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  • richardmitnick 8:40 pm on August 25, 2016 Permalink | Reply
    Tags: , Cancer, , Scientists have finally figured out how cancer spreads through the bloodstream   

    From Science Alert: “Scientists have finally figured out how cancer spreads through the bloodstream…” 

    ScienceAlert

    Science Alert

    24 AUG 2016
    DAVID NIELD

    1
    K. Hodivala-Dilke, M. Stone/Wellcome Images

    …And that means we might be able to stop it.

    In what could be a major step forward in our understanding of how cancer moves around the body, researchers have observed the spread of cancer cells from the initial tumour to the bloodstream.

    The findings suggest that secondary growths called metastases ‘punch’ their way through the walls of small blood vessels by targeting a molecule known as Death Receptor 6 (no, really, that’s what it’s called). This then sets off a self-destruct process in the blood vessels, allowing the cancer to spread.

    According to the team from Goethe University Frankfurt and the Max Planck Institute in Germany, disabling Death Receptor 6 (DR6) may effectively block the spread of cancerous cells – so long as there aren’t alternative ways for the cancer to access the bloodstream.

    “This mechanism could be a promising starting point for treatments to prevent the formation of metastases,” said lead researcher Stefan Offermanns.

    Catching these secondary growths is incredibly important, because most cancer deaths are caused not by the original tumour, but by the cancer spreading.

    To break through the walls of blood vessels, cancer cells target the body’s endothelial cells, which line the interior surface of blood and lymphatic vessels. They do this via a process known as necroptosis – or ‘programmed cell death’ – which is prompted by cellular damage.

    According to the researchers, this programmed death is triggered by the DR6 receptor molecule. Once the molecule is targeted, cancer cells can either travel through the gap in the vascular wall, or take advantage of weakening cells in the surrounding area.

    2
    MPI for Heart and Lung Research

    The team observed the same behaviour in both lab-grown cells and mice. In genetically modified mice where DR6 was disabled, less necroptosis and less metastasis was recorded.

    The scientists have reported their findings in Nature.

    The next step is to look for potential side effects caused by the disabling of DR6, and to figure out if the same benefits can be seen in humans. If so – and there’s no guarantee of that – this has the potential to be a seriously effective way of slowing down the spread of cancer.

    There are other hypotheses on how some metastases get around the body to cause secondary growths, though. Scientists at the University of California, Los Angeles (UCLA) are currently investigating the idea that tumour cells could also spread through the body outside blood vessels and the bloodstream.

    The researchers suggest that a mechanism known as angiotropism could be used by some melanoma cancers to cling to the outside of blood vessels, rather than penetrating them. If this is confirmed, they would escape the effects of disabled DR6 and chemotherapy alike.

    “If tumour cells can spread by continuous migration along the surfaces of blood vessels and other anatomical structures such as nerves, they now have an escape route outside the bloodstream,” explained researcher Laurent Bentolila from UCLA.

    The findings from that research, also conducted on mice, have been published in Nature Scientific Reports.

    As the two studies show, not all cancers behave in the same way, which makes figuring out how they operate doubly difficult. But the more we come to appreciate how complex and varied this disease can be, the better chance we have of fighting it.

    See the full article here .

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  • richardmitnick 3:29 pm on August 25, 2016 Permalink | Reply
    Tags: , Cancer,   

    From NOVA: “The ‘Quantum Theory’ of Cancer Treatment” 

    PBS NOVA

    NOVA

    20 Jul 2016 [This just appeared in social media.]
    Amanda B. Keener

    In April 2011, Christopher Barker, a radiation oncologist at Memorial Sloan Kettering Cancer Center in New York, received some unusual news about a participant in a clinical trial. The patient was battling a second recurrence of melanoma that had spread to several areas of her body. After more than a year on the experimental drug, her tumors had only gotten bigger, and after one near her spine started causing back pain, her doctors arranged for local radiation therapy to shrink the tumor and give her some relief.

    But the tumor near her spine was not the only one that shrank. “From one set of images to another, the radiologist noticed that there was a dramatic change in the extent of the melanoma,” Barker says. Although only one tumor was exposed to radiation, two others had started shrinking, too.

    The striking regression was a very rare effect of radiation therapy, Barker and his colleagues concluded, called an abscopal response. “It’s not common,” says Barker. “But we see it, and it’s pretty remarkable when it happens.”

    1
    A woman prepares to receive radiation treatment for cancer. Photo credit: Mark Kostich/iStockphoto.

    Although the abscopal response was first recognized back in 1953, and a smattering of case reports similar to Barker’s appeared in the literature throughout the 1960s, ’70s, and ’80s, the mystery behind the abscopal response largely went unsolved until a medical student named Silvia Formenti dusted it off.

    While studying radiation therapy in Milan during the 1980s, Formenti couldn’t shake the idea that local radiotherapy must have some effect on the rest of the body. “When you burn yourself, the burn is very localized, yet you can get really systemic effects,” says Formenti, now chair of the department of radiation oncology at Weill Cornell Medical College in New York. “It seemed that applying radiotherapy to one part of the body should be sensed by the rest of the body as well.”

    The primary goal of therapy with ionizing radiation—the type used to shrink tumors—is to damage the DNA of fast-growing cancer cells so they self-destruct. But like burns, radiation also causes inflammation, a sign of the immune system preparing for action. For a long time, it was unclear what effect inflammation might have on the success of radiation therapy, though there were some hints buried in the scientific literature. For example, a 1979 study showed that mice lacking immune cells called T cells had poorer responses to radiation therapy than normal mice. But exactly what those T cells had to do with radiation therapy was anyone’s guess.

    Better Together

    In 2001, shortly after arriving in New York, Formenti attended a talk by Sandra Demaria, a pathologist also at Weill Cornell. Demaria was studying slivers of breast tumors removed from patients who had received chemotherapy and had found that in some patients, chemotherapy caused immune cells to flood the tumors. This made Formenti wonder if the same thing could happen after radiation therapy.

    In addition to fighting off illness-causing pathogens, part of the immune system’s job is to keep tabs on cells that could become cancerous. For example, cytotoxic T cells kill off any cells that display signs of cancer-related mutations. Cancer cells become troublesome when they find ways to hide these signs or release proteins that dull T cells’ senses. “Cancer is really a failure of the immune system to reject [cancer-forming] cells,” Formenti says.

    Formenti and Demaria, a fellow Italian native, quickly joined forces to determine whether the immune system was driving the abscopal response. To test their idea, their team injected breast cancer cells into mice at two separate locations, causing individual tumors to grow on either side of the animals’ bodies. Then they irradiated just one of the tumors on each mouse. Radiation alone prevented the primary tumor from growing, but didn’t do much else. Yet when the researchers also injected a protein called GM-CSF into the mice, the size of the second tumor was also controlled.

