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  • richardmitnick 10:10 am on September 14, 2014 Permalink | Reply
    Tags: , , Cancer, , New Technology,   

    From Rutgers- “Novel Local Morphologic Scale: Applications in Disease Diagnosis and Prognosis” 

    Rutgers University
    Rutgers University

    Rutgers Technology

    Invention Summary

    Timely and accurate diagnosis of disease pathologies is critical to providing effective treatment to patients. Rutgers scientists have developed a novel local morphologic scale (LMS) to rapidly and automatically select, quantify and classify tissue/specimen topologies using parallelized computations. This unique tool has the ability to define features for every special image location and generate subsequent scene segmentation and classification for each location. Further this technology is free from shape constraints and generates output based on local structure attributes of complex histological images. This innovation has been successfully utilized in discriminating tumor versus stromal regions by classifying oncogenic tumor infiltrating lymphocytes (biomarker) in ovarian cancer tissue microarrays. Additionally, this technology has been applied across 3 other domains (prostate, breast) under two different stains illustrating its robustness to domain selection. This technology can be immensely useful to identify regions of interest, model heterogeneity of the underlying topology and generate digital signatures. It can also be used to train supervised classifiers to identify similar structural signatures in an image and therefore reduce or eliminate and observer variability.

    Market Application

    Disease Diagnosis, Digital Pathology, Histopathology, Computer Aided Diagnosis (CAD), Tissue Classification, Disease Monitoring and Prognosis, Lymphocyte Infiltration, Cancer.

    Advantages

    Signatures derived from cancerous versus non-cancerous tissues differ greatly. This tool can be highly instrumental in classifying cancerous versus non-cancerous tissue, can reliably and accurately account for cell shape and phenotypes, and provide accurate tissue classification, enabling pathologists to visually discern the two regions.

    Intellectual Property & Development Status
    Patent pending.

    Select Publication
    Janowczyk, A, Chandran S, Feldman MD, Madabhushi A. (2011). Local morphologic scale: Application to segmenting tumor infiltrating lymphocytes in ovarian cancer TMAs. SPIE http://lcib.rutgers.edu/publications/ Andrew/SPIE2011.pdf

    See the full articled here.

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

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

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  • richardmitnick 1:46 pm on September 5, 2014 Permalink | Reply
    Tags: , Cancer, ,   

    From PBS NOVA: “New Drug Clears Cancer Cells Through Immune System Judo” 

    PBS NOVA

    NOVA

    Fri, 05 Sep 2014
    Tim De Chant

    For years, scientists have been probing various immune response proteins in the hopes of finding a new way to target and destroy cancer cells. Yesterday, two months ahead of schedule, the FDA approved a drug that does just that, targeting the protein “programmed cell death 1,” or PD-1. While not the first drug to use the immune system to fight cancer, it may be the most promising to date.

    Pembrolizumab is currently approved for advanced melanoma patients who have no other treatment options left. In clinical trials, tumors shrank in 24% of patients, and in one particular trial, 69% of patients were alive after one year of pembrolizumab treatment, a number that shocked the doctors in charge.

    melanoma
    Melanoma cell

    Pembrolizumab works by suppressing the expression of PD-1. In a healthy cell, PD-1 is active and present on the surface of a cell. But when a cell is nearing the end of it’s life, PD-1 expression tapers off. Immune cells recognize this signal and come in to clear away the dead or dying cell. Researchers have discovered that, in many tumors, PD-1 continues to be expressed. By preventing PD-1 from appearing on the surface of a cell, they predicted that cancer cells would be eliminated by the body’s own defenses.

    Doctors are hopeful that therapies which target PD-1 will give patients new options with fewer side effects than traditional chemotherapy. Andrew Pollack, reporting for the New York Times:

    “This is really opening up a whole new avenue of effective therapies previously not available,” said Dr. Louis M. Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington and a spokesman for the American Association for Cancer Research. “It allows us to see a time when we can treat many dreaded cancers without resorting to cytotoxic chemotherapy.”

