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  • richardmitnick 2:28 pm on June 2, 2016 Permalink | Reply
    Tags: , , New Rutgers research aims at exploring gender differences in lung cancer,   

    From Rutgers: “New Rutgers research aims at exploring gender differences in lung cancer” 

    Rutgers University
    Rutgers University

    No writer credit found

    Recent lung cancer statistics from the American Lung Association have shown that in the last 38 years, lung cancer diagnoses for females have risen by double, while they have fallen 29% among males. Now Rutgers researchers are studying why this gender difference has occurred, with a $400,000 reward from the American Lung Association.

    “This research will allow me to explore questions that are important to both lung cancer patients and the medical community, as our findings may help reduce lung cancer incidence and mortality,” says Dr. Goyal, who is an associate professor of radiation oncology at Rutgers Robert Wood Johnson Medical School. “If our work is able to show a potential difference between men and women in response to these types of tests, patients will have an opportunity to better understand the benefits and alternatives to medical imaging of the heart and will be better informed of their risk of developing lung cancer. I am grateful for this support from the American Lung Association.”

    See the full article here .

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    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.

  • richardmitnick 7:17 am on June 1, 2016 Permalink | Reply
    Tags: , , , UCLA researchers identify protein that could prevent tumor growth in cervical cancer   

    From UCLA: “UCLA researchers identify protein that could prevent tumor growth in cervical cancer” 

    UCLA bloc


    May 31, 2016
    Reggie Kumar

    Cervical cancer cells. The disease is the second most common cause of cancer-related deaths in women.

    UCLA scientists have identified a protein that has the potential to prevent the growth of cervical cancer cells. The discovery could lead to the development of new treatments for the deadly disease.

    In a five-year study using human samples and mouse models, researchers led by Dr. Eri Srivatsan, a member of the UCLA Jonsson Comprehensive Cancer Center, found that a protein known as cystatin E/M can inhibit cellular inflammation, which is a major contributor to the growth of cervical cancer.

    Typically, inflammation develops after a woman contracts the human papilloma virus from a male partner; the virus can eventually lead to the development of cervical cancer. Environmental factors such as smoking also are closely associated with the disease.

    The UCLA researchers discovered that cystatin E/M prevents a protein called NFkB, which regulates inflammation, from entering the nucleus of cervical cancer cells. As a result, decreased inflammation slows tumor cell growth.

    “When key inhibitory mechanisms break down, cancer cells produce inflammation that helps fuel cancer cell growth,” said Srivatsan, who is a professor in UCLA’s department of surgery. “By identifying this protein, we have discovered a key regulator of this breakdown. This is the first time we have found that inhibition of the protein kinase by cystatin E/M plays a regulatory role in cell inflammation.”

    The study is published* online in the journal Molecular and Cellular Biology.

    Worldwide, cervical cancer is the second most common cause of cancer-related deaths in women. In the United States, HPV is detected in 90 percent of cervical cancer tumors and is the most common sexually transmitted disease, Srivatsan said.

    Although cystatin E/M and its basic function had previously been identified, little else was known about the protein’s molecular activity until 2008, when Srivatsan and colleagues’ initial findings were published in Genes Chromosomes and Cancer.

    The new study built upon that research. Srivatsan’s team analyzed 20,000 genes in two sets of cell lines — one set that expressed the cystatin E/M protein and the other that didn’t. They also analyzed 66 samples of normal and cancerous cervical tissues to determine the molecular mechanism that inhibits cancer cell growth.

    In future research, Srivatsan’s team will aim to determine whether cystatin E/M could inhibit tumor cell growth in chemo-radiation–resistant breast cancers in human tissue culture and animal models.

    Dr. Neda Moatamed, a UCLA assistant professor of pathology and laboratory medicine and a member of the Jonsson Cancer Center, was a co-author of the study. The research was supported by the VA Greater Los Angeles Healthcare System.

    *Science paper:
    Cystatin E/M suppresses tumor cell growth through cytoplasmic retention of NF-κB

    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 2:58 pm on May 29, 2016 Permalink | Reply
    Tags: , , Texas cancer research grant helps UTA recruit promising young biology researcherand expand health science focus,   

    From U Texas Arlington: “Texas cancer research grant helps UTA recruit promising young biology researcher, expand health science focus” 

    U Texas Arlington

    University of Texas at Arlington

    May 24, 2016
    Louisa Kellie

    Mark Pellegrino will join the UTA College of Science as an assistant biology professor in August.

    The Cancer Prevention and Research Institute of Texas has awarded The University of Texas at Arlington an $823,067 grant to recruit star cell biology researcher Mark Pellegrino from Memorial Sloan Kettering Cancer Center in New York.

    Pellegrino will join the UTA College of Science as an assistant biology professor in August. He is an internationally recognized biologist whose discovery that mitochondria are an important activator of innate immunity was published* in Nature in 2014.

    “Mark Pellegrino is positioned to become a leader among cell biologists,” said Morteza Khaledi, dean of the College of Science. “Studies of how cells respond to mitochondrial stress are of growing interest because of the implications for multiple conditions such as cancer, Parkinson’s disease and bacterial infections.”

    Pellegrino said that he has many important new research projects planned at UTA.