    GM-CSF expands the numbers of dendritic cells, which act as T cells’ commanding officers, providing instructions about where to attack. But the attack couldn’t happen unless one of the tumors was irradiated. “Somehow radiation inflames the tumor and makes it interesting to the immune system,” Formenti says.

    Formenti and Demaria knew that if their findings held up in human studies, then it could be possible to harness the abscopal effect to treat cancer that has metastasized throughout the body.

    Although radiation therapy is great at shrinking primary tumors, once a cancer has spread, the treatment is typically reserved for tumors that are causing patients pain. “Radiation is considered local therapy,” says Michael Lim, a neurosurgeon at Johns Hopkins University in Baltimore who is studying ways to combine radiotherapy with immunotherapy to treat brain tumors. But, he adds, “if you could use radiation to kindle a systemic response, it becomes a whole different paradigm.”

    When Demaria and Formenti first published their results in 2004, the concept of using radiation to activate immunity was a hard sell. At the time, research into how radiation affected the immune system focused on using high doses of whole-body irradiation to knock out the immune systems of animal models. It was counterintuitive to think the same treatment used locally could activate immunity throughout the body.

    That perspective, however, would soon change. In 2003 and 2004, James Hodge, an immunologist at the National Cancer Institute and his colleagues published two mouse studies showing that after radiation, tumor cells displayed higher levels of proteins that attract and activate cancer-killing T cells. It was clear radiation doesn’t just kill cancer cells, it can also make those that don’t die more attractive to immune attack, Hodge says.

    This idea received another boost in 2007 when a research team from Gustave Roussy Institute of Oncology near Paris reported that damage from radiation caused mouse and human cancer cells to release a protein that activates dendritic cells called HMGB1. They additionally found that women with breast cancer who also carried a mutation preventing their dendritic cells from sensing HMGB1 were more likely to have metastases in the two years following radiotherapy. In addition to making tumors more attractive to the immune system, Hodge says, the damage caused by radiation also releases bits of cancer cells called antigens, which then prime immune cells against the cancer, much like a vaccine.

    In some ways, Barker says, oncologists have always sensed that radiation works hand-in-hand with the immune system. For example, when his patients ask him where their tumors go after they’ve been irradiated, he tells them that immune cells mop up the dead cell debris. “The immune system acts like the garbage man,” he says.

    Now, immunologists had evidence that the garbage men do more than clean up debris: they are also part of the demolition team, and if they could coordinate at different worksites, they could generate abscopal responses. With radiation alone, this only happened very rarely. “Radiation does some of this trick,” Formenti says. “But you really need to help radiation a bit.”

    Formenti and Demaria had already shown in mice that such assistance could come in the form of immunotherapy with GM-CSF, and in 2003 they set out to test their theory in patients. They treated 26 metastatic cancer patients who were undergoing radiation treatment with GM-CSF. The researchers then used CT scans to track the sizes of non-irradiated tumors over time. Last June, they reported that the treatment generated abscopal responses in 20% of the patients. Patients with abscopal responses tended to survive longer, though none of the patients were completely cured.

    As the Weill Cornell team was conducting their GM-CSF study, a new generation of immunotherapeutic drugs arrived on the scene. Some, like imiquimod, activate dendritic cells in a more targeted way than GM-CSF does. Another group, the checkpoint inhibitors, release the brakes on the immune system and T cells in particular, freeing the T cells to attack tumors.

    In 2005, Formenti and her team found that a particular checkpoint inhibitor worked better with radiotherapy than alone and later reported that the same combination produces abscopal responses in a mouse model of breast cancer.

    Off-target, Spot-on

    In 2012, Formenti had an unexpected chance to test this treatment in the clinic when one of her patients who had read about her research requested that she try the combination on him. The patient had run out of options, so Formenti’s team obtained an exception to use the immunotherapy ipilimumab, which she had used in her 2005 study and had only been approved for melanoma, and proceeded to irradiate tumors in the patient’s liver. After five months, all but one of his tumors had disappeared. “We were ecstatic,” Formenti says. “He’s still alive and well.”

    The availability of checkpoint inhibitors seems to have opened the floodgates. Since the US Food and Drug Administration approved ipilimumab in 2011, there have been at least seven reports of suspected or confirmed abscopal responses in patients on checkpoint inhibitors, including the one Barker witnessed. Contrast that with the previous three decades, where less than one per year was reported, according to one review. Almost all of the recent cases involving checkpoint inhibitors have been in patients with melanoma, since that’s where the drugs have mainly been tested. But, abscopal responses with or without immunotherapy have been reported in patients with cancers of the liver, kidney, blood, and lung.

    There are now dozens of clinical trials combining radiation with a range of immunotherapies, including cancer vaccines and oncolytic viruses. “There’s quite a nice critical mass of people working on this,” Formenti says. She and Demaria are now finishing up a clinical trial in lung cancer patients using a protocol similar to the one that worked so well in their original patient.

    “I think we know that people who respond to checkpoint inhibitors already have more immune-activating tumors,” Demaria says. The question now, she says, is whether radiation can expand the 20% of people who respond to the combination therapy.

    One solution might be to match combinations to particular patients or tumor types. Demaria’s team is collecting blood and tissue samples from patients in a Weill Cornell lung cancer trial to look for differences in the immune responses of those who do and don’t generate abscopal responses. Such changes in the number or status of a cell type associated with particular outcomes are known as biomarkers.

    So far, there is little data about how the two types of responses differ. Barker and his team did publish measurements of a broad range of immune markers from their patient who experienced an abscopal response. “We didn’t really have a lot of clues in terms of what we should look at,” he says. They observed a bump in activated T cells and antibodies specific to tumor proteins following radiation, followed by steady declines of both as the tumors regressed. But, he says, there was no “smoking gun” that could explain why this particular patient responded the way she did.

    Understanding how the immune system responds to immunotherapy and radiation will be key to optimizing the combination of the two. “One needs to do these combinations to try and improve the outcome on both sides of the equation,” says William McBride, a radiation oncologist at the University of California, Los Angeles. There’s still controversy, for example, over whether the immune system responds better to high doses of radiation over short periods or low doses over longer periods. “We think we know the best sequence of therapy based on the pre-clinical studies, but that hasn’t been confirmed in clinical studies yet,” Barker says. “If we had a biomarker that would tell us in what way you should give the radiation, that would be enormously valuable.”

    Demaria says her research suggests that more tumor damage is not always better and that high radiation doses may be counterproductive, activating feedback responses that suppress immunity. She’s currently comparing immune signatures of different radiation regimens in mice. So far she says regimens that make the cancer look and act like virally-infected cells tend to elicit the best immune responses, but there is a long way to go in translating that work into humans.

    “Things are moving faster than they have for a long time, but at this point there are still a lot of unanswered questions,” she says.

    Fortunately, she and Formenti have plenty of motivation to work on those questions. Demaria says she still remembers examining a bit of tumor that was left behind after that first lung cancer patient received treatment. It was full of T cells which had presumably destroyed the cancer. “It’s the picture you never forget,” she says. “It is probably the biggest satisfaction to see somebody’s fate turned around by what you can do.”