    Pembrolizumab is being marketed as Keytruda by Merck, the drug’s developer. Priced at $12,500 per month or $150,000 per year, the drug is apparently more expensive than other cancer drugs. Pollack reports that some cancer doctors have expressed concern that the high price tag will be too dear for some patients.

    Pembrolizumab is an antibody that specifically targets PD-1, so side effects tend to be less severe than with more general chemotherapy. Patients still run the risk of a potentially harmful inflammatory response—a sign of a runaway immune system, though most tolerated the drug well.

    For now, pembrolizumab is limited to patients with advanced melanoma that doesn’t respond to other treatments, but Merck has seen promising results with lung and kidney cancers. Other pharmaceutical companies are racing to get their PD-1 drugs approved, too. As more drugs come on the market, and new ones are calibrated for different cancers, the next few years could be the beginning of a new era in clinical cancer treatments.

    See the full article here.

    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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  • richardmitnick 3:02 pm on August 16, 2014 Permalink | Reply
    Tags: , , , Cancer,   

    From Argonne Lab: “New nanotech invention improves effectiveness of the ‘penicillin of cancer'” 

    News from Argonne National Laboratory

    August 13, 2014
    Jared Sagoff

    Scientists at the U.S. Department of Energy’s Argonne National Laboratory have added a new weapon to oncologists’ arsenal of anti-cancer therapies.

    By combining magnetic nanoparticles with one of the most common and effective chemotherapy drugs, Argonne researchers have created a way to deliver anti-cancer drugs directly into the nucleus of cancer cells.

    nano
    “This new method gives a way of delivering the dose of therapeutic cargo much more directly, which will enable us to have the same overall effect with a lower total dose, reducing the unpleasant and dangerous side effects of chemotherapy,” said oncologist Ezra Cohen, an author of the study.

    Researchers at Argonne’s Center for Nanoscale Materials and oncologists at the University of Chicago created nano-sized bubbles, or “micelles,” that contained two ingredients at their centers: magnetic nanoparticles of iron oxide and cisplatin, a conventional chemotherapy drug also known as “the penicillin of cancer.”

    Cisplatin works by directly blocking DNA replication within the cancer cell. However, in order to work, the cisplatin has to make it from the bloodstream through the somewhat rigid barrier of the cell membrane.

    “When someone is given a dose of chemotherapy, typically much of the drug doesn’t actually make it into the cancer cells. In addition, some cancer patients are sensitive to this drug due to impaired kidney function,” said oncologist Ezra Cohen, an author of the study. “This new method gives a way of delivering the dose of therapeutic cargo much more directly, which will enable us to have the same overall effect with a lower total dose, reducing the unpleasant and dangerous side effects of chemotherapy.”

    “This technique could potentially allow us to increase the proportion of cisplatin in cancer cells by a hundredfold, making it that much more effective a chemotherapeutic agent,” he added.

    Like the membranes of cancer cells themselves, the micelles are made up of a polymer material whose outer surfaces are hydrophilic, which means they are attracted to water, while the inner parts are hydrophobic, repelling water. “In addition, the surface of micelles can be equipped with targeting molecules capable of recognizing malignancy,” said Argonne nanoscientist Elena Rozhkova, lead author of the study.

    Rozhkova and her colleagues still needed a way to get the cisplatin into the nucleus of the cancer cell after the micelle had attached to it. To do so, they also encapsulated iron oxide nanoparticles within the micelle along with the cisplatin. These nanoparticles served as tiny “heaters” that were turned on by an applied magnetic field, which caused the micelle container to collapse and release the cisplatin.

    This was not the first time scientists had used applied nanomagnetic heat sources as a way to attack cancer cells, but the more targeted approach of the micelles allowed the researchers to use a much lower amount of heat and much less magnetic material, thereby risking less damage to healthy cells.