    “My long term goal is to use my knowledge of mitochondrial stress response to develop reagents with therapeutic potential,” Pellegrino said. “I am especially excited to join UTA as the University gears up to become a leader in the area of biomedical sciences.”

    Pellegrino’s appointment comes as UTA is expanding its focus on research that advances health and the human condition under the Strategic Plan 2020: Bold Solutions |Global Impact. Construction is scheduled to begin this fall on a $125 million Science and Engineering Innovation and Research building with 200,000 square feet of teaching and research space that will enable enhanced activity in the health sciences.

    Duane Dimos, vice president of research, expressed appreciation for the strong support from the state and the University of Texas System that is allowing UTA to expand it health research programs.

    “With the state’s support, we are attracting and hiring leaders in multiple fields as we grow as a Research 1 university,” Dimos said. “We have an important role to play in the economy of North Texas and in the state’s ability to produce large numbers of degreed adults in high-demand fields including healthcare.”

    In the past year, UTA has attracted other world-renowned biologists, including the new chair of biology and biology professor Clay Clark, former head of biochemistry at North Carolina State University. Clark’s laboratory work focuses on imbalances in programmed cell death in the growth of cancers, and the potential therapeutic role of enzymes that can regulate cell death in cancer.

    Jon Weidanz also recently joined the university as associate vice president for research and professor of biology. Weidanz, a seasoned entrepreneur, has 20 years of experience in biotechnology research with emphasis in immunology, immunotherapy and immunodiagnostic product development, especially related to oncology and the development of products to diagnose and treat cancer.

    Clark said, “We are progressively building up our biology program with an increasing emphasis on health sciences. Dr. Pellegrino’s cancer research is a great fit for our department and we are excited that he is joining our team later this year.”

    Pellegrino earned his bachelor’s of science and master’s of science degrees at McGill University in Canada and his Ph.D. from the University of Melbourne in Australia. He worked as a post-doctoral fellow at the University of Zurich in Switzerland before joining Memorial Sloan Kettering Cancer Center in New York as a post-doctoral associate in their cell biology program.

    UTA has previously won more than $3 million in CPRIT grants to develop tools to determine where thyroid cancer is and to treat it, to improve cancer detection and for biomechanical profiling of migrating brain cancer genotypes in tightly confined space for drug screening.

    About the Cancer Prevention and Research Institute of Texas

    Beginning operations in 2009, CPRIT has to date awarded $1.57 billion in grants to Texas researchers, institutions and organizations. CPRIT provides funding through its academic research, prevention, and product development research programs. Programs made possible with CPRIT funding have reached all 254 counties of the state, brought more than 100 distinguished researchers to Texas, advanced scientific and clinical knowledge, and provided more than 2.8 million life-saving education, training, prevention and early detection services to Texans. Learn more at cprit.texas.gov.

    *Science paper:
    Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection.

    See the full article here .

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    U Texas Arlington Campus

    The University of Texas at Arlington is a growing research powerhouse committed to life-enhancing discovery, innovative instruction, and caring community engagement. An educational leader in the heart of the thriving North Texas region, UT Arlington nurtures minds within an environment that values excellence, ingenuity, and diversity.

    Guided by world-class faculty members, the University’s more than 48,000 students in Texas and around the world represent 120 countries and pursue more than 180 bachelor’s, master’s, and doctoral degrees in a broad range of disciplines. UT Arlington is dedicated to producing the lifelong learners and critical thinkers our region and nation demand. More than 60 percent of the University’s 190,000 alumni live in North Texas and contribute to our annual economic impact of $12.8 billion in the region.

    With a growing number of campus residents, UT Arlington has become a first-choice university for students seeking a vibrant college experience. In addition to receiving a first-rate education, our students participate in a robust slate of co-curricular activities that prepare them to become the next generation of leaders.

  • richardmitnick 10:48 am on May 29, 2016 Permalink | Reply
    Tags: , , , Scientists just made big progress in fighting this incurable form of brain cancer   

    From Science Alert: “Scientists just made big progress in fighting this incurable form of brain cancer” 


    Science Alert

    This post is dedicated to E.B.M., cancer researcher. I hope that he or his parents see it.

    27 MAY 2016


    Because chemo is just not good enough.

    Researchers working on a more effective treatment for brain tumours have achieved such amazing results, they thought there was an error in their calculations. But the results are real: and the implications could be huge.

    By using an organic ‘nanocarrier’ to deliver chemotherapy drugs directly to tumours in the brain, the scientists have been able to achieve significant improvements in the number of cancer cells being killed off.

    The technique has so far only been tested in mice, but if replicated in humans – which, to be clear, is no easy feat – it could eventually lead to new treatments for people with specific types of brain cancer.

    Lead researcher and radiologist Ann-Marie Broome at the Medical University of South Carolina has been targeting glioblastoma multiforme (GBM) – a particularly stubborn form of cancer that’s currently incurable.

    Its position in the brain makes it difficult to operate on, and the blood-brain barrier (designed to protect the brain from harm) means that getting an effective dose of drugs to the tumour isn’t easy.

    A schematic sketch of blood vessels in the brain.
    Date March 2009
    Armin Kübelbeck

    That’s where this new nanotechnology approach comes in. Broome and her colleagues used what they already knew about GBM and platelet-derived growth factor (PDGF) – which regulates cell growth and division – to create their new nanocarrier, built from an aggregate of molecules.

