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  • richardmitnick 2:42 pm on May 24, 2017 Permalink | Reply
    Tags: , , , Medicine, New imaging technique aims to ensure surgeons completely remove cancer,   

    From Wash U: “New imaging technique aims to ensure surgeons completely remove cancer” 

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    Washington University in St.Louis

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    May 17, 2017
    Tamara Bhandari

    A new imaging technique based on light and sound produces images doctors can use to distinguish cancerous breast tissue (below the dotted blue line) from normal tissue more quickly than is currently possible. Pathologists routinely inspect surgical specimens to make sure all cancerous tissue has been removed. The new technique (right) produces images as detailed and accurate as traditional methods (left), but in far less time. The researchers are working to make the technique fast enough to be used during a surgery, so patients don’t have to return for a second surgery. (Image: Terence T.W. Wong)

    Of the quarter-million women diagnosed with breast cancer every year in the United States, about 180,000 undergo surgery to remove the cancerous tissue while preserving as much healthy breast tissue as possible.

    However, there’s no accurate method to tell during surgery whether all of the cancerous tissue has been successfully removed. The gold-standard analysis takes a day or more, much too long for a surgeon to wait before wrapping up an operation. As a result, about a quarter of women who undergo lumpectomies receive word later that they will need a second surgery because a portion of the tumor was left behind.

    Now, researchers at Washington University School of Medicine in St. Louis and California Institute of Technology report that they have developed a technology to scan a tumor sample and produce images detailed and accurate enough to be used to check whether a tumor has been completely removed.

    Called photoacoustic imaging, the new technology takes less time than standard analysis techniques. But more work is needed before it is fast enough to be used during an operation.

    The research is published May 17 in Science Advances.

    “This is a proof of concept that we can use photoacoustic imaging on breast tissue and get images that look similar to traditional staining methods without any sort of tissue processing,” said Deborah Novack, MD, PhD, an associate professor of medicine, and of pathology and immunology, and a co-senior author on the study.

    The researchers are working on improvements that they expect will bring the time needed to scan a specimen down to 10 minutes, fast enough to be used during an operation. The current gold-standard method of analysis, which is based on preserving the tissue and then staining it to make the cells easier to see, hasn’t gotten any faster since it was first developed in the mid-20th century.

    For solid tumors in most parts of the body, doctors use a technique known as a frozen section to do a quick check of the excised lump during the surgery. They look for a thin rim of normal cells around the tumor. Malignant cells at the margins suggest the surgeon missed some of the tumor, increasing the chances that the disease will recur.

    But frozen sections don’t work well on fatty specimens like those from the breast, so the surgeon must finish a breast lumpectomy without knowing for sure how successful it was.

    “Right now, we don’t have a good method to assess margins during breast cancer surgeries,” said Rebecca Aft, MD, PhD, a professor of surgery and a co-senior author on the study. Aft, a breast cancer surgeon, treats patients at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

    Currently, after surgery a specimen is sent to a pathologist, who slices it, stains it and inspects the margins for malignant cells under a microscope. Results are sent back to the surgeon within a few days.

    To speed up the process, the researchers took advantage of a phenomenon known as the photoacoustic effect. When a beam of light of the right wavelength hits a molecule, some of the energy is absorbed and then released as sound in the ultrasound range. These sound waves can be detected and used to create an image.

    “All molecules absorb light at some wavelength,” said co-senior author Lihong Wang, who conducted the work when he was a professor of biomedical engineering at Washington University’s School of Engineering & Applied Science. He is now at Caltech. “This is what makes photoacoustic imaging so powerful. Essentially, you can see any molecule, provided you have the ability to produce light of any wavelength. None of the other imaging technologies can do that. Ultrasound will not do that. X-rays will not do that. Light is the only tool that allows us to provide biochemical information.”

    The researchers tested their technique by scanning slices of tumors removed from three breast cancer patients. For comparison, they also stained each specimen according to standard procedures.

    The photoacoustic image matched the stained samples in all key features. The architecture of the tissue and subcellular detail such as the size of nuclei were clearly visible.

    “It’s the pattern of cells – their growth pattern, their size, their relationship to one another – that tells us if this is normal tissue or something malignant,” Novack said. “Overall, the photoacoustic images had a lot of the same features that we see with standard staining, which means we can use the same criteria to interpret the photoacoustic imaging. We don’t have to come up with new criteria.”

    Having established that photoacoustic techniques can produce usable images, the researchers are working on reducing the scanning time.

    “We expect to be able to speed up the process,” Wang said. “For this study, we had only a single channel for emitting light. If you have multiple channels, you can scan in parallel and that reduces the imaging time. Another way to speed it up is to fire the laser faster. Each laser pulse gives you one data point. Faster pulsing means faster data collection.”

    Aft, Novack and Wang are applying for a grant to build a photoacoustic imaging machine with multiple channels and fast lasers.

    “One day we think we’ll be able to take a specimen straight from the patient, plop it into the machine in the operating room and know in minutes whether we’ve gotten all the tumor out or not,” Aft said. “That’s the goal.”

    This work was supported by the National Institutes of Health, grant number DP1 EB016986 and R01 CA186567, and by Washington University’s Siteman Cancer Center’s 2014 Research Development Award.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”

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    Wash U campus

    Washington University’s mission is to discover and disseminate knowledge, and protect the freedom of inquiry through research, teaching, and learning.

    Washington University creates an environment to encourage and support an ethos of wide-ranging exploration. Washington University’s faculty and staff strive to enhance the lives and livelihoods of students, the people of the greater St. Louis community, the country, and the world.

  • richardmitnick 11:19 am on May 24, 2017 Permalink | Reply
    Tags: Andres Villegas, Medicine, Mental Illness,   

    From Rutgers: “His Research Mission: Solving the Mysteries of Mental Illness” 

    Rutgers University
    Rutgers University

    John Chadwick


    Andres Villegas grew up in Elizabeth, the son of a single mom who had emigrated from Ecuador.
    He was uncertain about his future, and undecided about college.

    “I felt lost in high school,” Villegas says. “I didn’t know what I wanted to do in life.”

    But at Rutgers he found his calling in the research labs of scientists breaking new ground in the study and treatment of mental illness. Villegas emerged as a top student in the competitive field of neuroscience, leaving a lasting impression on his professors.

    “Andres is among the brightest undergraduate students that I have encountered in 30 years at Rutgers,” says Sidney Auerbach, a professor in the Department of Cell Biology and Neuroscience, who advised Villegas.

    Villegas graduates May 14 from the School of Arts and Sciences, and has been accepted into a prestigious Ph.D program in neurobiology and behavior at Columbia University. He’s committed to working on research aimed at finding new treatments for psychiatric illnesses such as schizophrenia and bipolar disorder.

    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.

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    As a ’67 graduate of University college, second in my class, I am proud to be a member of

    Alpha Sigma Lamda, National Honor Society of non-tradional students.