    See the full article here .

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    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

     
  • richardmitnick 8:54 am on August 24, 2016 Permalink | Reply
    Tags: , Cancer,   

    From Stanford: “An emerging view of evolution is informing cancer research” 

    Stanford University Name
    Stanford University

    Aug 19 2016
    Jennie Dusheck

    Cancer cells can be as cooperative as a flock of birds, making individual decisions yet somehow acting in unison. A Stanford researcher is using this insight to make a computer model of cancer.

    1
    Parag Mallick is working with colleagues to develop a model of how cancer cells behave in order to discover what triggers their sudden transformations, from quiet and comparatively harmless tumor cells into peripatetic, metastatic cells that invade other tissues. Norbert von der Groeben

    Sitting in his office, at the Canary Center at Stanford for Cancer Early Detection, Parag Mallick, PhD, played a video on a computer: It showed a flock of birds wheeling in a blue sky. An assistant professor of radiology, Mallick said the way birds in flight move like a single, giant, living thing is key to an emerging view of the way cancer cells behave.

    Such group behavior, whether in birds, fish or cells, arises from simple rules governing the behavior of each individual.

    In a flock of birds, the rules might include how each bird always flies in the same direction as nearby birds and always stays close, though not too close, to them. But the coordinated, dancelike behavior of flocks can’t be predicted by studying one bird at a time. Complex behaviors that only emerge in groups are called “emergent properties.” For example, no single molecule has a temperature, but groups of them do.

    What triggers metastasis?

    At the Canary Center, Mallick and other researchers are building on such insights to develop a computer model of cancer. Working with a team that includes the center’s director, Sam Gambhir, MD, PhD, professor of radiology; computer scientist Christopher Ré, PhD; and interns from local high schools, Mallick is looking at how cancer cells behave in order to discover what triggers their sudden transformations, or state changes, from quiet and comparatively harmless tumor cells into peripatetic, metastatic cells that migrate all over the body, invading and altering other tissues.

    Just as hundreds of birds can suddenly take flight together and head off in one direction, swooping and turning in unison, tumor cells can perform similar feats.

    When cancer cells transition to metastatic behavior, it can happen quite suddenly, said Mallick. Non-metastatic tumor cells might sit quietly inside a tumor with a clear boundary. But when metastasis starts, the same cells become lethal; they aggressively break through the wall of the tumor and launch themselves out into the rest of the body. “Cancer cells will spontaneously start to move in one direction,” he said. But what makes cancer cells suddenly get the travel itch? And more generally, added Mallick, “What are the origins of such state changes? How do you describe them? How do we model them? What’s governing their behavior?”

    Of course, the behavior of cancer cells, like that of healthy cells, is hugely complex. For example, cells might behave in a cancerous way for reasons that are deep in their genes, or the change could be driven by signals from the environment. And metastatic cells might circulate in the blood for long periods before beginning to colonize other parts of the body.

    Yet we do know that no single governor gives a top-down order to all the cells; instead, just like a flock of birds taking wing, the cells all begin moving at once, responding to one another.

    Building a model

    In an attempt to detect, predict and prevent such transitions, Mallick and his colleagues are building a massive computer model of cancer that includes every level of organization, starting from molecular processes and the behavior of individual cells to the growth of whole tumors and their metastasis, as well as immune responses throughout the body. “We’re working on coalescing all of that information into what, in our mind, is the first-ever truly multiscale data set,” he said.

    Mallick’s forte is finding ways to connect all these different levels of organization. One connection is the sudden transition from the independent behavior of cancer cells to group behavior. Another might be a nutrient gradient across a tumor that connects the effects of nutrients on individual cells with those on the whole tumor.

    “If you are modeling water,” he said, “there’s a particular sort of math that you use to describe the behavior of single atoms, and a very different sort of math for describing the flow of rivers.” For a multiscale model of water, you would need a way for those two models to connect.

    Putting the pieces together means accepting that the very theory of how cancer works is evolving.

    An evolving theory of cancer

    Decades of work had researchers convinced that cancer resulted from genetic mutations in individual cells. The theory was that a carcinogen, such as asbestos or cigarette smoke, induced mutations in a cell’s DNA that eventually caused it to become cancerous. That bad cell multiplied and spread.

    But it has turned out that most of the things that cause cancer, including tobacco smoke and asbestos, don’t cause mutations. Rather than modifying the genes themselves, smoke and asbestos alter the activity of genes through a collection of processes called epigenetics.

    Epigenetics consists of tiny modifications — either to the DNA itself or to proteins called histones that wrap around the DNA and change the activity of the genes. For example, if you spend every weekend gardening, changes in the activity of genes in the skin cells of your hands will produce callouses.

    Our callouses might seem very ordinary to us; they come and go depending on what we’ve been up to recently. But what if the genes whose activity changes to produce them could mutate so that our callouses became permanent? What if some babies were born with calloused hands?

    Amazingly, modern evolutionary biologists are moving to the view that that’s exactly how wild plants and animals often evolve.

    It all starts with the phenotype, which is every single trait of an organism or cell other than the genome itself. The phenotype includes the actual enzymes encoded by genes, myriad metabolic pathways, the shape of a nose or the hands, a vast repertoire of behavior and even memories of an equation or a loved one.

    We already know that the same genes can produce alternate phenotypes, depending on just how the genes are expressed. That phenotypic plasticity delivers different castes of ants, all from the same genotype; hands that look different from our feet, even though they have the same genotype; and identical twins of different heights and personalities. All these changes arise from the way the immediate environments of cells, or of organs, or of whole individuals interact with genes. The differences in gene activity are mediated by an array of hormones, transcription factors and other mechanisms.

    ‘Genes are followers, not leaders’

    Evolutionary biologist Mary Jane West-Eberhard, PhD, one of the leaders of the movement to reframe evolution, has laid out the experimental evidence showing that the plasticity of an organism’s characteristics, or phenotype, foreshadows its evolution. In essence, you can start with an epigenetic variant — think calloused hands — and later that particular trait can become permanently fixed in the genes.

    Famously, West-Eberhard said, “Genes are followers, not leaders, in evolution.” Now that same idea is invading the theory of cancer. It seems that cancer cells, too, can first begin to change through temporary epigenetic changes, instead of by means of mutations in the DNA.

    In cancer biology, the role of epigenetics is gaining acceptance, but it’s still meeting resistance from researchers who may have spent a lifetime with the idea that cancer cells are primarily the result of individual mutations, said Alexander Anderson, PhD, chair of integrated mathematical oncology at the Moffitt Cancer Center, in Tampa, Florida. “There’s still definitely an old-school crowd who think if we just sequence deep enough, we’ll solve all the problems.”

