadership in medicine, education, research and clinical care. To achieve our highest aspirations, and to ensure the success of all members of our community, we value and promote common ideals that center on collaboration and service, diversity, respect, integrity and accountability, lifelong learning, and wellness and balance. To be a citizen of this community means embracing a collegial spirit that fosters inclusion and promotes achievement.

    Harvard University campus

    Harvard is the oldest institution of higher education in the United States, established in 1636 by vote of the Great and General Court of the Massachusetts Bay Colony. It was named after the College’s first benefactor, the young minister John Harvard of Charlestown, who upon his death in 1638 left his library and half his estate to the institution. A statue of John Harvard stands today in front of University Hall in Harvard Yard, and is perhaps the University’s best known landmark.

    Harvard University has 12 degree-granting Schools in addition to the Radcliffe Institute for Advanced Study. The University has grown from nine students with a single master to an enrollment of more than 20,000 degree candidates including undergraduate, graduate, and professional students. There are more than 360,000 living alumni in the U.S. and over 190 other countries.

  • richardmitnick 9:48 am on December 5, 2016 Permalink | Reply
    Tags: , , Breakthrough Prizes, Medicine, Roeland Nusse, , , Wnt signaling proteins   

    From Stanford: “Roeland Nusse wins $3 million Breakthrough Prize” 

    Stanford University Name
    Stanford University

    Krista Conger

    Roeland Nusse was awarded the 2017 Breakthrough Prize in life sciences for his contributions to the understanding a signaling molecule called Wnt. Norbert von der Groeben

    The developmental biologist was honored for helping to decode how Wnt signaling proteins affect embryonic development, cancer and the activity of tissue-specific adult stem cells that repair damage after injury or disease.

    Roeland Nusse, PhD, the Virginia and Daniel K. Ludwig Professor in Cancer Research and a Howard Hughes Medical Institute investigator, was honored this evenng with a 2017 Breakthrough Prize in life sciences.

    Nusse was awarded the $3 million prize for his contributions to the understanding of how a signaling molecule called Wnt affects normal development, cancer and the functions of adult stem cells in many tissues throughout the body.

    “This is a complete surprise,” said Nusse, who is professor and chair of developmental biology. “My gratitude goes out to many people — my past and present postdoctoral scholars and graduate students and my former mentors have all contributed to the success of my research. The research and collaborative environment at Stanford and the long-term support from the Howard Hughes Medical Institute have also been fantastic. I see this award as a great honor for the entire community.”

    The Breakthrough Prizes, initiated in 2013, honor paradigm-shifting research and discovery in the fields of life sciences, fundamental physics and mathematics. In total, about $25 million was awarded at this year’s ceremony, a black-tie, red-carpet affair at the NASA Ames Research Center in Mountain View. The event was hosted by actor Morgan Freeman. The Grammy Award-winning pop star Alicia Keys provided entertainment.

    “Roel’s pioneering work has provided deep insights into an essential molecular signaling pathway that controls normal embryonic development and adult tissue repair, and that contributes to cancer when it is not properly regulated. His work has served as a model for many others in our field and accelerated further studies of these critical processes,” said Stanford President Marc Tessier-Lavigne, PhD. “We are grateful that the Breakthrough Prize recognizes the work of scientific leaders who are inspiring others to pursue discovery that is truly transformative, benefiting all of humanity.”

    Nusse’s interest in Wnt began in the 1980s as a postdoctoral scholar in the laboratory of Harold Varmus, MD, who was then on the faculty of UC-San Francisco. In 1982, Nusse discovered the Wnt1 gene, which was abnormally activated in a mouse model of breast cancer. He subsequently discovered that members of the Wnt family of proteins also play critical roles in embryonic development, cell differentiation and tissue regeneration.

    “Roel has devoted his career to identifying one of the major signaling molecules in embryonic development, and clarifying its role in cancer development and in tissue regeneration,” said Lloyd Minor, MD, dean of the School of Medicine. “The importance of Wnt signaling in these processes cannot be overestimated. His work has been the foundation of much of modern developmental biology, and we are very proud of his contributions.”

    Nusse’s more recent work has focused on understanding how Wnt family members control the function of adult stem cells in response to injury or disease. In 1996, he identified the cell-surface receptor to which Wnt proteins bind to control cells’ functions, and in 2002 he was the first to purify Wnt proteins — an essential step to understanding how they work at a molecular level.