  • richardmitnick 5:53 am on May 23, 2017 Permalink | Reply
    Tags: , , Discovery of an alga’s ‘dictionary of genes’ could lead to advances in biofuels and medicine, Medicine,   

    From UCLA: “Discovery of an alga’s ‘dictionary of genes’ could lead to advances in biofuels, medicine” 

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    May 22, 2017
    Stuart Wolpert

    Inside the alga’s cells, showing the nucleus (purple), mitochondria (red), chloroplast (green) and lipids (yellow). Melissa Roth/HHMI and Andreas Walters/Berkeley Lab

    Plant biologists and biochemists from UCLA, UC Berkeley and UC San Francisco have produced a gold mine of data by sequencing the genome of a green alga called Chromochloris zofingiensis.


    Scientists have learned in the past decade that the tiny, single-celled organism could be used as a source of sustainable biofuel and that it produces a substance called astaxanthin, which may be useful for treating certain diseases. The new research could be an important step toward improving production of astaxanthin by algae and engineering its production in plants and other organisms.

    The study is published online in the journal Proceedings of the National Academy of Sciences.

    Chromochloris zofingiensis is one of the most prolific producers of a type of lipids called triacylglycerols, which are used in producing biofuels.

    Knowing the genome is like having a “dictionary” of the alga’s approximately 15,000 genes, said co-senior author Sabeeha Merchant, a UCLA professor of biochemistry. “From there, researchers can learn how to put the ‘words’ and ‘sentences’ together, and to target our research on important subsets of genes.”

    C. zofingiensis provides an abundant natural source for astaxanthin, an antioxidant found in salmon and other types of fish, as well as in some birds’ feathers. And because of its anti-inflammatory properties, scientists believe astaxanthin may have benefits for human health; it is being tested in treatments for cancer, cardiovascular disease, neurodegenerative diseases, inflammatory diseases, diabetes and obesity. Merchant said the natural version has stronger antioxidant properties than chemically produced ones, and only natural astaxanthin has been approved for human consumption.

    The study also revealed that an enzyme called beta-ketolase is a critical component in the production of astaxanthin.

    Algae absorb carbon dioxide and derive their energy from sunlight, and C. zofingiensis in particular can be cultivated on non-arable land and in wastewater. Harnessing it as a source for renewable and sustainable biofuels could lead to new ways to produce clean energy, said Krishna Niyogi, co-senior author of the paper and a scientist at the Department of Energy’s Lawrence Berkeley National Laboratory.

    Over the past decade-plus, Merchant said, research with algae, a small plant called rockcress, fruit flies and nematode worms — all so-called “model organisms” — has been advanced by other scientists’ determining their genome sequences.

    “They are called model organisms because we use what we learn about the operation of their cells and proteins as a model for understanding the workings of more complex systems like humans or crops,” she said. “Today, we can sequence the genome of virtually any organism in the laboratory, as has been done over the past 10 to 15 years with other model organisms.”

    Merchant, Niyogi and Matteo Pellegrini, a UCLA professor of molecular, cell and developmental biology and a co-author of the study, maintain a website that shares a wealth of information about the alga’s genome.

    During the study, the scientists also used soft X-ray tomography, a technique similar to a CT scan, to get a 3-D view of the algae cells , which gave them more detailed insights about their biology.

    Niyogi is also a UC Berkeley professor of plant and microbial biology and a Howard Hughes Medical Institute Investigator.


    The study’s other authors are researchers Shawn Cokus and Sean Gallaher and postdoctoral scholar David Lopez, all of UCLA; postdoctoral fellow Melissa Roth, and graduate students Erika Erickson, Benjamin Endelman and Daniel Westcott, all of Niyogi’s laboratory; and Carolyn Larabell, a professor of anatomy, and researcher Andreas Walter, both of UC San Francisco.

    The research was funded by the Department of Energy’s Office of Science, the Department of Agriculture’s National Institute of Food and Agriculture, the National Institute of General Medical Sciences of the National Institutes of Health, and the Gordon and Betty Moore Foundation.

    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 5:35 am on May 23, 2017 Permalink | Reply
    Tags: , , Medicine, New cancer drug can prevent reactions to common airborne allergens, , Possibilities for food allergies   

    From Northwestern: “New cancer drug can prevent reactions to common airborne allergens” 

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    Northwestern University

    May 22, 2017
    Kristin Samuelson

    Targeted cancer treatment might treat food allergies, too.

    A person’s skin is tested for allergies. No image credit.

    A cancer drug for patients with certain types of leukemia and lymphoma can also prevent reactions to some of the most common airborne allergies, according to a recent Northwestern Medicine study. The promising data from this pilot study could have greater implications for adults with food allergies.

    The cancer patients who were allergic to allergens such as cat dander and ragweed saw their allergic skin test reactivity reduced by 80 to 90 percent in one week, and this persisted with continued use of the drug for at least one to two months. The findings were published in the Journal of Allergy and Clinical Immunology in May.

    “It almost completely knocked out the patients’ skin test and blood cell allergic reactivity,” said senior author Dr. Bruce Bochner, the Samuel M. Feinberg Professor of Medicine at Northwestern University Feinberg School of Medicine.

    This FDA-approved drug, ibrutinib, is currently on the market as a successful and less-toxic alternative to chemotherapy for patients with chronic lymphocytic leukemia and mantle cell lymphoma. In this recent study, Bochner and his team performed traditional allergy skin tests and the basophil activation test, a related allergy test using blood cells, on cancer patients before they had taken ibrutinib and again after one week and after one to two months of taking it.

    A rather unlikely pairing – cancer and allergies – Bochner thought to test if a cancer drug could prevent allergic reactions by collaborating with Feinberg’s oncology department.

    He knew that the generally well-tolerated cancer drug was successful in blocking a protein inside a cell called Bruton’s Tyrosine Kinase (BTK). BTK plays a crucial role in B cell activation, growth and maturation and mast cell and basophil activation, the latter two cells being responsible for immediate allergic reactions. Bochner teamed up with Northwestern oncologist Dr. Leo Gordon and colleagues to test if this BTK inhibitor could shut down an enzyme inside cells that is involved when you have an allergic reaction.

    “Ibrutinib is considered a game changer in these two types of cancers,” said Gordon, the Abby and John Friend Professor of Cancer Research at Feinberg. “We understood that it might have some biologic effects in what Bruce is interested in, so we were happy to participate in his study. It’s an interesting repurposing of that drug.”

    While the study was small – only two patients qualified out of about 35 that were screened for allergies – the implications are much larger for later phases of this study. Bochner and his colleagues Drs. Anne Marie Singh and Melanie Dispenza are now testing how successful the drug is at targeting allergies to food, such as tree nuts and peanuts.

    “Preventing or lessening the severity of an allergic reaction to a food you’ve ingested that you’re allergic to is kind of the holy grail of food allergy treatment,” Bochner said. “I don’t know if this or similar drugs will ever make it possible for a peanut-allergic person to eat peanut butter and jelly sandwiches, but we’re excited to use this approach to teach us how to lessen the risks of food allergy reactions.”

    Currently, the study is being expanded to adults with food allergy to see if their skin test and basophil activation test responses show a similar reduction with just a few doses of ibrutinib and how long such benefits might last. If the results are favorable, the next step would be to get funding to actually test whether taking a BTK inhibitor will improve the ability of food-allergic adults to eat foods they’re allergic to.

    “The hope is that drugs like BTK inhibitors will protect people with food allergies from having anaphylaxis, or at least increase how much of that food they can eat without reacting,” Bochner said. “Maybe they’ll increase from being able to eat just one peanut to 10 before they react. Or maybe they’ll be able to eat a full meal’s worth of peanuts. We want to know if this would safely change their actual ability to eat foods that they currently need to avoid.”