    In order to see the action of the nanoparticles and cisplatin as the micelle collapsed, the researchers used the Hard X-Ray Nanoprobe at Argonne’s Advanced Photon Source. “Normally, it’s difficult to see how cisplatin is delivered into organelles like the nucleus, but with this technology we can see simultaneously how the drug delivery happens, how the nanoparticles interact with the cell’s membrane and the cell’s response,” said Argonne nanoscientist Volker Rose.

    The study, entitled Efficient cisplatin pro-drug delivery visualized with sub-100 nm resolution: interfacing engineered thermosensitive magnetomicelles with a living system, appeared online in the June 6 issue of Advanced Materials Interfaces.

    The materials characterization and synthesis work was performed at the Center for Nanoscale Materials and the Advanced Photon Source, both DOE Office of Science User Facilities. The medical aspects of the research, including animal studies, were supported by the University of Chicago.

    The Center for Nanoscale Materials at Argonne National Laboratory is one of the five DOE Nanoscale Science Research Centers (NSRCs), premier national user facilities for interdisciplinary research at the nanoscale, supported by the DOE Office of Science. Together the NSRCs comprise a suite of complementary facilities that provide researchers with state-of-the-art capabilities to fabricate, process, characterize and model nanoscale materials, and constitute the largest infrastructure investment of the National Nanotechnology Initiative. The NSRCs are located at DOE’s Argonne, Brookhaven, Lawrence Berkeley, Oak Ridge and Sandia and Los Alamos National Laboratories. For more information about the DOE NSRCs, please visit the Office of Science website.

    See the full article here.

    Argonne National Laboratory seeks solutions to pressing national problems in science and technology. The nation’s first national laboratory, Argonne conducts leading-edge basic and applied scientific research in virtually every scientific discipline. Argonne researchers work closely with researchers from hundreds of companies, universities, and federal, state and municipal agencies to help them solve their specific problems, advance America’s scientific leadership and prepare the nation for a better future. With employees from more than 60 nations, Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science. For more visit http://www.anl.gov.

    The Advanced Photon Source at Argonne National Laboratory is one of five national synchrotron radiation light sources supported by the U.S. Department of Energy’s Office of Science to carry out applied and basic research to understand, predict, and ultimately control matter and energy at the electronic, atomic, and molecular levels, provide the foundations for new energy technologies, and support DOE missions in energy, environment, and national security. To learn more about the Office of Science X-ray user facilities, visit http://science.energy.gov/user-facilities/basic-energy-sciences/.

    Argonne is managed by UChicago Argonne, LLC for the U.S. Department of Energy’s Office of Science

    Argonne Lab Campus

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  • richardmitnick 2:20 pm on August 15, 2014 Permalink | Reply
    Tags: , , Cancer, Johns Hopkins University,   

    From PB S NOVA: “Modified Flesh-Eating Bacteria Could Be the Next Cancer Treatment” 

    PBS NOVA

    NOVA

    Fri, 15 Aug 2014
    Tim De Chant

    In a feat of microbial judo, researchers from Johns Hopkins have turned a flesh-eating bacteria into a highly-effective anti-cancer agent.

    Clostridium novyi is a common bacteria, found most frequently in soil and feces. The wild type consumes living cells and produces a protein known as an alpha-toxin, which disrupts the molecules that make up a cells skeleton. Without that skeleton, cells essentially fall apart, leaking their liquids into the surrounding tissue and dying. If untreated, a C. novyi infection can lead to death.

    micro
    Cancer cells in culture from human connective tissue

    But the Johns Hopkins team realized that C. novyi’s unique traits could be exploited. In addition to causing tissue death, it thrives in low-oxygen environments like tumors, which grow so quickly that they lack adequate blood supply. So the researchers removed the deadly alpha-toxin producing gene and tested the attenuated strain on tumors in various organisms ranging from rats to dogs and humans by injecting spores directly into the tumor sites.