    The carrier, technically known as a micelle, is small enough to cross the brain-blood barrier to apply the treatment directly. The researchers describe it as using a postal code to get the drugs to the right place – the micelle gets the dose to the right street, and then the PDGF is used to find the right house.

    “I was very surprised by how efficiently and well it worked once we got the nanocarrier to those cells,” says Broome. “When we perfect this strategy, we will be able to deliver potent chemotherapies only to the area that needs them.”

    “This will dramatically improve our cure rates while cutting out a huge portion of our side effects from chemotherapy,” she adds. “Imagine a world where a cancer diagnosis not only was not life-threatening, but also did not mean that you would be tired, nauseated, or lose your hair.”

    The brain tumour’s own natural chemistry actually gives the micelle nanocarriers their potency. As the tumour grows, it creates waste by-products that cause acidity in the blood, which triggers the release of the micelle’s payload.

    “It’s very important that the public recognise that nanotechnology is the future,” said Broome. “It impacts so many different fields. It has a clear impact on cancer biology and potentially has an impact on cancers that are inaccessible, untreatable, undruggable – that in normal circumstances are ultimately a death knell.”

    Now that the researchers have shown that nanocarrier delivery is possible – at least in mice – they need to test a wider range of drugs against a wider range of cancers. If all goes well, hopefully we’ll hear about clinical trials involving humans later on down the track.

    There’s obviously a ways to go before this technique will become available to treat cancer in people, but nanotechnology has been showing promising results in previous studies, so this might just be how we end up fighting the disease in the future.

    The findings have been published in Nanomedicine.

    See the full article here .

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  • richardmitnick 12:57 pm on May 28, 2016 Permalink | Reply
    Tags: , ,   

    From CUMC NY Presbyterian Hospital: “Unmasking a killer” 


    Columbia University Medical Center

    Unmasking a killer: how immunotherapy helps your body find cancer and destroy it.

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  • richardmitnick 3:02 pm on May 26, 2016 Permalink | Reply
    Tags: , , , TSRI Scientists Discover Mechanism that Turns Mutant Cells into Aggressive Cancers   

    From Scripps: “TSRI Scientists Discover Mechanism that Turns Mutant Cells into Aggressive Cancers” 

    Scripps Research Institute

    Scientists at The Scripps Research Institute (TSRI) have caught a cancer-causing mutation in the act.

    A new study shows how a gene mutation found in several human cancers, including leukemia, gliomas and melanoma, promotes the growth of aggressive tumors.

    “We’ve found the mechanism through which this mutation leads to a scrambling of the genome,” said TSRI Associate Professor Eros Lazzerini Denchi, who co-led the study with Agnel Sfeir of New York University (NYU) School of Medicine. “That’s when you get really massive tumors.”

    The research, published* May 26, 2016 by the journal Cell Reports, also suggests a possible way to kill these kinds of tumors by targeting an important enzyme.

    A Puzzling Finding

    The researchers investigated mutations in a gene that codes for the protein POT1. This protein normally forms a protective cap around the ends of chromosomes (called telomeres), stopping cell machinery from mistakenly damaging the DNA there and causing harmful mutations.

    POT1 is so critical that cells without functional POT1 would rather die than pass on POT1 mutations. Stress in these cells leads to the activation of an enzyme, called ATR, that triggers programmed cell death.

    Knowing this, scientists in recent years were surprised to find recurrent mutations affecting POT1 in several human cancers, including leukemia and melanoma.

    “Somehow those cells found a way to survive—and thrive,” said Lazzerini Denchi. “We thought that if we could understand how that happens, maybe we could find a way to kill those cells.”

    It Takes Two to Tango

    Using a mouse model, the researchers found that mutations in POT1 lead to cancer when combined with a mutation in a gene called p53.

    “The cells no longer have the mechanism for dying, and mice develop really aggressive thymic lymphomas,” said Lazzerini Denchi.

    P53, a well-known tumor suppressor gene, is a cunning accomplice. When mutated, it overrides the protective cell death response initiated by ATR. Then, without POT1 creating a protective cap, the chromosomes are fused together and the DNA is rearranged, driving the accumulation of even more mutations. These mutant cells go on to proliferate and become aggressive tumors.

    The findings led the team to consider a new strategy for killing these tumors.

    Scientists know that all cells—even cancer cells—will die if they have no ATR. Since tumors with mutant POT1 already have low ATR levels, the researchers think a medicine that knocks out the remaining ATR could kill tumors without affecting healthy cells. “This study shows that by looking at basic biological questions, we can potentially find new ways to treat cancer,” said Lazzerini Denchi.

    The researchers plan to investigate this new therapeutic approach in future studies.

    In addition to Lazzerini Denchi and Sfeir, authors of the study, “Telomere replication stress induced by POT1 inactivation accelerates tumorigenesis,” were Angela Beal and Nidhi Nair of TSRI; Alexandra M. Pinzaru, Aaron F. Phillips, Eric Ni and Timothy Cardozo of the NYU School of Medicine; Robert A. Hom and Deborah S. Wuttke of the University of Colorado; and Jaehyuk Choi of Northwestern University.