    The study was funded by a 2016 Dixon Translational Research Grant.

    See the full article here .

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    Northwestern South Campus
    South Campus

    On May 31, 1850, nine men gathered to begin planning a university that would serve the Northwest Territory.

    Given that they had little money, no land and limited higher education experience, their vision was ambitious. But through a combination of creative financing, shrewd politicking, religious inspiration and an abundance of hard work, the founders of Northwestern University were able to make that dream a reality.

    In 1853, the founders purchased a 379-acre tract of land on the shore of Lake Michigan 12 miles north of Chicago. They established a campus and developed the land near it, naming the surrounding town Evanston in honor of one of the University’s founders, John Evans. After completing its first building in 1855, Northwestern began classes that fall with two faculty members and 10 students.
    Twenty-one presidents have presided over Northwestern in the years since. The University has grown to include 12 schools and colleges, with additional campuses in Chicago and Doha, Qatar.

    Northwestern is recognized nationally and internationally for its educational programs.

  • richardmitnick 5:19 am on May 23, 2017 Permalink | Reply
    Tags: , , , Medicine, Unlocking the barrier   

    From HMS: “Unlocking the barrier” 

    Harvard University

    Harvard University

    Harvard Medical School

    Harvard Medical School

    May 3, 2017 [Another disciple of timely social media.]

    Disrupting an omega-3 fatty acid transporter could open blood-brain barrier for drug delivery.

    Normal brain blood vessels completely contain a fluorescent dye (left). Vessels without the lipid transport protein Mfsd2a exhibit a leaky blood-brain barrier (right). Image: Gu lab

    Already extolled for their health benefits as a food compound, omega-3 fatty acids now appear to also play a critical role in preserving the integrity of the blood-brain barrier, which protects the central nervous system from blood-borne bacteria, toxins and other pathogens, according to new research from Harvard Medical School.

    Reporting in the May 3 issue of Neuron, a team led by Chenghua Gu, associate professor of neurobiology at HMS, describes the first molecular explanation for how the barrier remains closed by suppressing transcytosis—a process for transporting molecules across cells in vesicles, or small bubbles.

    They found that the formation of these vesicles is inhibited by the lipid composition of blood vessel cells in the central nervous system, which involves a balance between omega-3 fatty acids and other lipids maintained by the lipid transport protein Mfsd2a.

    While the blood-brain barrier is a critical evolutionary mechanism that protects the central nervous system from harm, it also represents a major hurdle for delivering therapeutic compounds into the brain.

    Blocking the activity of Mfsd2a may be a strategy for getting drugs across the barrier and into the brain to treat a range of disorders such as brain cancer, stroke and Alzheimer’s.

    “This study presents the first clear molecular mechanism for how low rates of transcytosis are achieved in central nervous system blood vessels to ensure the impermeable nature of the blood-brain barrier,” Gu said. “There is still a lot we do not know about how the barrier is regulated. A better understanding of the mechanisms will allow us to begin to manipulate it, with the goal of getting therapeutics into the brain safely and effectively.”

    The blood-brain barrier is composed of a network of endothelial cells that line blood vessels in the central nervous system. These cells are connected by tight junctions that prevent most molecules from passing between them, including many drugs that target brain diseases. In a 2014 study published in Nature, Gu and colleagues discovered that a gene and the protein it encodes, Mfsd2a, inhibits transcytosis and is critical for maintaining the blood-brain barrier. Mice that lacked Mfsd2a, which is found only in endothelial cells in the central nervous system, had higher rates of vesicle formation and leaky barriers, despite having normal tight junctions.

    Unfavorable conditions

    In the current study, Gu, Benjamin Andreone, an HMS neurobiology student and their colleagues examined how Mfsd2a maintains the blood-brain barrier.

    Mfsd2a is a transporter protein that moves lipids containing DHA, an omega-3 fatty acid found in fish oil and nuts, into the cell membrane. To test the importance of this function to the barrier, the team created mice with a mutated form of Mfsd2a, in which a single amino acid substitution shut down its ability to transport DHA. They injected these mice with a fluorescent dye and observed leaky blood-brain barriers and higher rates of vesicle formation and transcytosis—mirroring mice that completely lacked Mfsd2a.

    A comparison of the lipid composition of endothelial cells in brain capillaries against those in lung capillaries—which do not have barrier properties and do not express Mfsd2a—revealed that brain endothelial cells had around two- to five-fold higher levels of DHA-containing lipids.

    Additional experiments revealed that Mfsd2a suppresses transcytosis by inhibiting the formation of caveolae—a type of vesicle that forms when a small segment of the cell membrane pinches in on itself. As expected, mice with normal Cav-1, a protein required for caveolae formation, and that lacked Mfsd2a exhibited higher transcytosis and leaky barriers. Mice that lacked both Mfsd2a and Cav-1, however, had low transcytosis and impermeable blood-brain barriers.

    Endothelial cells without Mfsd2a (top) have higher rates of caveolae vesicle formation, compared to cells with Mfsd2a (bottom). No image credit.

    “We think that by incorporating DHA into the membrane, Mfsd2a is fundamentally changing the composition of the membrane and making it unfavorable for the formation of these specific type of caveolae,” Andreone said. “Even though we observed low rates of vesicle formation and transcytosis in blood-brain barrier cells decades ago, this is the first time that a cellular mechanism can explain this phenomenon.”

    By revealing the role of Mfsd2a and how it controls transcytosis in the central nervous system, Gu and her colleagues hope to shed light on new strategies to open the barrier and allow drugs to enter and remain in the brain. They are currently testing the efficacy of an antibody that potentially can temporarily block the function of Msfd2a, and whether caveolae-mediated transcytosis can be leveraged to shuttle therapeutics across the barrier.

    “Many of the drugs that could be effective against diseases of the brain have a hard time crossing the blood-brain barrier,” Gu said. “Suppressing Mfsd2a may be an additional strategy that allows us to increase transcytosis, and deliver cargo such as antibodies against beta-amyloid or compounds that selectively attack tumor cells. If we can find a way across the barrier, the impact would be enormous.”

    This work was supported by The National Institutes of Health (grants F31NS090669, NS092473), the Mahoney postdoctoral fellowship, the Howard Hughes Medical Institute, the Kaneb Fellowship, Fidelity Biosciences Research Initiative and the Harvard Blavatnik Biomedical Accelerator.

    Additional authors include Brian Wai Chow, Aleksandra Tata, Baptiste Lacoste, Ayal Ben-Zvi, Kevin Bullock, Amy A. Deik, David D. Ginty and Clary B. Clish.

    See the full article here .

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    HMS campus

    Established in 1782, Harvard Medical School began with a handful of students and a faculty of three. The first classes were held in Harvard Hall in Cambridge, long before the school’s iconic quadrangle was built in Boston. With each passing decade, the school’s faculty and trainees amassed knowledge and influence, shaping medicine in the United States and beyond. Some community members—and their accomplishments—have assumed the status of legend. We invite you to access the following resources to explore Harvard Medical School’s rich history.