    “My work has shifted significantly over the years due to the influence of my Stanford colleagues, although it has always been focused on Wnt,” said Nusse. “When I arrived at Stanford, I was studying the involvement of the Wnt proteins in mouse development and cancer. I then switched to fruit flies, and then to the study of adult stem cells. Stanford has supported me during this evolution of my research career.”

    Nusse’s lab is currently devoted to understanding how Wnt signaling affects the function of adult stem cells in the liver to help the organ heal after injury, as well as what role Wnt signaling might play in the development of liver cancer.

    “The Breakthrough Prizes are a sign of the times,” said Nusse. “Together with the recently announced Chan Zuckerberg Initiative, they show how the wealth of Silicon Valley is now making an impact not just in the field of computer science, but also in biomedical fields. This is very exciting.”

    Nusse is a member of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford, of the Stanford Cancer Institute and of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. He was awarded the Peter Debye Prize from the University of Maastricht in 2000. He is a member of the U.S. National Academy of Sciences, the European Molecular Biology Organization and the Royal Dutch Academy of Sciences. He is also a fellow of the American Academy of Arts and Sciences.

    In all, seven $3 million Breakthrough Prizes — five in the life sciences, one in fundamental physics and one in mathematics — were awarded to 12 recipients. In addition, a special Breakthrough Prize in fundamental physics was awarded to the more than one thousand researchers who proved the existence of gravitational waves in February of 2016.

    Probing for dark matter

    Peter Graham. No image credit

    In addition, three $100,000 New Horizons in Physics Prizes were awarded at the ceremony. Peter Graham, PhD, an assistant professor of physics at Stanford, shared one of them with Asimina Arvanitaki of the Perimeter Institute in Ontario, Canada, and Surjeet Rajendran of the University of California-Berkeley, for “pioneering a wide range of new experimental probes of fundamental physics.”

    Graham earned a PhD at Stanford and completed postdoctoral studies at the Stanford Institute for Theoretical Physics before joining the Stanford faculty in 2010. In 2014, he received an Early Career Award from the Department of Energy.

    Graham has developed new experiments to detect particles known as dark matter, which physicists have reason to believe exist but haven’t yet been able to detect. Physicists have theorized about what dark matter might be, and based on that work have designed experiments to detect those theorized particles. However, those experiments would miss one possible variant of what dark matter might be, known as an axion.

    “It was a scary scenario that this might be what dark matter is and our current experiments wouldn’t detect it,” Graham said.

    Graham designed new experimental approaches that would detect axions if they turn out to be what make up dark matter. “This prize is a huge honor,” Graham said. “It’s great to get recognition from the community for this new direction; it will really help this emerging field.”

    Three $100,000 New Horizons in Mathematics prizes were also awarded at the Breakthrough Prize ceremony.

    In addition, two teenagers — one from Peru and one from Singapore — each won the 2017 Breakthrough Junior Challenge. They will each receive $400,000 in educational prizes.

    The Breakthrough Prizes are funded by grants from the Brin Wojcicki Foundation, established by Google founder Sergey Brin and 23andMe founder Anne Wojcicki; Mark Zuckerberg’s fund at the Silicon Valley Community Foundation; Alibaba founder Jack Ma’s foundation; and DST Global founder Yuri Milner’s foundation. Recipients are chosen by committees comprised of prior prizewinners.

    Amy Adams, director for science communications at the Stanford News Service, contributed to this article.

    See the full article here .

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    Leland and Jane Stanford founded the University to “promote the public welfare by exercising an influence on behalf of humanity and civilization.” Stanford opened its doors in 1891, and more than a century later, it remains dedicated to finding solutions to the great challenges of the day and to preparing our students for leadership in today’s complex world. Stanford, is an American private research university located in Stanford, California on an 8,180-acre (3,310 ha) campus near Palo Alto. Since 1952, more than 54 Stanford faculty, staff, and alumni have won the Nobel Prize, including 19 current faculty members

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  • richardmitnick 12:25 pm on December 4, 2016 Permalink | Reply
    Tags: , , Immunotherapy - success or failure?, Medicine,   

    From NYT: “Immune System, Unleashed by Cancer Therapies, Can Attack Organs” 

    New York Times

    The New York Times

    DEC. 3, 2016

    Chuck Peal, 61, at home in Southbury, Conn. He developed acute-onset diabetes, as did other patients who received immunotherapy at Yale. Credit Ángel Franco/The New York Times

    As Chuck Peal lay in a Waterbury, Conn., emergency room one Sunday in early September, doctors furiously tried to make sense of his symptoms. Mr. Peal, 61, appeared to be dying, and they were not sure why.