    The study was supported by the National Institutes of Health (grants AG038677, CA195767 and GM059414), a NYSTEM institutional training grant (C026880), a scholarship from the California Institute for Regenerative Medicine, a Ruth L. Kirschstein National Research Service Award (GM100532), The V Foundation for Cancer Research, two Pew Stewart Scholars Awards and the Novartis Advanced Discovery Institute.

    *Science paper:
    Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis

    See the full article here .

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

  • richardmitnick 8:44 pm on May 24, 2016 Permalink | Reply
    Tags: , , New Stanford-developed tool allows easier study of blood cancers,   

    From Stanford: “New Stanford-developed tool allows easier study of blood cancers” 

    Stanford University Name
    Stanford University

    May 24, 2016
    Christopher Vaughan

    In the history of science and medicine, the breakthrough discoveries get a lot of deserved attention, but often overlooked are the invention of the tools that made those discoveries possible. Galileo discovered moons around other planets, but it was the invention of the telescope that made his observation possible. Leeuwenhoek discovered microbes only after he created a simple but powerful microscope.

    Researchers in the laboratory of Stanford’s Ravi Majeti, MD, PhD, have just created one such tool — a method of implanting cells to create a human bone-like structure in mice. This allows investigators to study a whole host of blood cancers and other diseases that they had trouble studying before. Majeti and colleagues published* the work this week in the journal Nature Medicine.

    “Transplanting human leukemia cells into mice has been an important way of studying the disease,” postdoctoral fellow Andreas Reinisch, MD, PhD, first author of the paper, recently explained. “This method has given us important insights into how cancer develops and has been the way that all new anti-leukemia drugs have been tested and developed.” Mice engrafted with human leukemia cells are even sometimes used to test possible drug treatments for patients currently undergoing treatment for the blood cancer, he added.

    The problem, said Reinisch, is that even in the best cases, researchers can get human leukemia to take up residence and multiply in mice only half the time. For many types of blood cancers, engraftment doesn’t happen at all. It’s like Galileo’s telescope could only be pointed at a small spot of sky visible through a hole in his roof.

    Majeti, Reinisch, and their co-workers have metaphorically blown the roof off by transplanting special bone marrow-derived cells called stromal cells in mice. These human stromal cells multiply and divide to create a miniature, bone-like structure, complete with a bony outer shell and an internal, marrow-like compartment. This structure allows implanted human blood cells to live and grow in their natural environment — human bone.

    “I’m really excited about this technique because we now have a way to look closely at all kinds of leukemia, as well as many other profilerative disorders of blood cells,” Majeti said. “It also opens up the study of other, non-blood diseases such as metastatic breast cancer, which often spreads to bone in humans but simply won’t spread in existing mouse models.”

    Science paper:
    A humanized bone marrow ossicle xenotransplantation model enables improved engraftment of healthy and leukemic human hematopoietic cells

    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 4:25 pm on May 22, 2016 Permalink | Reply
    Tags: , , U Penn   

    From Penn: “Breaking Down Cancer Cell Defenses” 

    U Penn bloc

    University of Pennsylvania

    May 20, 2016
    No writer credit found

    Inhibiting Membrane Enzyme May Make Some Cancer Cells More Vulnerable to Chemotherapy, Finds Penn Study

    The mistaken activation of certain cell-surface receptors contributes to a variety of human cancers. Knowing more about the activation process has led researchers to be able to induce greater vulnerability by cancer cells to an existing first-line treatment for cancers (mainly lung) driven by a receptor called EGFR. The team, led by Eric Witze, PhD, an assistant professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania, published* their findings this month in Molecular Cell.

    “We found that inhibiting an enzyme that adds the fatty acid palmitate onto proteins creates dependence by cancer cells on EGFR signaling for survival,” Witze said. By using a small molecule called 2-bromo-palmitate (2BP) that inhibits these palmitate-adding enzymes, the researchers surmise that cancer patients might be able to one day make their cells more sensitive to cancer-fighting EGFR inhibitors.

    Palmitate is the most common fatty acid found in animals, plants, and microbes, although is not well studied. Proteins that have palmitate bound to them are usually associated with the cell membrane. Palmitate allows these proteins to transfer chemical signals from outside the cell to inside via the cell membrane.

    EGFR itself is a transmembrane protein associated with palmitate, and by blocking palmitate, EGFR becomes hyperactivated. “We thought that this finding would be ‘good’ for the cancer, but ‘bad’ for a cancer patient,” Witze said. In cancers not related to EGFR signaling, this relationship is correct; however, in cancers related to EGFR, if the palmitate-adding enzyme is inhibited, EGFR is activated, but cancer cells grow more slowly.

    In addition, if genifitib, an inhibitor to EGFR itself on the market for lung cancer, is added to the cell, the cells die. This finding is somewhat counterintuitive with regard to cell growth since EGFR activation functions as a positive growth signal, the researchers note; however, that fact cells die when EGFR is inhibited is not counterintuitive, but shows the cells are now addicted to the EGFR signal.

    “It’s as if a switch is stuck on,” Witze said. “The cell loses control of the growth signal.” If no palmitate is associated with EGFR, then it the cell loses control of this signal, and if the EGFR inhibitor is added, cells die.”