    A recent article in The New Yorker about epigenetics by Siddhartha Mukherjee, MD, DPhil, triggered a storm of complaints from molecular biologists who felt that standard genetics had been ignored. But while it’s possible to quibble about whether Mukherjee, an assistant professor of medicine at Columbia University, should have put his discussion of epigenetics in context, there’s no question that epigenetics is deeply altering our understanding of both evolution and cancer. “There’s a feeling in the field that we have to start thinking more holistically,” said Anderson. And the key to that, he said, is math.

    A systems approach

    Mallick, said Anderson, is one of a few researchers with a strong understanding of both cancer biology and the mathematics needed to build a model of cancer based on a systems approach.

    Said Mallick, “We just had a paper accepted where we found that when you treated cells with a chemotherapeutic drug over long periods of time, you could make cells that were 40 times more drug-resistant. Yet the cells had no genetic alterations.” Instead, all the changes were epigenetic. “If you treated the cells with the drug, they were like, ‘Oh, OK, let me change my histones,’” he said. “It’s a crazy thought.”

    While the mechanisms for changes may be modifications to the histone proteins or the DNA, the driver of change is the environment. It is now well-established that epigenetic changes play a role in both cancer initiation and progression. The same processes may also determine if cells are cancerous or healthy, metastatic or not.

    Cancer, explained renowned developmental biologist Scott Gilbert, PhD, of Swarthmore College, can result not only from bad cells but from a bad cellular environment.

    For cancer cells, said Mallick, that means where the cells live in a tumor, how close they are to nutrient-rich blood vessels, the behavior of nearby cells and where the cells are in the body. Each of these situations can induce a range of epigenetic reactions that can impact, for example, how resistant or sensitive the cells are to chemotherapy drugs or how likely the cells are to begin to metastasize.

    A tumor comprises an array of ecological niches, each of which can induce a different kind of behavior or phenotype in the cancer cells that live there, said Anderson. But just as a tropical rainforest functions similarly whether it’s on one continent or another, different kinds of tumors share common rules that govern their overall behavior and the phenotypes of individual cells in different parts of the tumor.

    Animals and other organisms can pass epigenetically mediated traits to multiple generations without any change in the genes themselves. And at least some of these phenotypic traits can become permanently fixed in the genome, as demonstrated in lab studies. It makes sense then that cancer cells could do the same.

    Mallick said the epigenetic changes that incite tumor cells to resist deadly drugs are passed on to daughter cells. Although no one has witnessed it happen, it’s pretty clear that the right mutation could turn the trait for drug resistance from plastic to permanent, making the trait part of the cancer cells’ permanent genetic repertoire.

    As Gilbert said, “You start off with an epigenetically induced phenotype. And then if any mutations occur that allow this to be fixed into the genome, it goes for it.”

    Markerville

    This new way of understanding evolution is the theoretical engine that drives Mallick’s research. Viewing cancer as a dynamically evolving adaptive system, his team’s big focus is the giant model of cancer behavior that integrates all the different levels. “Our entire purpose in life is to build a virtual model of cancer,” said Mallick.

    The ultimate goal of the model is to explain cancer, but the model also has immediate medical uses. For instance, Mallick is using the model as a tool to help identify markers of important transitions in the life of populations of cells — to cancer, to drug resistance or to metastasis. Such markers are essential to developing tests for diagnosing cancer and for investigating how patients respond to treatment over the course of their disease.

    Mallick and his colleagues are on the verge of launching a publicly accessible, interactive database and model of cancer called Markerville. “It includes both a model of cancer and a collection of data we’ve pulled from the literature about each protein,” he said. Markerville will tell users everything known about a particular protein and also how it might be expected to serve as a marker in a given cancer. “Our goal is to build a computer program that you could come to with any protein and say, ‘OK, I’m interested in this protein and I’m looking at this cancer. Do you think it has potential to be a good biomarker?’”

    Our understanding of cancer biology has taken off in recent years, but it’s not yet clear where it’s leading researchers. Just as it’s difficult to see which way the individual birds in a flock will turn from moment to moment, it’s difficult to predict which discoveries will transform our understanding of cancer. But changes in the understanding of both basic evolutionary biology and systems biology are helping researchers see things in new ways.

    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 9:38 am on August 23, 2016 Permalink | Reply
    Tags: , Cancer, , Stanford chemists develop a new method of cancer immunotherapy   

    From Stanford: “Stanford chemists develop a new method of cancer immunotherapy” 

    Stanford University Name
    Stanford University

    August 22, 2016
    Amy Adams

    1
    Stanford postdoctoral scholar Han Xiao, Professor Carolyn Bertozzi and graduate student Elliot Woods discuss how to make cancer cells visible to the immune system. (Image credit: L.A. Cicero)

    Cancer has proven to be a wily foe, in part because the cells are so effective at hypnotizing the immune system that should act to destroy them.

    In recent years, cancer therapies that activate the body’s own immune system to destroy tumors have improved the odds against some cancers, including formerly incurable skin cancers like that afflicting former President Jimmy Carter. But the immunotherapies currently available only activate one arm of the multi-pronged immune system – the adaptive immune system – and aren’t always effective.

    Carolyn Bertozzi, a Stanford professor of chemistry, has now shown that removing certain sugars surrounding breast cancer cells can recruit a second arm of the immune system – the innate immune system. The approach, described in a study published Aug. 22 in Proceedings of the National Academy of Sciences, greatly improved the effectiveness of a breast cancer drug in a lab dish, opening up a new avenue in the fight against cancer.

    “This is a whole new dimension to immune therapy,” Bertozzi said, adding that she thinks it could be the first of many therapeutic approaches involving the sugars that surround cells, called the glycocalyx.

    “People in this field are starting to appreciate that there are many different nodes that you need to affect to get a more robust immune reaction against a tumor, and the glycocalyx appears to be one of those nodes,” she said.

    Nothing to see here

    Scientists have long known that if certain sugars are present on a tumor, it is less likely to respond well to therapies. But nobody knew what that halo of sugars was doing, in part because such a small number of labs study the glycocalyx.

    Evidence had been mounting within those few labs that do study the glycocalyx, including Bertozzi’s, that a subset of sugars called sialic acids act as a signal for the innate immune system to ignore the otherwise suspicious-looking tumor. Eliminate those sugars, and maybe innate immune cells would be more likely to recognize and attack the cancer cells, Bertozzi thought.

    And essentially that’s exactly what happened.

    Chemical lawn mower

    Bertozzi and her team worked with breast cancer cells in the lab that had varying amounts of a protein called HER2 on the surface. This is a well-known protein that’s present at some level on about three-quarters of breast cancers. Women whose tumors have that protein at high levels generally receive a therapy called Herceptin, which is an antibody that binds to HER2 and flags the tumor cell for destruction by innate immune cells, such as natural killer (NK) cells and macrophages.

    But Herceptin doesn’t always work, especially in tumors with less abundant HER2, and if sialic acids are present on the cancer cell surface, then it’s even less likely to be effective.