    In each case, the modified bacteria fervently consumed tumor cells while leaving the surrounding healthy tissue in tact. C. novyi thrived in the hypoxic conditions inside the tumors but, when it strayed from the cancer site into healthy regions, it met stiff resistance from the body’s immune system. Rats with cancer that were treated with C. novyi injections lived more than twice as long, and tumors shrunk in six of the 16 dogs in the test and were eliminated in three more.

    The first human patient treated with C. novyi had metastasized abdominal cancer, and researchers focused on a tumor in her shoulder, injecting spores directly into the site.

    Carl Engelking, writing for Discover Magazine:

    The treatment wasn’t a walk in the park: the patient experienced severe pain in the shoulder, plus a fever as her body battled the bacteria. Eventually, her tumor formed an abscess that needed to be drained of fluid and debris. Two months after treatment her tumor showed all the signs of defeat, without evidence of a persistent infection.

    The patient’s other tumors, which weren’t treated with C. novyi, continued to grow, meaning the treatment was confined to the injection site. That’s both good news and bad—it means C. novyi isn’t straying beyond the tumor site and causing other problems, but it also means each individual tumor would need to be targeted.

    Human trials of C. novyi are still ongoing, so scientists are holding their breath to see if it’s successful in other cases. But they’re hopeful that this surprising microbial helper could pair with existing treatments to form a combination that’s both more deadly and more targeted, potentially adding years to patients’ lives.

    See the full article here.

    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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  • richardmitnick 6:45 pm on August 6, 2014 Permalink | Reply
    Tags: , , Cancer, , ,   

    From M.I.T.: “A new way to model cancer” 


    MIT News

    August 6, 2014
    Anne Trafton | MIT News Office

    Sequencing the genomes of tumor cells has revealed thousands of mutations associated with cancer. One way to discover the role of these mutations is to breed a strain of mice that carry the genetic flaw — but breeding such mice is an expensive, time-consuming process.

    Now, MIT researchers have found an alternative: They have shown that a gene-editing system called CRISPR can introduce cancer-causing mutations into the livers of adult mice, enabling scientists to screen these mutations much more quickly.

    gene
    Image: Thinkstock

    In a study appearing in the Aug. 6 issue of Nature, the researchers generated liver tumors in adult mice by disrupting the tumor suppressor genes p53 and pten. They are now working on ways to deliver the necessary CRISPR components to other organs, allowing them to investigate mutations found in other types of cancer.

    “The sequencing of human tumors has revealed hundreds of oncogenes and tumor suppressor genes in different combinations. The flexibility of this technology, as delivery gets better in the future, will give you a way to pretty rapidly test those combinations,” says Institute Professor Phillip Sharp, an author of the paper.

    Tyler Jacks, director of MIT’s Koch Institute for Integrative Cancer Research and the David H. Koch Professor of Biology, is the paper’s senior author. The lead authors are Koch Institute postdocs Wen Xue, Sidi Chen, and Hao Yin.

    Gene disruption

    CRISPR relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have copied this bacterial system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.

    In some cases, the researchers simply snip out part of a gene to disrupt its function; in others, they also introduce a DNA template strand that encodes a new sequence to replace the deleted DNA.

    To investigate the potential usefulness of CRISPR for creating mouse models of cancer, the researchers first used it to knock out p53 and pten, which protect cells from becoming cancerous by regulating cell growth. Previous studies have shown that genetically engineered mice with mutations in both of those genes will develop cancer within a few months.

    Studies of such genetically engineered mice have yielded many important discoveries, but the process, which requires introducing mutations into embryonic stem cells, can take more than a year and costs hundreds of thousands of dollars. “It’s a very long process, and the more genes you’re working with, the longer and more complicated it becomes,” Jacks says.

    Using Cas enzymes targeted to cut snippets of p53 and pten, the researchers were able to disrupt those two genes in about 3 percent of liver cells, enough to produce liver tumors within three months.