    The research shows that the reversible modification of EGFR with palmitate “pins” the tail of EGFR to the cell, impeding EGFR activation. The researchers think when the tail is no longer able to be pinned to the membrane the switch is stuck in the “on” position.

    Currently, the experimental 2BP compound inhibits any enzyme that uses palmitate as a substrate, making it toxic to most cells. “We need to find a compound specific for the palmitate-adding enzyme and or modify 2BP to make it more specific to decrease unwanted side effects.” Witze said.

    Kristin B. Runkle, Akriti Kharbanda, Ewa Stypulkowski, Xing-Jun Cao, Wei Wang, and Benjamin A. Garcia, all from Penn are co-authors.

    This work was funded by the National Institute for Health (R01CA181633, T32-CA-557726-07), the American Cancer Society (RSG-15-027-01, IRG –78-002-34) and the Department of Defense (BC123187P1).

    *Science paper:
    Inhibition of DHHC20-Mediated EGFR Palmitoylation Creates a Dependence on EGFR Signaling

    See the full article here .

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    U Penn campus

    Academic life at Penn is unparalleled, with 100 countries and every U.S. state represented in one of the Ivy League’s most diverse student bodies. Consistently ranked among the top 10 universities in the country, Penn enrolls 10,000 undergraduate students and welcomes an additional 10,000 students to our world-renowned graduate and professional schools.

    Penn’s award-winning educators and scholars encourage students to pursue inquiry and discovery, follow their passions, and address the world’s most challenging problems through an interdisciplinary approach.

  • richardmitnick 4:29 pm on May 21, 2016 Permalink | Reply
    Tags: , , Glowing tumors light a path to cancer treatment,   

    From MIT: “Glowing tumors light a path to cancer treatment” 

    MIT News
    MIT News

    MIT Widget

    May 20, 2016
    Kylie Foy | Lincoln Laboratory

    An NIR-II band near-infrared fluorescence image of cancerous tissue. The “glowing” regions have single-walled carbon nanotube probes attached, showing precisely where the tumors are. Image courtesy of the researchers.

    A Massachusetts General Hospital surgeon demonstrates the Lincoln Laboratory’s near-infrared fluorescence imaging (NIRF) system. The system’s camera detects probes attached to tumors, and displays their “glow” on a monitor as he performs surgery. Photo courtesy of the researchers.

    The research team that developed and demonstrated the near-infrared fluorescence imaging system includes: (standing left to right) Nandini Rajan and Andrew Siegel of the Lincoln Laboratory; Angela Belcher of MIT; Michael Birrer, Lorenzo Ceppi, and Young Jeong Na of the Massachusetts General Hospital (MGH); (kneeling left to right) Neelkanth Bardhan of MIT; and Giulia Fulci of MGH. Photo courtesy of the researchers.

    Every year, 200,000 women worldwide are diagnosed with ovarian cancer, often in its late stages. Ovarian cancer is very hard to detect in its early stages, and once it is detected, the body is already riddled with dozens of tumors. A 2010 Massachusetts General Hospital (MGH) study found that if tumors down to millimeter size are removed during surgery, the patient’s lifespan could be greatly extended. Since then, a team of MIT Lincoln Laboratory staff, MIT researchers, and MGH surgeons has pursued a method for finding and removing tumors otherwise invisible to a surgeon’s eye.

    A team at MIT, headed by Professor Angela Belcher at the Koch Institute for Integrative Cancer Research, had been targeting a variety of cancers that pose challenges caused by delays in diagnosis. They developed novel fluorescent “probes” based on single-walled carbon nanotubes (SWNTs) — chemical compounds that re-emit light when excited by a laser. When injected into a patient, the SWNT probes bind only to tumors, so the tumors appear to glow when seen through an infrared camera.

    This fluorescent glow can best be detected in the optical spectrum ranging from 1000 nm to 1800 nanometers, called the near-infrared second-window (NIR-II) band. However, a video fluorescence imaging system, which would allow surgeons to view this phenomenon in real time, didn’t yet exist. Belcher, who wanted to test these SWNT probes on mice with the help of surgeons at the Birrer Lab at MGH, called on Lincoln Laboratory’s expertise to develop a near-infrared fluorescence (NIRF) imaging system in order to do this. “A few other labs were exploring NIR-II band imaging, but their equipment was designed for still imaging, not video,” says Nandini Rajan, a Lincoln Laboratory researcher who joined the project.

    “Honestly, I knew this would work the first time I saw tumors smaller than pinheads lighting up on the screen like fireflies,” says Andrew Siegel, describing his reaction to initial tests of the system. Siegel and Rajan, supported by colleagues, designed the NIRF imaging system to work seamlessly with the surgeon. During surgery, the system illuminates the patient’s tissue with an 808 nm infrared laser after the SWNT probe solution has been injected into the cancerous region. The tumors, now covered in fluorescent probes, convert the 808 nm light into a range of wavelengths in the NIR-II spectral band, which the system’s camera can detect. A “blocking” filter prevents laser light from reaching the camera, revealing a sharp view of the glowing tumors on a monitor. In contrast, healthy tissue, with no probes attached to it, appears dark.