    Bertozzi and her team used chemistry tools they’d created in previous work to attach what is essentially a chemical lawn mower onto the Herceptin antibody. Once the drug bound to HER2 molecules on the cancer cell, the chemical mower sliced off the neighboring sialic acids.

    With those sugars gone, Herceptin became significantly more likely to activate NK cells to kill the cancerous cells, especially in cases where the cells had lower levels of HER2 and higher levels of sugars. This all took place in a lab dish, but Bertozzi is hopeful a version of this strategy could be effective in people.

    Tilting the scale

    Bertozzi said that cancer immunotherapies are a matter of tilting the scale of signals present on tumors, some of which tell immune cells to attack, and others of which tell immune cells to turn a blind eye.

    “All of the world of immune therapy is now thinking about the immune system as calculating pluses and minuses. If you want to tilt the scale toward immune activation, you can either augment the activator or remove inhibitor, or both,” said Bertozzi, who is also an investigator with the Howard Hughes Medical Institute.

    Current immunotherapies on the market work by blocking one of the inhibitory signals that are recognized by the adaptive immune system. Block those and the balance tilts in such a way that the immune system will attack the now recognizable cancer.

    Bertozzi’s approach provides a second way of tiling the balance in favor of attack, this time for the innate immune system. She said this study shows just one example of how it could work, but her sugar-removing lawnmower could be used on a wide variety of cell types, not just those expressing HER2, and on different types of sugars.

    “It’s almost always the case that you need a component of both the adaptive and innate immunity to get a robust reaction against infectious pathogens, such as during vaccination,” said Bertozzi. “The smart money suggests that the same will be true with tumors.”

    Bertozzi said the approach also highlights the importance of paying attention to the much ignored glycocalyx.

    “The fact that people don’t study and understand the contribution of the glycocalyx to interactions means there’s lost opportunity there,” Bertozzi said. “I think this work might turn the tide on that situation.”

    The study is titled “Precision glycocalyx editing as a strategy for cancer immunotherapy.” The work was funded by the National Institutes of Health.

    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 4:49 pm on August 18, 2016 Permalink | Reply
    Tags: , Cancer, Decoy drug could prevent cancer's spread, , ,   

    From Stanford and SLAC: “Decoy drug could prevent cancer’s spread” 

    Stanford University Name
    Stanford University


    SLAC Lab

    March 31, 2016 [This just appeared or re-appeared in social media.]
    By Amy Adams

    1
    A representation of the Axl protein reconstructed from X-ray crystallography data. Illustration: SLAC National Accelerator Laboratory

    Creating a molecular snapshot of the way proteins interact could help development of new cancer drugs

    When new cancer cells break free of their original tumor, they travel the blood system and land in distant organs to kindle new tumors. It’s these new cancer settlements, through a process called metastasis, that are often deadly.

    One approach to preventing that spread has involved blocking the interaction of two proteins: one called Gas6 in the bloodstream and another called Axl that bristles along the outside of cancer cells. When these two interact, it signals the cell to pack up and go.

    Despite the promise, attempts at blocking that interaction haven’t worked.

    Jennifer Cochran, an associate professor of bioengineering, and Amato Giaccia, a professor of radiation oncology, thought they might try an alternate approach. Their idea was to create a decoy Axl protein that would latch onto Gas6 in the bloodstream, sopping up all the available Gas6 and preventing any from being available to bind to the real Axl.

    2
    Protein crystal mounted on the X-Ray beam line with raw data in the background. The data represents the organization of atoms in the crystal. Image: SLAC National Accelerator Laboratory

    To create that drug, the duo made more than 10 million mutations to the Axl protein, then tested those variants to find one that stuck most tightly to Gas6. One in particular stood out. It latched on to Gas6 much more tightly than the normal protein.

    In mice, this Axl decoy protein when injected into the bloodstream sequesters the Gas6 and prevents metastasis in both breast and ovarian cancers. The team is now working to translate that success to people.

    An additional question for Cochran was what changed in their mutated protein to make it so effective. “We wanted to understand the interaction on a deeper level,” she said. “That curiosity is part of being an engineer.”

    Satisfying that curiosity could also help the team understand how the two proteins interact and predict ways of mutating other proteins to create drugs. “The idea is that if you could study this interaction you could use it in a predictive way down the road,” she said.

    Working with Irimpan Mathews, a structural biology scientist at SLAC’s Stanford Synchotron Radiation Lightsource, Cochran and her team formed crystals of the mutant Axl interacting with Gas6.

    SLAC/SSRL
    SLAC/SSRL

    They then used a technique called X-ray crystallography, which essentially creates a molecular portrait of the proteins and their interactions.

    “The crystallography revealed unique features that couldn’t have been predicted,” says Cochran, who is also a member of Stanford Bio-X. The tightest binding variant of Axl had a little pocket that helped it bind even tighter to the Gas6.

    The Stanford-SLAC collaborators are now using similar methods to interfere with two proteins that help blood vessels infiltrate and support tumors, supported by a Stanford ChEM-H program to encourage Stanford faculty collaborations with SLAC.

    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

    Stanford University Seal

    SLAC Campus
    SLAC is a multi-program laboratory exploring frontier questions in photon science, astrophysics, particle physics and accelerator research. Located in Menlo Park, California, SLAC is operated by Stanford University for the DOE’s Office of Science.
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  • richardmitnick 9:46 am on August 18, 2016 Permalink | Reply
    Tags: , Cancer, Computers trounce pathologists in predicting lung cancer type, , severity,   

    From Stanford: “Computers trounce pathologists in predicting lung cancer type, severity” 

    Stanford University Name
    Stanford University

    1
    Assessing a biopsied slice of tissue to determine the grade and severity of a tumor can be highly subjective, but Stanford researchers found that computers could be trained to make accurate assessments of lung cancer tissue. Science Photo/Shutterstock

    8.16.16

    Krista Conger
    650-725-5371
    kristac@stanford.edu

    Becky Bach
    530-415-0507
    retrout@stanford.edu

    Computers can be trained to be more accurate than pathologists in assessing slides of lung cancer tissues, according to a new study by researchers at the Stanford University School of Medicine.

    The researchers found that a machine-learning approach to identifying critical disease-related features accurately differentiated between two types of lung cancers and predicted patient survival times better than the standard approach of pathologists classifying tumors by grade and stage.

    “Pathology as it is practiced now is very subjective,” said Michael Snyder, PhD, professor and chair of genetics. “Two highly skilled pathologists assessing the same slide will agree only about 60 percent of the time. This approach replaces this subjectivity with sophisticated, quantitative measurements that we feel are likely to improve patient outcomes.”

    The research was published Aug. 16 in Nature Communications. Snyder, who directs the Stanford Center for Genomics and Personalized Medicine, shares senior authorship of the study with Daniel Rubin, MD, assistant professor of radiology and of medicine. Graduate student Kun-Hsing Yu, MD, is the lead author of the study.