    Many models possible

    The researchers also used CRISPR to create a mouse model with an oncogene called beta catenin, which makes cells more likely to become cancerous if additional mutations occur later on. To create this model, the researchers had to cut out the normal version of the gene and replace it with an overactive form, which was successful in about 0.5 percent of hepatocytes (the cells that make up most of the liver).

    The ability to not only delete genes, but also to replace them with altered versions “really opens up all sorts of new possibilities when you think about the kinds of genes that you would want to mutate in the future,” Jacks says. “Both loss of function and gain of function are possible.”

    Using CRISPR to generate tumors should allow scientists to more rapidly study how different genetic mutations interact to produce cancers, as well as the effects of potential drugs on tumors with a specific genetic profile.

    “This is a game-changer for the production of engineered strains of human cancer,” says Ronald DePinho, director of the University of Texas MD Anderson Cancer Center, who was not part of the research team. “CRISPR/Cas9 offers the ability to totally ablate gene function in adult mice. Enhanced potential of this powerful technology will be realized with improved delivery methods, the testing of CRISPR/Cas9 efficiency in other organs and tissues, and the use of CRISPR/Cas9 in tumor-prone backgrounds.”

    In this study, the researchers delivered the genes necessary for CRISPR through injections into veins in the tails of the mice. While this is an effective way to get genetic material to the liver, it would not work for other organs of interest. However, nanoparticles and other delivery methods now being developed for DNA and RNA could prove more effective in targeting other organs, Sharp says.

    The research was funded by the National Institutes of Health and the National Cancer Institute.

    See the full article here.

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  • richardmitnick 11:18 am on July 19, 2014 Permalink | Reply
    Tags: , , , Cancer, , , , ,   

    Mapping Cancer Markers From WCG 

    Mapping Cancer Markers

    Mapping Cancer Markers Banner

    Mapping Cancer Markers

    Cancers, one of the leading causes of death worldwide, come in many different types and forms in which uncontrolled cell growth can spread to other parts of the body. Unchecked and untreated, cancer can spread from an initial site to other parts of the body and ultimately lead to death. The disease is caused by genetic or environmental changes that interfere with biological mechanisms that control cell growth. These changes, as well as normal cell activities, can be detected in tissue samples through the presence of their unique chemical indicators, such as DNA and proteins, which together are known as “markers.” Specific combinations of these markers may be associated with a given type of cancer.

    The pattern of markers can determine whether an individual is susceptible to developing a specific form of cancer, and may also predict the progression of the disease, helping to suggest the best treatment for a given individual. For example, two patients with the same form of cancer may have different outcomes and react differently to the same treatment due to a different genetic profile. While several markers are already known to be associated with certain cancers, there are many more to be discovered, as cancer is highly heterogeneous.

    Mapping Cancer Markers on World Community Grid aims to identify the markers associated with various types of cancer. The project is analyzing millions of data points collected from thousands of healthy and cancerous patient tissue samples. These include tissues with lung, ovarian, prostate, pancreatic and breast cancers. By comparing these different data points, researchers aim to identify patterns of markers for different cancers and correlate them with different outcomes, including responsiveness to various treatment options.

    This project runs on BOINC software. Visit BOINC or WCG, download and install the software and attach to the project. While you are at BOINC and WCG, look over the other projects for some that you might find of interest.

    WCG

    BOINC


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  • richardmitnick 10:10 am on July 6, 2014 Permalink | Reply
    Tags: , Cancer, ,   

    From physicsworld.com: “New proton detectors could lead to better cancer treatment” 

    physicsworld
    physicsworld.com

    Jul 3, 2014
    Jude Dineley

    A new detector that could improve the effectiveness of proton-beam cancer therapies has been developed by researchers in the UK and South Africa. The system tracks protons that have travelled through the body and gives medical physicists a detailed picture of how a therapeutic proton beam will interact with the treatment area. Having this information could lead to better cancer therapy and the team plans to build a prototype scanner that could eventually be commercialized.

    dyna
    Model of PRaVDA’s proton CT telescope

    Protons are ideal for some cancer treatments because when fired into living tissue, a beam of protons deposits most of its energy at a very specific depth that depends on its initial energy. As a result, protons can be used to destroy tumours while leaving surrounding healthy tissue relatively unharmed.