    While the fluorescence made tumors easy to locate against a dark background, surgeons could no longer see their instruments in relation to the tissue. “So we introduced a novel feature: an ‘in-band’ light source that the NIR-II camera can see,” Siegel said. The in-band light reflects off tissue to create a realistic gray-scale image, appearing on the monitor almost the same as it would appear in visible light — a view surgeons are familiar with. The surgeons can use a footswitch to adjust the in-band light as they work, shifting between the gray-scale view and fluorescent view as needed. “Instead of surgeons having to switch their gaze back and forth between the NIRF display and the patient, they can perform the surgical procedure looking at the NIRF display the whole time,” Rajan says.

    The real challenge, according to Siegel, was proving that the NIRF imaging actually provided a measurable survival advantage to patients. Over the course of two years, MGH surgeons using SWNT probes with the NIRF imaging system performed more than 200 surgical procedures on mice. First, the surgeons removed all the tumors they spotted visually. Then, switching to fluorescent mode, the surgeons were able to see and remove tumors as tiny as 200 nm in diameter — smaller than a poppy seed. They also discovered many larger tumors they thought they had already removed. The data show promising results: Despite the “NIRF” mice’s undergoing longer surgeries, they survived longer than did the mice operated without the use of the NIRF. “Discovering that we actually observed a measurable increase in post-surgical survival, even with the negative confound created by the longer surgery these ‘NIRF’ mice endured, was a pleasant surprise,” Siegel says.

    This spring, aspects of this work were presented at national technical conferences, and a more detailed manuscript discussing the results of the survival study will be published later this year. Moving forward, the team plans to progress toward human trials on ovarian cancer patients. “Our MGH collaborators are currently applying for Federal Drug Administration approval for the SWNT probes,” Siegel says. In the meantime, Lincoln Laboratory researchers will likely be building a larger-scale system.

    “My ultimate goal would be to simplify this technology to the point that any general surgeon has the ability to provide sufficient tumor debulking to completely obviate the need for post-operative chemotherapy,” Rajan says. “Without early detection, this may be the best we can do.”

    See the full article here .

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  • richardmitnick 11:43 am on May 21, 2016 Permalink | Reply
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    From NOVA: “The Quest for a Simple Cancer Test” 



    19 May 2016
    Jeffrey Perkel

    Embedded in a small translucent wafer measuring just under an inch a side, the spiraling coils—like neatly packed iPod earbuds—aren’t much to look at.

    But judging on appearance alone would sell short the brainchild of Chwee Teck Lim of National University Singapore and Jongyoon Han of the Massachusetts Institute of Technology. Those coils sift through millions upon millions of blood cells for faintly detectable indicators of a solid tumor lurking in a patient’s body—the handful of cancer cells that are often found circulating in the blood. Called circulating tumor cells, these cells may well be the seeds of distant metastases, which are responsible for 90% of all cancer deaths.

    Over the past several years, researchers and clinicians have become increasingly fixated on these circulating cells as cellular canaries-in-the-coalmine, indicators of distant disease. The blood of cancer patients is chock-full of potentially telling molecules, and researchers and clinicians are hotly investigating these materials for their efficacy as indicators and predictors of illness, disease progression, response to treatment, and even relapse.

    Soon, a simple blood test could reveal whether a person has cancer.

    For patients with cancer, such tests could provide a welcome respite from painful, invasive, and sometimes dangerous biopsies that typically are used to track and diagnose disease—a fact reflected in the terminology often used to describe the new assays: liquid biopsy. For researchers and clinicians, they provide a noninvasive and repeatable way to monitor how a disease changes over time, even in cases when the tumor itself is inaccessible.

    And unlike the finger-stick testing used by the embattled company Theranos, which recently voided two years of results from their proprietary blood-testing machines, the liquid biopsy methods being researched and developed by teams of scientists around the world use standard blood-drawing techniques and have been subject to peer review.

    In the short term, researchers hope to use liquid biopsies to monitor tumor relapse, track a tumor’s response to targeted therapies, and match patients with the treatments most likely to be effective—the very essence of “personalized medicine.” But longer term, some envision tapping the blood for early diagnosis to catch tumors long before symptoms start, the time when they’re most responsive to treatment.

    For now, most such promises are just that: promises. With the exception of one FDA-approved test, a handful of lab-developed diagnostics, and a slew of clinical trials, few cancer patients today are benefitting from liquid biopsies. But many are betting they soon will be. Liquid biopsies, says Daniel Haber, director of the Massachusetts General Hospital (MGH) Cancer Center, “currently are aspirational—they don’t yet exist in that they’re not part of routine care. But they have the possibility to become so.”

    Revealing Information

    Despite its name, liquid biopsies are not exactly an alternative to solid tissue biopsies, says Mehmet Toner, a professor of biomedical engineering at MGH who studies circulating tumor cells. Patients who are first diagnosed with cancer via a liquid biopsy would likely still undergo a tissue biopsy, both in order to confirm a diagnosis and to guide treatment.

    But liquid biopsies do provide molecular intel that might otherwise be impossible to obtain—for instance, in the treatment of metastatic disease. Oncologists typically biopsy patients with metastatic disease only once, to confirm the diagnosis, says Keith Flaherty, director of the Henri and Belinda Termeer Center for Targeted Therapies at the MGH Cancer Center. But such a test reveals the genetics of the cancer only at the sampled site. Many patients harbor multiple metastases, some in relatively inaccessible locations like the lungs, brain, or bones, and each may contain cells with different genetic signatures and drug susceptibilities. “Liquid biopsies provide an aggregate assessment of a cancer population,” he says.