    Harvard University campus

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

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

  • richardmitnick 5:03 am on May 23, 2017 Permalink | Reply
    Tags: , Medicine, Pulmonary Thrombosis-on-a-Chip provides new avenue for drug development, WYSS Institute at Harvard   

    From Wyss: “Pulmonary Thrombosis-on-a-Chip provides new avenue for drug development” 

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    Wyss Institute bloc
    Wyss Institute

    May 22, 2017
    Lindsay Brownell

    Model of blood clot formation in the lung allows for unprecedented study of human blood responses to organ-level injury and inflammation in vitro

    An image of a thrombus (blood clot) formed on endothelial tissue in the pulmonary-thrombosis-on-a-chip, demonstrating the characteristic “teardrop” shape observed in vivo. Credit: Wyss Institute at Harvard University

    The average human pair of lungs is permeated by a network of about 164 feet of blood vessels (roughly the width of a football field), including microscopic blood capillaries, which facilitate the diffusion of oxygen into the bloodstream in exchange for carbon dioxide. Damage to any of those vessels can cause a blood clot, or thrombus, to form, which can cause or exacerbate a number of lung diseases, including pneumonia, acute lung injury and acute chest syndrome. The use of some drugs is also limited by their propensity to promote clot formation in lung vessels. Developing and testing drugs to treat or prevent pulmonary thrombosis is difficult because the complex interplay between the many different cell types in the lung hampers efforts to tease out the exact causes of clot formation. A new study conducted by members of the Wyss Institute at Harvard University, Emulate Inc., and Janssen Pharmaceutical Research and Development, published this week in the journal Clinical Pharmacology and Therapeutics, is the first to successfully recreate a human pulmonary thrombosis within an organ-level model of the lung in vitro.

    “It’s very difficult to distill out specific mechanisms inside an animal, and a lot of work in toxicology or drug discovery fails when it goes to human clinical trials,” says co-first author Abhishek Jain, Ph.D., former Wyss Institute Postdoctoral Fellow and current Assistant Professor of Biomedical Engineering at Texas A&M University. “In vitro models like our Thrombosis-on-a-Chip are made from the ground-up, so you can build them to be exactly as complex as you need for the problem you want to study.”

    To meet this challenge, the team used Organ-on-a-Chip (Organ Chip) technology developed at the Wyss Institute, which involves engineering microfluidic culture devices with two parallel channels separated by a porous extracellular-matrix-coated membrane. The key innovation in this new design relative to a previously described Lung-on-a-Chip is that the upper surface of the porous membrane is lined by primary human alveolar epithelial cells, and all sides of the lower vascular channel are coated with a layer of lung microvascular endothelium to accurately mimic human lung capillaries. Because thrombosis is perpetrated by platelets and other cells, the team perfused whole human blood through the lower endothelium-lined channel of the chip for the first time, while air was introduced into the upper channel. When an inflammatory stimulus was applied to the endothelial cells followed by perfusing whole blood, platelets clumped and formed blood clots on the surface of the endothelium in a characteristic teardrop shape that has been observed in living animals, but never before in vitro.

    “This is the first time we’re seeing clots form with the same dynamics and morphology that you see in vivo, which is a major step forward in studying and eventually treating blood clots that cause many life-threatening diseases.” says Donald Ingber, M.D., Ph.D., senior author of the study and the Judah Folkman Professor of Vascular Biology at Harvard Medical School (HMS) and the Vascular Biology Program at Boston Children’s Hospital, as well as Professor of Bioengineering at Harvard’s School of Engineering and Applied Sciences (SEAS).

    The team further tested the chip’s functionality by replicating an inflammatory lung injury that originates in the lung’s airways – the most likely source of a pathogen or other damaging substance. They introduced lipopolysaccharide endotoxin (LPS), an inflammatory chemical found on the surface of certain types of bacteria and is known to induce clot formation in vivo, into both the upper and lower channels of the chip. They were surprised to find that LPS had no effect on blood clot formation when they added it directly to the endothelium-lined blood channel; but, when added to the air channel, it induced the air-facing epithelium to trigger a cascade of cytokines, a class of inflammatory signaling molecules that initiate blood clot formation, in the underlying endothelium. “Epithelial cells are the guardians of the airways – they need to be sensitive to airborne pathogens and then signal the danger to the rest of the body,” says co-author Riccardo Barrile, Ph.D., also a former Wyss Institute Postdoctoral Fellow and current principal investigator at Emulate, Inc. “This study demonstrated that information travels from the epithelium to the endothelium, but I was surprised to see that the entire system is so well-connected.”

    In addition to facilitating the discovery of crucial insights into the mechanism of how lung injury promotes blood clot formation, the Thrombosis-on-a-Chip allows for the testing of potential drugs on an organ-level system in vitro, an approach that has become highly attractive to pharmaceutical companies. Working with Robert Flaumenhaft, M.D., Ph.D., Associate Professor of Hematology at HMS and Beth Israel Deaconess Medical Center, the team introduced parmodulin-2 (PM2), an inflammation inhibitor, into the vascular channel of the device, and found that it significantly decreased the number of clots on the vessel wall following the addition of LPS to the airway channel. This confirmation of drug activity, as well as the insight that LPS causes thrombosis only by acting directly on the epithelium, would have been very difficult to achieve in vivo, as blood flow and individual cellular compartments cannot be controlled individually as they can in Organ Chips.

    The team plans to continue their pulmonary thrombosis work by introducing mechanical forces that imitate breathing to the Chip and analyzing the role that immune cells such as neutrophils play in blood clot formation. “By including whole blood, we’re reaching a new standard of complexity and precision for mimicking a human body in both health and disease,” says Barrile. “This study affirms that we are recapitulating organ-level responses to lung injury, emphasizing that this is a true Organ-on-a-Chip, not just a tissue-on-a-chip,” adds Ingber.

    Andries D. van der Meer, Ph.D., former Senior Research Fellow at the Wyss Institute and current Assistant Professor at the MIRA Institute for Biomedical Technology and Technical Medicine, was the third co-author of this study. Additional authors include Akiko Mammoto, M.D., Ph.D., Instructor in the Vascular Biology Program at Boston Children’s Hospital and HMS; Tadanori Mammoto, M.D., Ph.D., Instructor in Surgery at Boston Children’s Hospital and HMS; Karen De Ceunynck, Ph.D., Postdoctoral Research Fellow at Beth Israel Deaconess Medical Center and HMS; Omozuanvbo Aisiku, Ph.D., former Postdoctoral Research Fellow at Beth Israel Deaconess Medical Center and HMS, currently a Scientist at Instrumentation Laboratory; Monicah A. Otieno, Ph.D., Senior Research Investigator at Bristol-Myers Squibb; Calvert S. Louden, D.V.M., Ph.D., Senior Director at Johnson & Johnson Pharmaceuticals; and Geraldine A. Hamilton, Ph.D., President and Chief Scientific Officer of Emulate, Inc.

    This work was funded by DARPA contract N66001-11-1-4180, HR0011-13-C-0025, Janssen Pharmaceuticals, and the Wyss Institute for Biologically Inspired Engineering at Harvard University. Ingber and Hamilton are founders and hold equity in Emulate, Inc, and Ingber chairs its scientific advisory board; van der Meer serves as a scientific consultant to the company.