    Although the current study focused on lung cancer, the researchers believe that a similar approach could be used for many other types of cancer.

    “Ultimately this technique will give us insight into the molecular mechanisms of cancer by connecting important pathological features with outcome data,” said Snyder.

    Assessing grade, severity of cancer

    For decades, pathologists have assessed the severity, or “grade,” of cancer by using a light microscope to examine thin cross-sections of tumor tissue mounted on glass slides. The more abnormal the tumor tissue appeared — in terms of cell size and shape, among other indicators — the higher the grade. A stage is also assigned based on whether and where the cancer has spread throughout the body.

    Often a cancer’s grade and stage can be used to predict how the patient will fare. They also can help clinicians decide how, and how aggressively, to treat the disease. This classification system doesn’t always work well for lung cancer, however. In particular, the lung cancer subtypes of adenocarcinoma and squamous cell carcinoma can be difficult to tell apart when examining tissue culture slides. Furthermore, the stage and grade of a patient’s cancer doesn’t always correlate with their prognosis, which can vary widely. Fifty percent of stage-1 adenocarcinoma patients, for example, die within five years of their diagnosis, while about 15 percent survive more than 10 years.

    The researchers used 2,186 images from a national database called the Cancer Genome Atlas obtained from patients with either adenocarcinoma or squamous cell carcinoma. The database also contained information about the grade and stage assigned to each cancer and how long each patient lived after diagnosis.

    The researchers then used the images to “train” a computer software program to identify many more cancer-specific characteristics than can be detected by the human eye — nearly 10,000 individual traits, versus the several hundred usually assessed by pathologists. These characteristics included not just cell size and shape, but also the shape and texture of the cells’ nuclei and the spatial relations among neighboring tumor cells.

    “We began the study without any preconceived ideas, and we let the software determine which characteristics are important,” said Snyder, who is the Stanford W. Ascherman, MD, FACS, Professor in Genetics. “In hindsight, everything makes sense. And the computers can assess even tiny differences across thousands of samples many times more accurately and rapidly than a human.”

    Bringing pathology into the 21st century

    The researchers homed in on a subset of cellular characteristics identified by the software that could best be used to differentiate tumor cells from the surrounding noncancerous tissue, identify the cancer subtype, and predict how long each patient would survive after diagnosis. They then validated the ability of the software to accurately distinguish short-term survivors from those who lived significantly longer on another dataset of 294 lung cancer patients from the Stanford Tissue Microarray Database.

    Identifying previously unknown physical characteristics that can predict cancer severity and survival times is also likely to lead to greater understanding of the molecular processes of cancer initiation and progression. In particular, Snyder anticipates that the machine-learning system described in this study will be able to complement the emerging fields of cancer genomics, transcriptomics and proteomics. Cancer researchers in these fields study the DNA mutations and the gene and protein expression patterns that lead to disease.

    “We launched this study because we wanted to begin marrying imaging to our ‘omics’ studies to better understand cancer processes at a molecular level,” Snyder said. “This brings cancer pathology into the 21st century and has the potential to be an awesome thing for patients and their clinicians.”

    The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

    Stanford co-authors of the study are former postdoctoral scholar Ce Zhang, PhD; professor of pathology Gerald Berry, MD; professor of bioengineering, of genetics and of medicine Russ Altman, MD, PhD; and assistant professor of computer science Christopher Re, PhD.

    The study was supported by the National Cancer Institute and the National Institutes of Health (grants U01CA142555 and 5U24CA160036-05).

    Stanford’s Department of Genetics also supported the work.

    See the full article here .

    Please help promote STEM in your local schools.
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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 11:14 am on August 17, 2016 Permalink | Reply
    Tags: A tiny wire with a memory to diagnose cancer, , Biomarkers, Cancer, ,   

    From EPFL: “A tiny wire with a memory to diagnose cancer” 

    EPFL bloc

    École Polytechnique Fédérale de Lausanne EPFL

    17.08.16
    Laure-Anne Pessina

    1
    A nanowire can detect cancer © I2016 Thinkstock

    EPFL researchers have used a nanowire to detect prostate cancer with greater accuracy than ever before. Their device is ten times more sensitive than any other biosensor available.

    One indicator that a cancer has started to develop is the presence of biomarkers. These are molecules that are produced by the cancer and pass into the bloodstream.

    Researchers at EPFL’s Integrated Systems Laboratory (LSI/STI) have developed a new type of sensor that can detect tiny quantities of these markers and thus improve diagnostic accuracy. The sensor comes in the form of a tiny wire and is ten times more sensitive than any other biosensor ever realized. It is therefore capable of detecting cancer at a very early stage so that patients can receive better treatment. The researchers’ work has been published in Nano Letters.

    An electrical component with a memory

    When doctors suspect that a patient has cancer, they look for biomarkers in their body. But it’s not easy to detect these molecules in very small quantities – blood is a very dense fluid, full of molecules and cells that get in the way.

    EPFL researchers have managed to get around this obstacle by inventing a new detection technique. The trick is to trap the molecules of interest by the blood sample and then detect them in a dry environment, where measurements won’t be disturbed by all the molecules. To do this, the researchers used a Memristor – a new electrical component that can “remember” all the electrical currents that pass through it. The device has been successfully tested on the biomarker for prostate cancer, known as the Prostate Specific Antigen (PSA).

    A nanowire, DNA fragments and an electric current

    To begin with, fragments of modified DNA are grafted onto a silicon nanowire. The DNA is used to trap the molecules. It is modified so that it traps only the biomarkers for prostate cancer.

    The wire is dipped into a cancer sample for close to an hour, giving the DNA time to get hold of the molecules. It is then dried and an electric charge is first sent through it. If there are molecules on the wire, they create resistance, which alters the wire’s conductivity in places. But this alone is not enough to accurately detect the biomarkers.

    It is only when the same charge is sent through the wire a second time in the opposite direction that the molecules can be properly detected. “If the wire had no memory, the two currents’ curves would be superimposed, which means there’s no memory effect,” said Sandro Carrara, from the Integrated Systems Lab.

    If the right biomarkers are trapped at the wire surface, then at the exact spot where the current reverse during the phases of sending charges into the wire, there will be a difference in the curve known as a voltage gap. It is this phenomenon that makes it possible to detect the biomarkers with so high sensitivity together with the use of modified DNA to trap the biomarkers.

    “It’s the first time a Memristor has been used to make such type of biosensor,” said Carrara.

    For now, the technique has only been used to detect biomarkers for prostate cancer. But it could be used for all types of markers. “We are also working with the Ludwig Institute and the CHUV hospital, which are providing us with samples and tumor extracts. Our next step is to use the same technique to detect breast cancer.”

    —–

    Project partners:

    Experimental Oncology Group, Ludwig Institute for Cancer Research (Lausanne)
    Senology Unit, Department of Obstetrics and Gynecology, CHUV hospital (Lausanne)
    Department of Electronic & Electrical Engineering, University of Bath (United Kingdom)
    Department of Informatics and Microsystem Technology, University of Applied Sciences Kaiserslautern, Zweibrücken (Germany)

    See the full article here .