    He slipped in and out of consciousness, his blood pressure plummeted, his potassium levels soared and his blood sugar spiked to 10 times the normal level. A doctor suspected a heart attack, but uncertainty left him urgently researching the situation on his phone.

    This was not a heart attack. Mr. Peal’s body was attacking itself, a severe reaction by his immune system that was a side effect of a seemingly miraculous cancer treatment aimed at saving his life.

    In the seven weeks prior, doctors at Yale had combated Mr. Peal’s melanoma with two of the most promising drugs in cancer treatment today. These medicines work by stimulating the immune system to attack cancer as ferociously as it does other threats, like viruses and bacteria.

    These so-called immunotherapy drugs have been hailed as a breakthrough in cancer treatment, attracting billions of research dollars and offering new hope to patients out of options. But as their use grows, doctors are finding that they pose serious risks that stem from the very thing that makes them effective. An unleashed immune system can attack healthy, vital organs: notably the bowel, the liver and the lungs, but also the kidneys, the adrenal and pituitary glands, the pancreas and, in rare cases, the heart.

    Doctors at Yale believe immunotherapy is causing a new type of acute-onset diabetes, with at least 17 cases there so far, Mr. Peal’s among them. In cancer clinics around the world, and in drug trials, myriad other side effects are showing up. Studies are finding that severe reactions occur nearly 20 percent of the time with certain drugs, and in more than half of patients when some drugs are used in combination.

    Another recent paper [NCBI] found that 30 percent of patients experienced “interesting*, rare or unexpected side effects,” with a quarter of the reactions described as severe, life-threatening or requiring hospitalization. Some patients have died, including five in recent months in clinical trials of a new immunotherapy drug being tested by Juno Therapeutics Inc.

    The upshot, oncologists and immunologists say, is that the medical field must be more vigilant as these drugs soar in popularity. And they say more research is needed into who is likely to have reactions and how to treat them.

    “We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient to side effects. The woman’s immunotherapy drugs had successfully “melted away” her cancer, he said, but some weeks later, she got cold and flulike symptoms and died in the emergency room from an inflammatory response that Dr. Timmerman described as “a mass riot, an uprising” of her immune system.

    “We’ve heard about immunotherapy as God’s gift, the chosen elixir, the cure for cancer,” he said. “We haven’t heard much about the collateral damage.”

    Despite the warnings, physicians like Dr. Timmerman remain hugely supportive of drugs that are saving the lives of people who would otherwise die. Far better to cope with diabetes, hepatitis or arthritis, the thinking goes, than to die. Most reactions are not nearly so bad and are treatable.

    The rub, doctors and researchers say, is that the medical system — from front-line nurses to oncologists to emergency rooms — is too often caught off guard. This is happening for a number of reasons: The drugs are new, so many side effects just have not been seen. Symptoms appear at random, sometimes months after treatment, and can initially seem innocuous. Finally, oncologists are now trying to treat patients with a combination of two or more immunotherapy drugs, hoping for more effective treatment but sometimes getting amplified risks.

    In the meantime, these drugs are moving from academic centers into cancer clinics across the country, where oncologists in smaller cities most likely have less experience with the side effects.

    And with lives to be saved and billions of dollars to be made — $250,000 or more is the list price for a year of some regimens — not enough research has been done into the risks of the new therapies, said William Murphy, a professor of dermatology at the University of California, Davis, who reviews immunotherapy-related grants for the government.

    It is “a massively understudied area,” Dr. Murphy said, adding: “The No. 1 priority is anti-tumor effects. Everything else, however severe, is considered the price worth paying.”

    Caught in the middle are patients like Mr. Peal, whose stories show the delicacy of tinkering with the immune system. It may hold the keys to curing cancer if it can be at once stoked and tamed.

    Real Promise, and Real Risks

    Mr. Peal, bespectacled and lean, was dealing with melanoma that had spread to his lungs in June 2015 when he saw a Yale oncologist, Dr. Harriet Kluger. In the past, a patient like him would have been given little chance.