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    Wyss Institute campus

    The Wyss (pronounced “Veese”) Institute for Biologically Inspired Engineering uses Nature’s design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world.

    Working as an alliance among Harvard’s Schools of Medicine, Engineering, and Arts & Sciences, and in partnership with Beth Israel Deaconess Medical Center, Boston Children’s Hospital, Brigham and Women’s Hospital, Dana Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Tufts University, and Boston University, the Institute crosses disciplinary and institutional barriers to engage in high-risk research that leads to transformative technological breakthroughs.

  • richardmitnick 8:45 pm on May 22, 2017 Permalink | Reply
    Tags: , “Driver” mutations, “Passenger” mutations, , Cancer is a disease of the genome, Genomic medicine requires massive data sharing and analysis, Medicine, Slit/Robo signaling, Treehouse Childhood Cancer Initiative, , Understanding the pathways that drive cancer   

    From UCSC: Cancer in the Cross Hairs” 

    UC Santa Cruz

    UC Santa Cruz


    UC Santa Cruz may not have a medical school, but its scientists are tackling some of the most challenging problems in cancer genomics, drug discovery, and basic cancer biology

    Tim Stephens

    Scott Lokey is not easily discouraged. In fact, he seems to thrive on scientific challenges, like taking on what the pharmaceutical industry calls “undruggable targets.” The term applies to molecules known to play a key role in disease but not susceptible to control by the kinds of small molecules that make good drugs.

    Lokey, a professor of chemistry and biochemistry and director of the Chemical Screening Center at UC Santa Cruz, is working with compounds that he thinks could overcome the obstacles presented by “undruggable” targets. If successful, his work could lead to a whole new class of drugs to fight cancer and other diseases.

    One such target is the retinoblastoma tumor suppressor protein, which normally puts the brakes on cell division. Its function is disrupted in most human cancers, allowing cancer cells to proliferate.

    Scott Lokey, professor of chemistry and biochemistry at UC Santa Cruz and director of the UCSC Chemical Screening Center, discusses how UCSC researchers are taking on “undruggable” targets.

    “The retinoblastoma protein is just the tip of the iceberg. There’s a huge inventory of potential targets that we haven’t been able to get at with conventional drugs,” says Lokey. “I actually get the majority of my funding from pharmaceutical companies for work on undruggable targets.”

    Taking on challenging drug targets is just one way to make progress against cancer. Researchers at UC Santa Cruz are attacking the disease from every angle. While the Chemical Screening Center searches for new cancer-fighting compounds, biologists are identifying new targets for the next generation of cancer drugs, and genomics experts are harnessing the power of big data to usher in a new era of precision therapies. The campus may not have a medical school, but that doesn’t keep its scientists and engineers from working at the cutting edge of biomedical research.

    All advances in cancer treatment­—from the development of new therapies and diagnostic tools to the use of genomics to guide treatment decisions—are rooted in understanding the fundamental biology of cancer cells.

    Cancer is a disease of the genome, caused by genetic changes that lead to uncontrolled growth and proliferation of tumor cells. Genomic analysis of tumor cells can reveal the genetic errors driving a patient’s cancer, but the enormous diversity of genetic abnormalities found in cancer cells makes interpreting the genomic data a huge challenge. Researchers at the UC Santa Cruz Genomics Institute are developing sophisticated computational methods for analyzing genomic data to help doctors choose the most effective drugs for individual patients.

    Known as “cancer genomics,” it’s a powerful approach that builds on decades of ongoing work by biologists to understand exactly how genetic changes drive cancer.

    Pathways to cancer

    The genetic abnormalities in cancer cells disrupt the signaling networks or “pathways” that regulate cellular activities. The life of a cell is orchestrated by a vast interconnected web of these pathways. Each pathway involves a complex series of interactions between cellular proteins, complete with feedback loops, cascading amplifications, and intersections with other pathways. Some of the proteins in these pathways have crucial interactions with the cell’s genetic material: the chromosomal DNA where genes are encoded and the RNA molecules involved in gene expression.

    Biologists like Lindsay Hinck, Doug Kellogg, Jeremy Sanford, and others in UCSC’s Department of Molecular, Cell, and Developmental Biology (MCD Biology) have made remarkable progress in unraveling the details of signaling pathways and their roles in cancer. Hinck’s lab, for example, has been studying the “Slit/Robo” pathway, which controls breast development and is disrupted in breast cancer and other cancers.

    Lindsay Hinck, professor of molecular, cell and developmental biology at UC Santa Cruz and co-director of the Institute for the Biology of Stem Cells discusses how understanding the fundamentals of cancer biology is the key to developing new cancer therapies.

    Slit/Robo signaling is actually involved in several critical pathways controlling cell proliferation and migration. The tumor suppressing effects of these pathways make them potential targets for drug development efforts. Hinck’s investigations of these pathways continue to reveal new insights, most recently on their roles in hormonal regulation of breast cancer cells.

    “Understanding how subpopulations of breast cancer cells respond to hormones such as estrogen and develop resistance to anti-estrogen treatments is likely to be very important for the next level of drug targets,” Hinck says.

    Clinical applications

    Working out the cellular signaling pathways involved in cancer can lead to clinical applications in a variety of ways. The most obvious is identifying a key molecule as a promising target for drug development, which often leads to more focused research on that particular molecule.

    Much of Seth Rubin’s research, for example, is focused on the retinoblastoma tumor suppressor protein (called Rb). Rb is a central player in many signaling pathways that are disrupted in cancer cells. It is called a tumor suppressor because it blocks the proliferation of abnormal cancer cells.

    “Rb is a stop sign that keeps cells from proliferating, so cancer cells have to turn it into a go sign,” explains Rubin, a professor of chemistry and biochemistry who has worked out the detailed structure of Rb and how it interacts with other proteins.

    Rubin has been working with Lokey’s lab and the Chemical Screening Center, developing a strategy to directly activate the Rb protein with a drug and turn it back into a stop sign. There are two issues that make this especially challenging. One is the goal of activating a protein that isn’t functioning properly. Most drugs are inhibitors that interfere with the function of their target; many cancer therapies target overactive pathways and aim to shut them down using inhibitors.

    “It’s a lot easier to knock down the function of something with a drug, because you’re basically just throwing a wrench into the system, whereas fixing something that’s not working is a lot harder to do,” Rubin explains.

    The other challenge is structural. Most drugs are small molecules that easily penetrate cells and block the target molecule by binding to its active site, typically just a deep pocket in its structure. “The standard analogy is that it fits like a lock and key, but it’s more like a baseball in a glove. That describes the vast majority of drugs and their targets,” Lokey says.

    But the active sites of many undruggable targets like Rb are large and complex, so an effective drug would have to be correspondingly large and interact with the target in complex ways, not just fit into a pocket. Lokey’s lab is working on the synthesis of large molecules that can bind to more complex targets and can also penetrate cells.

    In work led by Cameron Pye, a graduate student in Lokey’s lab, the team developed an assay to screen large numbers of these compounds (called cyclic peptides) for their ability to activate Rb. The lab has begun preliminary screening through a collaboration with Roche NimbleGen.

    “We’ve gone from no hits with small molecules to getting some hits for Seth’s target through this collaboration,” Lokey says. “Industry funding has been good for us. They have amazing technology for building these libraries of compounds.”