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    EPFL campus

    EPFL is Europe’s most cosmopolitan technical university with students, professors and staff from over 120 nations. A dynamic environment, open to Switzerland and the world, EPFL is centered on its three missions: teaching, research and technology transfer. EPFL works together with an extensive network of partners including other universities and institutes of technology, developing and emerging countries, secondary schools and colleges, industry and economy, political circles and the general public, to bring about real impact for society.

     
  • richardmitnick 8:56 am on August 17, 2016 Permalink | Reply
    Tags: , Autophagy, Cancer, Kras protein, RCINJ   

    From Rutgers Cancer Institute of New Jersey (RCINJ): “Cutting Off the Cancer Fuel Supply” 

    Rutgers University
    Rutgers University

    Rutgers Cancer Institute of New Jersey

    Cancer Institute of New Jersey

    August 10, 2016
    Michele Fisher
    732-235-9872
    michele.fisher@rutgers.edu

    Research from investigators at Rutgers Cancer Institute of New Jersey and Princeton University has identified a new approach to cancer therapy in cutting off a cancer cell’s ‘fuel supply’ by targeting a cellular survival mechanism known as autophagy. Rutgers Cancer Institute Deputy Director Eileen P. White, PhD, distinguished professor of molecular biology and biochemistry in the School of Arts and Sciences at Rutgers, The State University of New Jersey, and Rutgers Cancer Institute researcher ‘Jessie’ Yanxiang Guo, PhD, assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, are the co-corresponding authors of the work published in the August 10 edition of Genes & Development. They share more about the research, which focused on lung cancers driven by the Kras protein:

    Q: Why is this topic important to explore?

    A: Between 85 to 90 percent of lung cancers are non-small-cell lung cancer (NSCLC), and response to standard treatment is typically poor. Some subsets of patients with metastatic disease have seen improved survival thanks to recently developed therapies that target particular lung cancer mutations in the EGFR, MAPK, and PI3K signaling pathways. Mutations in the Ras protein family – including Kras – are frequently detected in NSCLC, but drugs directly targeting Ras mutations in NSCLC have not been effective. Understanding the critical cellular process of autophagy and its role in Kras-driven tumor cells may lead to new therapeutic approaches for NSCLC.

    Q: What is autophagy and how does this process relate to what we already know?

    A: Cells eat themselves in times of starvation and stress by a process called autophagy. It was long believed that autophagy allows cells to digest and recycle part of themselves to support their metabolism and survive interruptions in their supply of nutrients. But whether this is true, and what the recycling was needed for, was not known. Cancer cells turn on autophagy and use it to survive too, even more so than normal cells. Previously, the White and Guo groups discovered that cancer cells activated by the Ras protein family require autophagy for cell maintenance, metabolic stress tolerance and tumor development. When Ras proteins are ‘switched on,’ they have the ability to turn on other proteins that can activate genes responsible for cell growth and survival. Therefore, understanding what autophagy does can reveal an inherent weakness exploitable for cancer therapy.

    Q: How did your team approach the work and what did you learn?

    A: The Guo, Chang and White groups at Rutgers worked together with the Rabinowitz group at Princeton University to find out how autophagy enables cancer cells to survive stress. Using the tumor derived cell lines generated from genetically engineered mouse models for Kras-driven NSCLC, we traced the path of intracellular components cannibalized by autophagy through an analytical laboratory technique known as mass spectroscopy. We found that cancer cells do indeed breakdown and recycle themselves to survive starvation. This cannibalization of cellular parts provides fuel to the powerhouses of the cell, the mitochondria, to maintain their energy levels. Thus, blocking autophagy cuts off the fuel supply to the powerhouses, creating and energy crisis and ultimately cancer cell death.

    Q: What is the implication of this finding?

    A: This finding suggests that cutting of ‘fuel’ to cancer cells by blocking autophagy may be a potential therapeutic strategy for Kras-driven lung cancers. Future research should clarify if the autophagy pathways identified in Kras-driven lung cancers can be applied to other forms of cancer.

    This work was supported in part by National Institutes of Health grants: R01 CA130893, R01 CA188096, R01 CA193970, R01 CA163591, K22 CA190521, P30 CA072720; and the Functional Genomics shared resources of Rutgers Cancer Institute for mitochondrial DNA extraction and DNA sequencing.

    See the full article here .

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    About Rutgers Cancer Institute of New Jersey
    Rutgers Cancer Institute of New Jersey (www.cinj.org) is the state’s only National Cancer Institute-designated Comprehensive Cancer Center. As part of Rutgers, The State University of New Jersey, the Cancer Institute of New Jersey is dedicated to improving the detection, treatment and care of patients with cancer, and to serving as an education resource for cancer prevention. Physician-scientists at Rutgers Cancer Institute engage in translational research, transforming their laboratory discoveries into clinical practice. To make a tax-deductible gift to support the Cancer Institute of New Jersey, call 848-932-8013 or visit http://www.cinj.org/giving. Follow us on Facebook at http://www.facebook.com/TheCINJ.

    The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Affiliate Hospitals: JFK Medical Center, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), and Robert Wood Johnson University Hospital Somerset.

    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

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  • richardmitnick 6:34 am on August 16, 2016 Permalink | Reply
    Tags: , Cancer, ,   

    From UCLA: “Cancer spreading: Caught in the act” 

    UCLA bloc

    UCLA

    August 15, 2016
    David Avery

    1
    The scientists used a technique called confocal fluorescence microscopy to produce 3-D images of melanoma cells (green) spreading along the external surfaces of blood vessels (red). Laurent Bentolila, Roshini Prakash, Raymond Barnhill and Claire Lugassy

    Scientists at the California NanoSystems Institute at UCLA have taken a major step toward confirming an unusual theory of how some cancer cells metastasize. Their findings may lead to new strategies for keeping melanoma from spreading.

    A commonly held theory about how cancer spreads is that tumor cells break off from the primary tumor and travel through the bloodstream to reach other organs, where they attach and grow into new tumors. But questions about that process have remained because circulating tumor cells in the blood sometimes have a short lifespan, and because of a lack of knowledge about how the cells leave the bloodstream and attach to organs.

    The research team was led by Laurent Bentolila, director of UCLA’s Advanced Light Microscopy/Spectroscopy lab, and included Claire Lugassy and Raymond Barnhill (formerly of UCLA and now of France’s Institut Curie). They theorized that — in addition to the prevailing theory about how cancer spreads — tumor cells also could spread through the body by a mechanism called angiotropism, meaning that they could travel along the outside of blood vessels, without entering into the bloodstream.