    Today, says Max Diehn, an assistant professor of radiation oncology at the Stanford University School of Medicine, oncologists can get a read on how a patient responds to therapy using a handful of protein biomarkers found in blood, urine, or other biofluids, such as prostate-specific antigen (PSA) in the case of prostate cancer, or using noninvasive imaging technologies like magnetic resonance imaging (MRI) or computed tomography (CT). But those tests often fall short. Many biomarkers aren’t specific enough to be useful, and imaging is relatively expensive and insensitive. Also, not everything that appears to be a tumor on a scan actually is. And, Flaherty notes, imaging studies reveal little or no molecular information about the tumor itself, information that’s useful in guiding the treatment.

    In contrast, liquid biopsies can reveal not only whether patients are responding to treatment, but also catch game-changing genetic alterations in real time. In one recent study, Nicholas Turner of the Institute for Cancer Research in London and his colleagues examined cell-free tumor DNA (ctDNA), or tumor DNA that’s floating free in the bloodstream, in women with metastatic breast cancer. They were looking for for the presence of mutations in the estrogen receptor gene, ESR1. Breast cancer patients previously treated with so-called aromatase inhibitors often develop ESR1 mutations that render their tumors resistant to two potential treatments, hormonal therapies that target the estrogen receptor and further use of aromatase inhibitors that block the production of estrogen. Turner’s team detected ESR1 mutant ctDNA in 18 of 171 women tested (10.5%), and those women’s tumors tended to progress more rapidly when treated with aromatase inhibitors than did women who lacked such mutations. Those findings had no impact on the patients in the study—the women were analyzed retrospectively—but they suggest that prospective use of ctDNA analysis might be used to shift treatment toward different therapeutic strategies.

    Viktor Adalsteinsson of the Broad Institute of MIT and Harvard, whose group has sequenced more than a thousand liquid biopsy genomes, calls the ESR1 study “promising and illuminating.” At the moment, he says, such data are not being actively used to influence patient treatment, at least not in the Boston area. But Jesse Boehm, associate director of the Broad Cancer Program, says he thinks it could take as little as two years for that to change. “I’ve been here at the Broad for ten years, and I don’t think I’ve ever seen another project grow from scientific concept to potentially game-changing so quickly,” he says.

    Varied Approaches

    Liquid biopsies generally come in one of three forms. One, ctDNA—Adalsteinsson’s material of choice—is the easiest to study, but also the most limited as it relies on probing short snippets of DNA in the bloodstream for a collection of known mutations. The blood is full of DNA, as all cells jettison their nuclear material when they die, so researchers must identify those fragments that are specifically diagnostic of disease. While the genetic mutations behind some prominent cancers have been identified, many more have not. Also, not all genetic changes are revealed in the DNA itself, says Klaus Pantel, director of the Institute of Tumor Biology at the University Medical Center Hamburg-Eppendorf.

    A second class of liquid biopsy focuses on tiny membrane-encapsulated packages of RNA and protein called exosomes. Exosomes provide researchers a glimpse of cancer cells’ gene expression patterns, meaning they can reveal differences that are invisible at the DNA level. But, because both normal and cancerous cells release exosomes, the trick, as with ctDNA, is to isolate and characterize those few particles that stem from the tumor itself.

    The third counts circulating tumor cells, or CTCs. They are not found in healthy individuals, but neither are they prevalent even in very advanced cases, accounting for perhaps one to 100 per billion blood cells, according to Lim. Researchers can simply count the cells, as CTC abundances tend to scale with prognosis.

    But there’s much more that CTCs can do, Pantel says. “You can analyze the DNA, the RNA, and the protein, and you can put the cells in culture, so you can get some information on responsiveness to drugs.” Stefanie Jeffrey, a professor of surgery at Stanford University School of Medicine, has purified CTCs and demonstrated that individual breast cancer CTCs express different genes than the immortalized breast cancer cells typically used in drug development. That, she says, “raises questions” about the way potential drugs are currently evaluated in the early stages of development.

    Similarly, Toner and Haber have developed a device called the CTC-iChip to count and enrich CTCs from whole blood. The size of a CD—indeed, the chips are fabricated using high-throughput CD manufacturing technology—these devices take whole blood, filter out the red cells, platelets, and white blood cells, and keep what’s left, including CTCs. The team has used this device to evaluate hundreds of individual CTCs from breast, pancreatic, and prostate tumor patients to identify possible ways to selectively kill those cells.

    Elsewhere, Caroline Dive, a researcher at the University of Manchester, has even injected CTCs isolated from patients with small-cell lung cancer into mice. The resulting tumors exhibit the same drug sensitivities as the starting human tumors, providing a platform that could be used to better identify treatment options.

    A Range of Uses

    According to Lim, liquid biopsies have five potential applications: early disease detection, cancer staging, treatment monitoring, personalized treatment, and post-cancer surveillance. Of those, most agree, the likely near-term applications are personalized treatment and treatment monitoring. The most difficult is early detection.