    “We’d sit the patient down and say, ‘I’m really sorry, the median life expectancy is nine months. Get your affairs in order,’” said Dr. Kluger, who runs immunotherapy clinical trials focusing on skin and kidney cancer.

    Now she could offer Mr. Peal hope. Consider: One study [New England Journal of Medicine] co-authored by Dr. Kluger found positive responses in more than 40 percent of advanced melanoma patients when they used a combination of two major immunotherapy drugs, nivolumab and ipilimumab.

    Other research, however, shows that the promise comes with real risks. A 2015 paper in The New England Journal of Medicine showed that use of these drugs carried a risk of side effects that were severe, required hospitalization or were life-threatening 54 percent of the time.

    “It’s at least that high, at least,” Dr. Kluger said. But, she noted, most of the side effects are manageable through immune suppression, such as with steroids.

    The effectiveness of immunotherapy drugs and their side effects are intimately bound by the same biological mechanisms.

    Called checkpoint inhibitors, the drugs work by essentially reversing a trick that cancer plays on the immune system: The cancer cells send nefarious signals to immune-system cells that cause them to stand down. Cancer is turning on the immune system’s brake.

    There is a valuable reason the brake exists: It can shut down the body’s powerful defenders so that they do not inadvertently attack the body itself. Cancer is taking advantage of this key survival mechanism.

    When an immunotherapy drug turns the brake off, the immune system can sometimes shrink tumors in mere days.

    By The New York Times

    Mr. Peal, an engineering technician who tests the performance of helicopter parts, started taking nivolumab and ipilimumab on July 8. Dr. Kluger told him he might feel drowsy or nauseated, or he could get a rash. A rash indeed struck with a vengeance on Aug. 30: red welts from his knees to his waist. On Sept. 1, a Thursday, he visited Dr. Kluger’s office, where he was given a steroid.

    The next day, he had a fever, nausea and was “dying of thirst — like beyond being in the desert,” he said. He threw up everything. His girlfriend, Jo-ann Keating, called Dr. Kluger’s office, and an on-call doctor prescribed an antinausea drug. Later, Ms. Keating called back to say it was not working, and he was prescribed a second antinausea drug. By Sunday morning, Mr. Peal, unable to move, took an ambulance to the emergency room.

    In his wallet, he kept an information card published by Bristol-Myers Squibb. It lists dozens of risks, including that the therapy “can cause serious side effects in many parts of your body, which can lead to death.” Mr. Peal’s family told the emergency room doctor about the treatment, Ms. Keating recalled.

    “The doctor kept on saying he was on chemotherapy,” she said. “I said, ‘They’re calling it immunotherapy.’ He went on his phone and started looking for information.”

    But even Dr. Kluger’s experienced team, which answered the distressed phone calls that weekend, was caught off guard and did not react immediately to the symptoms.

    “It took us by surprise. He looked absolutely fine on Friday,” Dr. Kluger said. Part of the problem, she thinks, is that Mr. Peal was relatively new to the clinic, and so she and her staff members did not have the experience with him to accurately assess his symptoms. “It also happened very quickly. It spiraled within hours.”

    Ultimately, Mr. Peal spent 24 days in the hospital, where trouble mounted. First his pancreas failed, then his bowels inflamed and his kidneys became dysfunctional, and “to top it off, he has a fever of 103 for which we can’t find a source,” Dr. Kluger said in an interview during the crisis. She was trying to figure it out and had emailed other experts around the country to see if they had ever had a patient with this combination of acute immune reactions. No one had seen it before.

    The pancreas problem was particularly noteworthy. Mr. Peal’s is among a growing number of such cases that have led a Yale endocrinologist, Dr. Kevan Herold, an authority on autoimmunity, to conclude that he is seeing a new form of Type 1 diabetes. Typically, the peak age of onset of Type 1 diabetes is 6 to 12, and it involves the immune system’s destroying, bit by bit, the cells in the pancreas that make the insulin needed to metabolize sugar into energy.

    But this is different: Patients are 50 or older and are losing insulin production all at once, including in one case of an 83-year-old. Dr. Herold said he was hearing similar stories from peers around the country. “A single case like this is uncommon,” he said. “As an aggregate, it’s unheard-of.”