    Marking the way

    Understanding the pathways that drive cancer cells can yield not only drug targets but also clinically useful “biomarkers” to guide prognosis and therapeutic decision-making. In Zhu Wang’s research on prostate cancer, for example, he is studying the molecular mechanisms that make some prostate cancers highly aggressive. Many prostate cancers are slow-growing and may never threaten a patient’s health.

    “My work focuses on the cell types and molecular mechanisms that give rise to more aggressive cancers. The clinical applications could be new biomarkers that can be used to distinguish aggressive cancers from indolent cancers,” says Wang, an assistant professor of MCD biology. “Finding a molecular signature that is predictive of aggressive prostate cancer would have great prognostic value.”

    Pathway analysis plays a critical role in cancer genomics and has been a major focus of research in Josh Stuart’s lab. Stuart, the Baskin Professor of biomolecular engineering, recently published a study of metastatic prostate cancer yielding a detailed map of the abnormal signaling pathways that enable prostate cancer cells to proliferate and evade treatment. In collaboration with a team at UCLA, Stuart’s lab developed a novel computational analysis to produce personalized diagrams of the signaling pathways driving a patient’s cancer cells.

    “For now it’s a research tool, but the hope is to have a strategy like this to use in the clinic,” Stuart says. “These mutations in the genome create a lot of havoc in the cell, and trying to interpret the genomic information can be overwhelming. You need the computer to help you make sense of it and find the Achilles heel in the network that you can hit with a drug.”

    Drivers and passengers

    A persistent problem in cancer genomics has been distinguishing “driver” mutations from “passenger” mutations. Cancer cells often accumulate large numbers of genetic mutations that do not play a role in driving the uncontrolled growth. These passenger mutations effectively create static that interferes with the signal for mutations that are the real drivers of cancer. Aggregating data from large numbers of patients can give researchers enough statistical power to identify driver mutations.

    “Genomic medicine requires massive data sharing and analysis,” says David Haussler, professor of biomolecular engineering and director of the Genomics Institute. For years, Haussler has been an evangelist for data sharing to advance genomic medicine. In 2012, his team created the first public cancer genome database for the National Cancer Institute, the Cancer Genomics Hub. A year later, he cofounded the Global Alliance for Genomics and Health, an international nonprofit that is helping establish the infrastructure for data sharing in genomic medicine.

    Research led by the Genomics Institute has demonstrated the value of massive datasets in cancer genomics. In 2014, a groundbreaking study led by Stuart’s lab, based on analyses of molecular data from thousands of patients with 12 different tumor types, revealed that classifying tumors based on molecular subtypes, rather than the traditional tissue-of-origin system (i.e., breast cancer, lung cancer, etc.), could lead to different therapeutic options for as many as one in ten cancer patients. This type of “pan-cancer” analysis is only possible with data from large numbers of patients.

    Childhood cancers are rare, which makes it especially hard to assemble data from large numbers of patients. The Genomics Institute launched the Treehouse Childhood Cancer Initiative to address this problem and recently received a major grant from St. Baldrick’s Foundation to support the effort. A clinical pilot project launched in 2015 showed that real-time data sharing can identify new and better treatment options for children with cancer.

    Treehouse Childhood Cancer Initiative aims to make a huge difference in the world of pediatric cancer.

    “We need to think beyond sharing data after the research is published, which can take years, and move toward sharing patient genomic data in real time,” says Treehouse cofounder Olena Morozova, a research scientist at the Genomics Institute. “With real-time data sharing, the pediatric cancer community is poised to lead the way in revolutionizing how we share genomic data to benefit patients right now.”

    No silver bullet

    Experts have long understood that there is no silver bullet for cancer and that it is not, in fact, one disease but hundreds of diseases with different causes requiring different approaches to treatment. At the same time, there are good reasons to be optimistic about the prospects for more effective cancer treatments.

    “People sometimes overlook the fact that we are having success and bringing on new cancer therapies all the time,” Hinck says. “The problem is that every type of cancer is heterogeneous–there are at least five types of breast cancer, and some would say ten or 15, depending on how you classify them. We still have a lot to understand, and that’s why we need to keep doing this fundamental research.”

    Cancer immunotherapy, which uses drugs to coax the patient’s own immune system to eliminate the cancer, has shown particular promise in recent clinical trials. Haussler is collaborating with protein chemist Nik Sgourakis to advance immunotherapy using genomics. They are developing new computational tools for analyzing tumor genomes to predict which mutated proteins are displayed on the surface of tumor cells where they can be “seen” by the body’s immune system. These predictions are then evaluated on patient samples from medical collaborators at NIH, UCLA, and Children’s Hospital of Philadelphia. With this information, it may be possible to more specifically train the immune system to find and eliminate tumor cells, Haussler said.

    Whether in cancer genomics, drug discovery, or basic cancer biology, cancer researchers at UC Santa Cruz tend to tackle the most challenging problems and pursue ambitious projects.

    “We have a unique perspective based on who we are and the expertise we have here at UCSC,” says Kellogg, professor of MCD biology.

    For example, UC Santa Cruz is known as a leading center for research on the biology of RNA, and that has attracted talented young faculty such as Angela Brooks in biomolecular engineering and Jeremy Sanford in MCD biology, who are investigating the role of RNA in gene regulatory networks and cancer. “We’ve always had strength in RNA biology, and now there’s a good core of people here who are thinking more about RNA and disease. It’s an area that has not been well studied in cancer biology,” Sanford says.

    “You could say we tackle the hard problems and take on things that no one else is doing,” says Hinck.

    Most of the cancer researchers at UC Santa Cruz are funded by major grants from the National Institutes of Health (NIH), including the National Cancer Institute. As the single largest funding source for UCSC research, NIH awarded nearly $40 million in grants to support campus research projects in 2015-16.

    Private foundations like St. Baldrick’s are also important sources of funding for cancer research. The Santa Cruz Cancer Benefit Group (SCCBG), a local charity supporting cancer research and patient care, has awarded small grants to a number of UCSC faculty, including Rubin, Lokey, Hinck, and Wang. These grants fund pilot studies, the results of which can lead to much larger grants from NIH and other major funders.

    “That kind of seed funding is really important,” Rubin says.

    SCCBG funding has enabled Lokey to start a new project searching for compounds that could improve the effectiveness of cancer immunotherapy drugs. Immunotherapy drugs known as checkpoint inhibitors have taken the oncology world by storm, he says, but they work for only a subset of patients. Lokey hopes to find compounds that can make tumors more visible to the patient’s immune system.

    “It’s the kind of high risk, high reward research that’s hard to get funding for,” he says. “If we’re successful, though, it could really have a big impact.”


    Writing: Tim Stephens
    Video: Tim Stephens, Lisa Nielsen, Lucid Sound & Picture
    Photos: Carolyn Lagatutta
    Design and development: Rob Knight
    Project managers: Sherry Main, Scott Hernandez-Jason, Tim Stephens

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    UCO Lick Shane Telescope
    UCO Lick Shane Telescope interior
    Shane Telescope at UCO Lick Observatory, UCSC

    Lick Automated Planet Finder telescope, Mount Hamilton, CA, USA

    Lick Automated Planet Finder telescope, Mount Hamilton, CA, USA

    UC Santa Cruz campus
    The University of California, Santa Cruz, opened in 1965 and grew, one college at a time, to its current (2008-09) enrollment of more than 16,000 students. Undergraduates pursue more than 60 majors supervised by divisional deans of humanities, physical & biological sciences, social sciences, and arts. Graduate students work toward graduate certificates, master’s degrees, or doctoral degrees in more than 30 academic fields under the supervision of the divisional and graduate deans. The dean of the Jack Baskin School of Engineering oversees the campus’s undergraduate and graduate engineering programs.