    Among other things, early detection requires testing thousands of early-stage patients and healthy volunteers to demonstrate that the tests are sufficiently sensitive to detect cancer early yet specific enough to avoid false positives. A widely adopted assay that was, say, 90% specific could yield perhaps millions of false positives, Pantel says. “I’m sure that’s fantastic for the lawyers, but not for the patients.”

    Still, researchers have begun demonstrating the possibility. In one 2014 study describing a new method for analyzing ctDNA, Diehn, the Stanford radiation oncologist, and his colleague, Ash Alizadeh, an assistant professor of medical oncology also at Stanford, showed that they could detect half of the stage I non-small-cell lung cancer samples it was confronted with, and 100% of tumors stage II and above. That’s despite the fact that ctDNA fragments are only about 170 bases long—a very short amount—and disappear from the blood within about 30 minutes. “There’s constant cell turnover in tumors,” Diehn says. “There’s always some cells dying, and that’s what lets you detect it.”

    In another study, Nickolas Papadopoulos, a professor of oncology and pathology at the Johns Hopkins School of Medicine, and his colleagues surveyed the ctDNA content of 185 individuals across 15 different types of advanced cancer. For some tumor types, including bladder, colorectal, and ovarian, they found ctDNA in every patient tested; other tumors, such as glioblastomas, were more difficult to pick up. “It made sense,” Papadopoulos says. “These tumors are beyond the blood-brain barrier…and they do not shed DNA into the circulation.” In later studies, the team demonstrated that some tumors are more easily found in bodily fluids other than blood. Certain head and neck cancers are readily detected in saliva, for example, and some urogenital cancers can be detected in urine. But in their initial survey, Papadopoulos and his colleagues also tested blood plasma for the ability to detect localized (that is, non-metastatic) tumors, identifying disease in between about half and three-fourths of individuals.

    Though 50% sensitivity isn’t perfect, it’s better than nothing, Papadopoulos says, especially for cancers of the ovaries and pancreas. “Right now, we get 0% of them because there’s no screening test for these cancers.”

    In the meantime, researchers are focusing on personalized therapy. Alizadeh and Diehn, for instance, have tested patients with stage IV metastatic non-small cell lung cancer, a grave diagnosis, who had been taking erlotinib, a drug that targets specific mutations in the EGFR gene. Over time, all patients develop resistance to these drugs, half of them via a new mutation, Diehn says. Diehn and Alizadeh have begun looking for that mutation in the ctDNA of patients whose disease progresses, or returns, as such tumors can be specifically targeted by a new drug, osimertinib. “It’s been shown in a couple of studies that such patients then have a good response rate,” Diehn says, with the median “progression-free survival” doubling from about ten months to 20.

    Toward the Clinic

    Most scientists working on liquid biopsies agree that the technology itself is mature. What’s needed to make a difference in patients’ lives is clinical evidence of sensitivity, selectivity, and efficacy.

    Fortunately, they’re working on it. According to the National Institutes of Health’s clinical trials database, clinicaltrials.gov, over 350 trials are currently studying the use of liquid biopsies in cancer detection, identification, or treatment.

    One recent trial, published in April in JAMA Oncology, examined the ability of ctDNA analysis to detect key mutations in two genes associated with treatment decision, response, and resistance in non-small cell lung cancer. The 180-patient prospective trial determined that the method used could detect the majority (64% –86%) of the tested mutations with no false-positive readings in most cases. Results were returned on average within three days, compared to 12 to 27 days for solid-tissue biopsy. The technique is ready for clinical use, the authors concluded.

    In an ongoing trial, Pantel and his colleagues are focusing on a breast cancer-associated protein called HER2. Several anticancer therapies specifically target HER2-positive tumors, including trastuzumab and lapatinib. The trial is looking for instances of HER2-expressing CTCs in patients with metastatic breast cancer whose original tumor did not express HER2. About 20% of HER2-negative tumors meet that criterion, Pantel says, but before liquid biopsies became an option, there was really no way to find them. Now, his team is testing “whether the change to HER2-positive CTCs is a good predictor for response to HER2-targeted therapy.” If it is, it could unlock potential treatments for patients.

    In another trial, Flaherty, the center director at MGH, and his colleagues are using a series of liquid biopsies in several hundred patients with metastatic melanoma to determine if they could retrospectively predict drug resistance by monitoring for mutations in a particular gene.

    In the meantime, diagnostics firms are developing assays of their own. Currently, there is only one FDA-approved liquid biopsy test on the market in the United States. But there also are a growing handful of lab-developed assays for specific genetic mutations available and several more in development.

    Early cancer screening is farther out, and while many researchers still express skepticism, the application received a high-profile boost in January when sequencing firm Illumina announced it was launching a spinoff company called Grail. The company, which has already raised some $100 million in funding, will leverage “very deep sequencing” to identify rare ctDNA mutations, and plans to launch a “pan-cancer” screening test by 2019.

    Only time will tell, though, whether Grail or any other company is able to fundamentally alter how patients are treated for cancer. But one thing is certain, Flaherty says: Genetic testing, however it is done, only addresses the diagnostics side of the personalized medicine challenge; progress is also required on the drug development side. After all, what good is a test if there’s no way to act on it?

    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.

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