    Colleen Platt, 65, at home in Torrington, Conn. She has been treated by Dr. Kluger for late-stage kidney cancer, which immunotherapy has largely beaten. Credit Ángel Franco/The New York Times

    Another case at Yale involved Colleen Platt, 65, a real estate agent from Torrington, Conn., who was being treated by Dr. Kluger for late-stage kidney cancer. Ms. Platt opted for a clinical trial involving two immunotherapy drugs, atezolizumab and a second drug that Dr. Kluger declined to name because the trial is continuing.

    Days after the second treatment in November 2014, Ms. Platt started feeling dizzy and numb and was vomiting water. She went to Dr. Kluger’s office, where they did lab tests that “were so profoundly abnormal, we thought this was lab error,” Dr. Kluger recounted. “We thought the machine was messed up.”

    The tests were right. Like Mr. Peal, Ms. Platt had gone into diabetic ketoacidosis, a condition in which her body, desperate to compensate for energy it was missing when her pancreas shut down, created a flux of acid that could keep her functioning in the short term, at the risk of gravely harming organs throughout her body. Outside the emergency room, while a chaplain visited Ms. Platt to comfort her, Dr. Kluger called the drug company to report the extraordinary reaction.

    Today, like Mr. Peal, Ms. Platt takes multiple insulin shots each day, and still her sugar level fluctuates wildly. On the other hand, immunotherapy has largely beaten her cancer. In fact, after consulting with other doctors and one of the drug companies, Dr. Kluger recommended Ms. Platt continue with treatment, which she did.

    “Her pancreas isn’t coming back,” Dr. Kluger said, referring to the diabetic effects of immunotherapy. “She has her life.”

    Mr. Peal — who, like Ms. Platt, agreed to let Dr. Kluger and Dr. Herold discuss his case — feels the trade-off will be well worth it. In fact, on Friday, he got the results from a scan taken the day before and learned that immunotherapy had eliminated two of his cancer lesions and shrunk two others. “I can deal with diabetes,” he said, “if I can beat melanoma.”

    ‘Nature of the Beast’

    Evidence of these challenges is decades old.

    Matthew Krummel, above at his lab in San Francisco last month, worked in the 1990s at a lab at the University of California, Berkeley, that would become one of the most influential in the development of immunotherapy. Credit Jim Wilson/The New York Times

    In the mid-1990s, Matthew Krummel, a young immunology graduate student known as Max, worked at a lab at the University of California, Berkeley, that would become one of the most influential in the development of immunotherapy. The lab was run by Dr. James Allison, who, along with Dr. Krummel, published a seminal paper in 1995 showing that they could eliminate tumors in mice by turning off a brake on the immune system.

    But the lab got less attention for a related experiment: The skin of some mice treated this way turned from black to white. They had lost their pigmentation, a result of the immune system’s attacking the cells that make melanin. The startling change was not life-threatening but indicated the power of tinkering with the immune system.

    This discovery was novel but not particularly celebrated compared with the promise of curing cancer, Dr. Krummel recalled. The skin study “was kind of a footnote,” he said.

    A microscopic view of tissue from a dead patient shows T-cells — the dark bluish dots — from the immune system invading and attacking muscle fibers in the heart. Credit Johnson et al., New England Journal of Medicine, 2016

    Then came the TeGenero tragedy in 2006.

    TeGenero Immuno Therapeutics designed a drug to stimulate the immune system to fight leukemia. At Northwick Park Hospital in London, a Phase 1 trial took place, with six healthy patients getting the drug. Within hours, all suffered multiorgan failure.

    The devastating results tempered the enthusiasm and suggested that more work needed to be done in advance of human trials. But enthusiasm came roaring back. Part of the reason was that, ultimately, the autoimmune reactions were seen not only as an acceptable cost of these drugs but as evidence they were working.

    “It’s the nature of the beast,” said Martin Bachmann, a professor and immunologist at the Jenner Institute, which is affiliated with Oxford University. “I’m not sure you can get rid of the side effects — it’s really what you want.”

    Chemotherapy, too, has side effects, but Dr. Kluger prefers immunotherapy’s trade-offs because the drugs may offer enduring control of cancer without the need for continued treatment. So she is joining others looking to address largely unanswered questions: Who is likely to be at risk, can the side effects be recognized before turning dangerous, and how should they be treated?