    UCSC is the home base for the Lick Observatory.

    Lick Observatory's Great Lick 91-centimeter (36-inch) telescope housed in the South (large) Dome of main building
    Lick Observatory’s Great Lick 91-centimeter (36-inch) telescope housed in the South (large) Dome of main building

    Search for extraterrestrial intelligence expands at Lick Observatory
    New instrument scans the sky for pulses of infrared light
    March 23, 2015
    By Hilary Lebow
    The NIROSETI instrument saw first light on the Nickel 1-meter Telescope at Lick Observatory on March 15, 2015. (Photo by Laurie Hatch) UCSC Lick Nickel telescope

    Astronomers are expanding the search for extraterrestrial intelligence into a new realm with detectors tuned to infrared light at UC’s Lick Observatory. A new instrument, called NIROSETI, will soon scour the sky for messages from other worlds.

    “Infrared light would be an excellent means of interstellar communication,” said Shelley Wright, an assistant professor of physics at UC San Diego who led the development of the new instrument while at the University of Toronto’s Dunlap Institute for Astronomy & Astrophysics.

    Wright worked on an earlier SETI project at Lick Observatory as a UC Santa Cruz undergraduate, when she built an optical instrument designed by UC Berkeley researchers. The infrared project takes advantage of new technology not available for that first optical search.

    Infrared light would be a good way for extraterrestrials to get our attention here on Earth, since pulses from a powerful infrared laser could outshine a star, if only for a billionth of a second. Interstellar gas and dust is almost transparent to near infrared, so these signals can be seen from great distances. It also takes less energy to send information using infrared signals than with visible light.

    UCSC alumna Shelley Wright, now an assistant professor of physics at UC San Diego, discusses the dichroic filter of the NIROSETI instrument. (Photo by Laurie Hatch)

    Frank Drake, professor emeritus of astronomy and astrophysics at UC Santa Cruz and director emeritus of the SETI Institute, said there are several additional advantages to a search in the infrared realm.

    “The signals are so strong that we only need a small telescope to receive them. Smaller telescopes can offer more observational time, and that is good because we need to search many stars for a chance of success,” said Drake.

    The only downside is that extraterrestrials would need to be transmitting their signals in our direction, Drake said, though he sees this as a positive side to that limitation. “If we get a signal from someone who’s aiming for us, it could mean there’s altruism in the universe. I like that idea. If they want to be friendly, that’s who we will find.”

    Scientists have searched the skies for radio signals for more than 50 years and expanded their search into the optical realm more than a decade ago. The idea of searching in the infrared is not a new one, but instruments capable of capturing pulses of infrared light only recently became available.

    “We had to wait,” Wright said. “I spent eight years waiting and watching as new technology emerged.”

    Now that technology has caught up, the search will extend to stars thousands of light years away, rather than just hundreds. NIROSETI, or Near-Infrared Optical Search for Extraterrestrial Intelligence, could also uncover new information about the physical universe.

    “This is the first time Earthlings have looked at the universe at infrared wavelengths with nanosecond time scales,” said Dan Werthimer, UC Berkeley SETI Project Director. “The instrument could discover new astrophysical phenomena, or perhaps answer the question of whether we are alone.”

    NIROSETI will also gather more information than previous optical detectors by recording levels of light over time so that patterns can be analyzed for potential signs of other civilizations.

    “Searching for intelligent life in the universe is both thrilling and somewhat unorthodox,” said Claire Max, director of UC Observatories and professor of astronomy and astrophysics at UC Santa Cruz. “Lick Observatory has already been the site of several previous SETI searches, so this is a very exciting addition to the current research taking place.”

    NIROSETI will be fully operational by early summer and will scan the skies several times a week on the Nickel 1-meter telescope at Lick Observatory, located on Mt. Hamilton east of San Jose.

    The NIROSETI team also includes Geoffrey Marcy and Andrew Siemion from UC Berkeley; Patrick Dorval, a Dunlap undergraduate, and Elliot Meyer, a Dunlap graduate student; and Richard Treffers of Starman Systems. Funding for the project comes from the generous support of Bill and Susan Bloomfield.

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    UCSC is the home base for the Lick Observatory.

  • richardmitnick 3:13 pm on May 22, 2017 Permalink | Reply
    Tags: A lack of the protein citrin slows children's growth; blocking it in cancer slows tumor growth., , , Dr. Ayelet Erez, Medicine, ,   

    From Weizmann: Women in STEM – “Rare Genetic Defect May Lead to Cancer Drug” Dr. Ayelet Erez 

    Weizmann Institute of Science logo

    Weizmann Institute of Science

    No writer credit found

    Dr. Ayelet Erez says rare genetic diseases provide a lens on cancer.

    A lack of the protein citrin slows children’s growth; blocking it in cancer slows tumor growth.

    The path to understanding what goes wrong in cancer could benefit from a detour through studies of rare childhood diseases. Dr. Ayelet Erez explains that cancer generally involves dozens – if not hundreds – of mutations, and sorting out the various functions and malfunctions of each may be nearly impossible. Rare childhood diseases, in contrast, generally involve mutations to a single gene. Erez, a geneticist and medical doctor who treats families with genetic cancer in addition to heading a research lab in the Weizmann Institute of Science’s Biological Regulation Department, says that children with rare genetic syndromes may serve as a “lens” when trying to understand the role of a specific gene in a complex disease such as cancer. She and her team have been focusing their sights on a protein they discovered in this way; promising lab tests indicate that blocking this protein might slow the progression of some cancers.

    Her findings place this research in the new field of “cancer metabolism,” which seeks to understand how the aberrant, or uncontrolled metabolic processes in cancers might turned against them to stop their growth.

    She and her team studied cells from children suffering from an extremely rare disease, citrullinemia type II, who are missing the gene for a protein called citrin. Clinically, children with this disease tend to be smaller than average, and to avoid candy. Her research revealed that this protein normally helps keep the body supplied with an amino acid called aspartate which is required to produce DNA and RNA in addition to the breakdown of glucose; so deficiency in this protein causes the cells to divide less.

    Research into another genetic childhood disease, citrullinemia type I, had already given the team the lens they needed to understand how cancer cells rely on aspartate to divide and migrate. Children born with this disease are missing a gene called ASS1; the lack of ASS1 connects the disease to particularly aggressive, hard-to-treat cancers in which this gene tends to be silenced or mutated. Since this gene also requires aspartate to function, Erez and her team surmised that the silencing had less to do with the gene’s function and more with competition for aspartate and the cancer cells’ craving for ever more of this amino acid to help them divide and spread. Interestingly, the dependence on citrin for aspartate supplementation is seen in cancers both with and without ASS1 expression.