    Over the past decade, Lugassy and Barnhill gathered proof that tumor cells, especially those of the deadly skin cancer melanoma, creep along the outside of blood vessels like tiny spiders to spread cancer. They also found that the migrating cancer cells mimicked pericytes — cells that line the capillary blood vessels — which prevented the cancer cells from being killed by the human immune system.

    The research by Bentolila’s team marks the first time that these migrating cells have been imaged in 3-D.

    To do the imaging, the scientists infused blood vessels with red fluorescent dye while human melanoma cells, which were dyed green, were injected into the brain of a mouse. They used a microscopic technique called confocal fluorescence microscopy, which provides true three-dimensional optical resolution, to create 3-D images in which the dyed tumor cells and the vessels glowed under specific light. The images showed the cells begin to grow as a primary tumor at the injection site. Soon, the researchers observed the green cells spreading from the tumor and migrating along the outer surfaces of the red-dyed blood vessels.

    “Lugassy and Barnhill’s research on angiotropism has questioned the assumption that all metastatic tumor cells break off and flow through the bloodstream to spread disease,” Bentolila said. “If tumor cells can spread by continuous migration along the surfaces of blood vessels and other anatomical structures such as nerves, they now have an escape route outside the bloodstream.”

    If tumor cells are found circulating in the bloodstream, Bentolila said, doctors might prescribe chemotherapy.

    “But if the metastasizing cells are on the outside of the blood vessels,” he said, “they escape exposure to the treatment and continue to spread cancer.”

    The findings will enable researchers to seek new targets for deadly cancers such as glioma, glioblastoma, pancreatic cancer, prostate cancer and gynecological carcinosarcomas.

    Imaging for the study, which was published in the journal Nature Scientific Reports, was performed at the Advanced Light Microscopy/Spectroscopy core technology center at the California NanoSystems Institute at UCLA.

    2
    Advanced Light Microscopy/ Spectroscopy. clms.cnsi.ucla.edu2

    The research was supported by the National Institutes of Health and the UCLA Clinical Translational Science Institute.

    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 2:27 pm on August 15, 2016 Permalink | Reply
    Tags: , Cancer, Grad student’s discovery could enable rapid screening of anti-cancer compounds,   

    From U Chicago: “Grad student’s discovery could enable rapid screening of anti-cancer compounds” 

    U Chicago bloc

    University of Chicago

    August 11, 2016
    Carla Reiter

    1
    Graduate student Di Liu co-authored an article describing how to create tiny, knotted chemical structures that may provide a way to rapidly screen hundreds of chemicals for anti-cancer activity. Photo by Joel Wintermantle

    It isn’t often that a graduate student makes a spectacular technical leap in his field, or invents a process that can have a significant impact on a real-world problem. Di Liu did both.

    A chemistry graduate student at UChicago, Liu devised a way to make tiny knotted and interlocked chemical structures that have been impossible for chemists to fabricate until now, and he invented a way that those knots might be used to quickly screen hundreds of chemicals for fighting cancer.

    Many chemicals have knots or links as part of their structure. But synthesizing new substances that tie themselves in knots at the molecular scale is prodigiously difficult. Liu found a way to generate a large variety of tiny knots, 15 to 20 nanometers in diameter (smaller than a virus), in a piece of single-stranded DNA.

    2
    Asst. Prof. Yossi Weizmann co-authored the paper on generating knotted chemical structures. Photo by Joel Wintermantle

    “Nobody could do it before,” said Yossi Weizmann, an assistant professor in chemistry and a co-author on the paper. “Di found a way to synthesize something that’s very challenging.” The challenge was part of what attracted him. Liu, Weizmann and three co-authors published their findings July 4 in Nature Chemistry.

    “Some people want to run faster; some people want to jump higher. Chemists want to create more complex molecules,” Liu said. “It’s a demonstration of our capability.”

    The knots are a way to mimic what happens to DNA inside cells, and they offer a possible tool for attacking an enzyme crucial to the survival of cancer cells.

    ‘Super-coiled’ DNA

    DNA is a long molecule. In living cells, it must coil itself up in order to fit into the cell nucleus, and in doing so it becomes “super-coiled”—an effect similar to being knotted. Like a piece of string twisted too tightly, short segments twist back on themselves, tangle and poke off to the side of the main strand, interfering with the DNA’s ability to function.

    When the DNA needs to replicate, an enzyme called DNA topoisomerase snips the super-coils and untangles them, relaxing the tension in the strand. Then it rejoins the snipped ends so the DNA can function. It’s a feat so complex that James Wang, the enzyme’s discoverer, dubbed it “the magician of the DNA world.” It also makes topoisomerase a prime target for anti-cancer drugs: If the topoisomerase in a cancer cell doesn’t function, the cancer cell will die.

    Liu uses knotted DNA as a probe to detect the activity of topoisomerase. He first gets the knots to form themselves from strategically designed sequences of single-stranded DNA and shorter segments he calls “staples.” The four nucleotides that make up DNA bond with each other according to strict rules: A bonds only with T; C bonds only with G. So by picking the sequence of nucleotides on the staples, Liu can manipulate where each will attach to the long strand.

    Using this method Liu has encouraged the formation of nine different knot structures, some, he acknowledged, simply for the satisfaction of being able to do it. After the structure forms, an enzyme seals the ends and another enzyme removes the staples.

    When topoisomerase is introduced into a vial containing the knotted DNA, it snips the knot, untangles it and seals its ends to form a circle, “unknotting” the knot. The relative quantities of knots and circles after adding topoisomerase show how active the enzyme has been in unknotting the knots: fewer circles equal less action.

    Testing, retesting

    To test a potential anti-topoisomerase drug, researchers could run the test before and after introducing the drug, and see if the drug had inhibited the action of the enzyme. But the method chemists typically use for such assays, gel electrophoresis, is too slow to be a practical way to screen drug candidates.

    Liu invented an alternative. He realized that he didn’t need to see the knots themselves, he just needed to see evidence that the enzyme had unknotted them. Since the circles of DNA can replicate while the knots can’t, he looked for replication, which is easily detectable using a fluorescent dye that binds to DNA.

    “You’re detecting the activity of topoisomerase, because it can unknot the knot to a circle,” said Weizmann. “And if the DNA is unknotted, then you can detect the replication. And because this method is electrophoresis-free, it can be used in high through-put screening for drugs against this enzyme.”

    Liu and Weizmann plan to begin testing a library of chemicals, beginning with molecules already approved by the FDA. “There are hundreds, Weizmann said. “If you hit something, then you start to study it. If you don’t, you go on to others. It’s trial by error. But you have the ability to screen hundreds because the method is very easy.”

    Funding: Howard Hughes Medical Institute and the National Science Foundation.

    See the full article here .

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    U Chicago Campus

    An intellectual destination

    One of the world’s premier academic and research institutions, the University of Chicago has driven new ways of thinking since our 1890 founding. Today, UChicago is an intellectual destination that draws inspired scholars to our Hyde Park and international campuses, keeping UChicago at the nexus of ideas that challenge and change the world.

     
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