    In June, Dr. Kluger and Dr. Herold submitted a grant proposal to the National Institutes of Health to study whether they could predict which patients would develop these symptoms. They based the proposal on a hypothesis that some patients have a biology or a genetic background that might make them more likely to have side effects. The proposal has not yet been funded.

    Thus far, only a modicum of work has been done on these questions. Several studies found that older mice were more susceptible than younger mice to autoimmune reactions; another study, also in mice, found that obese subjects were more likely to have adverse effects.

    “Old or fat mice were literally dead within hours,” said Dr. Murphy, the professor at Davis who believes too little is being done. He is well positioned to see the trends: In the past year, he sat on eight government grant review committees focused on immunotherapy, and he said only three out of 500 research proposals he reviewed focused on the toxicity side of immunotherapy.

    Part of the problem, he said, is that the drug companies that are driving research prefer working with labs that support trials’ moving quickly. As a result, Dr. Murphy said, human trials are advancing faster than the background research can be done.

    Hoping to push access to lifesaving drugs, the Food and Drug Administration has a “breakthrough therapy designation” that allows faster approval. Since 2012, the agency has granted breakthrough designation about 110 times, almost a quarter of them for immunotherapy.

    “When people talk about moonshots, they’re talking about curing cancer, but it has to look at the whole picture,” Dr. Murphy said.

    With so much momentum pushing for a cure, the emphasis from researchers and front-line oncologists is on more vigilance about the side effects. Dr. Timmerman, from U.C.L.A., said he wished he had seen the signs of trouble in his patient, who survived cancer only to die in the emergency room after exhibiting seemingly modest flulike symptoms.

    “If we had only known the power we had unleashed that was causing such a toll on her organ system, we might have saved her,” he said.

    “You have to manage this hour by hour,” he added. “Minute by minute.”

    *If a doctor ever tells you your case is “interesting”, you are in a lot of trouble.

    See the full article here .

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  • richardmitnick 11:32 am on November 30, 2016 Permalink | Reply
    Tags: , , Medicine,   

    From popsci.com: “IBM Creates A Molecule That Could Destroy All Viruses” 


    Popular Science

    May 13, 2016 [Just found this in social media.]
    Claire Maldarelli

    Finding a cure for viruses like Ebola, Zika, or even the flu is a challenging task. Viruses are vastly different from one another, and even the same strain of a virus can mutate and change–that’s why doctors give out a different flu vaccine each year. But a group of researchers at IBM and the Institute of Bioengineering and Nanotechnology in Singapore sought to understand what makes all viruses alike. Using that knowledge, they’ve come up with a macromolecule that may have the potential to treat multiple types of viruses and prevent them from infecting us. The work was published recently in the journal Macromolecules.

    For their study, the researchers ignored the viruses’ RNA and DNA, which could be key areas to target, but because they change from virus to virus and also mutate, it’s very difficult to target them successfully.

    Instead, the researchers focused on glycoproteins, which sit on the outside of all viruses and attach to cells in the body, allowing the viruses to do their dirty work by infecting cells and making us sick. Using that knowledge, the researchers created a macromolecule, which is basically one giant molecule made of smaller subunits. This macromolecule has key factors that are crucial in fighting viruses. First, it’s able to attract viruses towards itself using electrostatic charges. Once the virus is close, the macromolecule attaches to the virus and makes the virus unable to attach to healthy cells. Then it neutralizes the virus’ acidity levels, which makes it less able to replicate.

    As an alternative way to fight, the macromolecule also contains a sugar called mannose. This sugar attaches to healthy immune cells and forces them closer to the virus so that the viral infection can be eradicated more easily.

    The researchers tested out this treatment in the lab on a few viruses, including Ebola and dengue, and they found that the molecule did work as they thought it would: According to the paper, the molecules bound to the glycoproteins on the viruses’ surfaces and reduced the number of viruses. Further, the mannose successfully prevented the virus from infecting immune cells.

    This all sounds promising, but the treatment still has a ways to go before it could be used as a disinfectant or even as a potential pill that we could take to prevent and treat viral infections. But it does represent a step in the right direction for treating viruses: figuring out what is similar about all viruses to create a broad spectrum antiviral treatment.



    See the full article here .

    Please help promote STEM in your local schools.

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