    Ayelet and her team realized that citrin – the protein that helps regulate childhood growth – could present a possible target for anticancer therapies. Blocking this protein would hopefully disrupt the cancer’s overactive metabolic cycle, diminish the cancer cells’ aspartate supply and slow their growth, thus making them less aggressive, less likely to spread and possibly more treatable with other, conventional means. To that end, Erez and her group have been developing a molecule to block citrin, and testing it in the lab. Yeda Research and Development Co., Ltd., the technology transfer arm of the Weizmann Institute of Science, is working with Erez to advance her research to the point that it can be developed for biomedical application.

    Dr. Ayelet Erez’s research is supported by the Moross Integrated Cancer Center; the Irving B. Harris Fund; the Adelis Foundation; the Rising Tide Foundation; the Comisaroff Family Trust; and the European Research Council. Dr. Erez is the incumbent of the Leah Omenn Career Development Chair.

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    Weizmann Institute Campus

    The Weizmann Institute of Science is one of the world’s leading multidisciplinary research institutions. Hundreds of scientists, laboratory technicians and research students working on its lushly landscaped campus embark daily on fascinating journeys into the unknown, seeking to improve our understanding of nature and our place within it.

    Guiding these scientists is the spirit of inquiry so characteristic of the human race. It is this spirit that propelled humans upward along the evolutionary ladder, helping them reach their utmost heights. It prompted humankind to pursue agriculture, learn to build lodgings, invent writing, harness electricity to power emerging technologies, observe distant galaxies, design drugs to combat various diseases, develop new materials and decipher the genetic code embedded in all the plants and animals on Earth.

    The quest to maintain this increasing momentum compels Weizmann Institute scientists to seek out places that have not yet been reached by the human mind. What awaits us in these places? No one has the answer to this question. But one thing is certain – the journey fired by curiosity will lead onward to a better future.

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

    From MedicalXpress: “Antibody for fighting cancer emerges” 

    Medicalxpress bloc



    Brigham and Women’s Hospital

    May 19, 2017
    No writer credit found

    Killer T cells surround a cancer cell. Credit: NIH

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

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

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

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

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

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

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

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

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

  • richardmitnick 12:09 pm on May 20, 2017 Permalink | Reply
    Tags: , Medicine, NBC, Robotic eye surgery   

    From NBC: “Robot Performs First-Ever Surgery Inside Human Eye” 

    NBC News

    NBC News

    May 9 2017
    Christopher Wanjek

    The technique is being called “a vision of eye surgery in the future.” air009/Shutterstock

    In a medical first, surgeons have used a robot to operate inside the human eye, greatly improving the accuracy of a delicate surgery to remove fine membrane growth on the retina. Such growth distorts vision and, if left unchecked, can lead to blindness in the affected eye.

    Currently, doctors perform this common eye surgery without robots. But given the delicate nature of the retina and the narrowness of the opening in which to operate, even highly skilled surgeons can cut too deeply and cause small amounts of hemorrhaging and scarring, potentially leading to other forms of visual impairment, according to the researchers who tested out the new robotic surgery in a small trial. The pulsing of blood through the surgeon’s hands is enough to affect the accuracy of the cut, the researchers said.

    In the trial, at a hospital in the United Kingdom, surgeons performed the membrane-removal surgery on 12 patients; six of those patients underwent the traditional procedure, and six underwent the new robotic technique. Those patients in the robot group experienced significantly fewer hemorrhages and less damage to the retina, the findings showed.

    The technique is “a vision of eye surgery in the future,” Dr. Robert E. MacLaren, a professor of ophthalmology at the University of Oxford in the United Kingdom, who led the study team and performed some of the surgeries, said in a statement. MacLaren presented the results Monday at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), happening this week in Baltimore.

    “These are the early stages of a new, powerful technology,” said MacLaren’s colleague Dr. Marc de Smet, an ophthalmologist in the Netherlands who helped design the robot. “We have demonstrated safety in a delicate operation. The system can provide high precision [at] 10 microns in all three primary [directions], which is about 10 times” more precise than what a surgeon can do, de Smet said. (The three primary directions are up/down, left/right, and towards the head/towards the feet.)

    Membrane growth on the retina results in a condition called epiretinal membrane, a common cause of visual impairment. The retina is the thin layer at the back of the eye that converts light waves into nerve impulses that the brain then interprets as images.

    An epiretinal membrane can form because of eye trauma or conditions such as diabetes, but more commonly it is associated with natural changes in the vitreous, the gel-like substance that fills the eye and helps it maintain a round shape. As people age, the vitreous slowly shrinks and pulls away from the retinal surface, sometimes tearing it.

    The membrane is essentially a scar on the retina. It can act like a film, obscuring clear vision, or it can distort the shape of the retina. The membrane can form over the macula, a region near the center of the retina that sharply focuses images, a crucial process for reading or seeing fine detail. When membranes form here, a person’s central vision becomes blurred and distorted, in a condition called a macular pucker.

    Removing the membrane can improve vision, MacLaren said, but the surgery is very intricate. The membrane is only about 10 microns thick, or about a tenth the width of a human hair, and it needs to be dissected from the retina without damaging the retina … all while the eye of the anesthetized patient is jiggling with each heartbeat, MacLaren said.

    Faced with the need for such precision, de Smet and his Dutch-based group developed a robotic system over the course of about 10 years. Robot-assisted surgery is now commonplace, particularly for the removal of cancerous tumors and diseased tissues, as in the case of hysterectomies and prostatectomies. But it has never been tried on the human eye, given the finer precision needed, the researchers said.

    De Smet’s group had a working model of the robotic system in 2011, devised by de Smet and Maarten Steinbuch, an engineering professor at the University of Eindhoven in the Netherlands. They demonstrated the system’s utility in 2015 on pigs, which have similar size eyes as humans.

    MacLaren’s team first used the system on a human, a 70-year-old priest from Oxford, England, in September 2016. Upon the success of that surgery, MacLaren’s team conducted a study on 11 more patients in a randomized clinical trial, hoping to measure the robotic system’s accuracy compared to the human hand.

    The robot acts like a mechanical hand with seven independent motors that can make movements as precise as 1 micron. The robot operates inside the eye through a single hole less than 1 millimeter in diameter and goes in and out of the eye through this same hole during various steps of the procedure. But the surgeon is in control, using a joystick and touch screen to maneuver the robot hand while monitoring movements through the operating microscope, MacLaren explained.

    During the trial, two patients who underwent the robotic surgery developed micro-hemorrhages, which means a little bit of bleeding, and one experienced a “retinal touch,” which means there was an increased risk of retinal tear and detachment. In the traditional surgery group, five patients experienced micro-hemorrhages, and two had retinal touches.

    MacLaren said the precision offered by the robotic system may enable new surgical procedures that surgeons have dreamed about but figured were too difficult to accomplish. For example, MacLaren said he hopes to next use the robotic system to place a fine needle under the retina and inject fluid through it, which could aid in retinal gene therapy, a promising new treatment for blindness.

    “The robotic technology is very exciting, and the ability to operate under the retina safely will represent a huge advance in developing genetic and stem cell treatments for retinal disease,” MacLaren told Live Science.

    The surgical system was developed by Preceyes BV, a Dutch medical robotics firm established at the University of Eindhoven by de Smet and others.

    See the full article here .

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