    Before a patient can receive treatment, medical physicists must calculate the appropriate radiation dose distribution to be delivered by the proton beam. Normally this is done by doing a conventional X-ray computed-tomography (CT) scan of the treatment area and using this information to calculate how much energy will be absorbed from the proton beam – a quantity called the “stopping power”. However, uncertainties can arise in these calculations and therefore medical physicists are keen on developing better methods for determining the stopping power.

    Researchers at the Proton Radiotherapy Verification and Dosimetry Applications (PRaVDA) consortium – funded by the Wellcome Trust – are designing and building the first proton transmission CT scanner based on silicon-based CMOS active pixel sensor (APS) technology. Such scanners work by exposing the treatment area to a beam of protons and then detecting the protons that have passed through the body. This information is used to build up a 3D image of the region to be treated, which provides an accurate measure of the stopping power. The benefit of using these APS detectors over existing calorimeter detectors is that they can track more than one proton at a time, which reduces the amount of time needed to perform a scan.

    Localized interactions

    In their latest work, the researchers have shown that their DynAMITe sensor can resolve individual protons passing through it. Developed by PRaVDA researchers in a previous project, the radiation-hard pixellated sensor has a 12.8 × 12.8 cm area and two wafer diode layers, one with 100 µm pixels and another with 50 µm pixels. The pixelated design allows proton-sensor interactions to be localized within the sensor area.

    “This allows you to measure the passage of more than one proton in the device at once,” explains team member Gavin Poludniowski, a medical physicist at the University of Surrey. The capability is an advantage over calorimeter-based sensors that handle one proton at a time. “[For these] it has been a challenge to get the event rate high enough to take a scan in a practicable time,” explained Poludniowski.

    Telescopic tracking

    In the planned proton CT scanner, a stack of the CMOS sensors – essentially a “telescope” – will determine proton energy loss in the patient. Combined with other detectors that were not a subject of this study, data from the telescope will also determine the direction of protons exiting the patient. With this information, the path of the proton in the patient – that is a result of multiple coulomb scattering events – can be reconstructed, generating images with superior spatial resolution to those achievable by detectors that assume an unscattered, linear trajectory.

    The researchers demonstrated the sensor’s proton counting ability by irradiating it with a 36 MeV beam produced by the MC40 cyclotron at the University of Birmingham in the UK and a therapeutic 200 Mev beam at the iThemba treatment facility in Somerset West in South Africa. Low beam currents and high frame rates of 1400 Hz – achieved by reading 10 of the 2520 rows on the sensor – maximized the ability of the sensor to resolve individual proton interactions.

    Detected events increased linearly with beam current up to a nominal current of 0.1 nA, then fell off with further increases. The observation is consistent with pulse pile-up in the sensor pixels that, in turn, indicates the detection of individual protons. Experimental observations also agreed with Monte Carlo simulations of the same set-up, providing further evidence of proton counting by the sensor.
    Stacks of DynAMITe

    When two DynAMITe sensors were stacked together – double DynAMITe – event distributions in the two matched. Eliminating fluctuations in beam current as a confounding factor, the high correlation that the researchers observed (r = 0.854) indicated that the pair was detecting the same protons, confirming its tracking ability.

    With proof-of-concept established, the researchers are redesigning the DynAMITe sensors for improved performance, with increased frame rates a major focus of their efforts. Estimating that the proton CT scans will require tens of millions of image frames, their goal is to achieve a 1000 Hz frame rate for the readout of the entire sensor area to limit scan duration to a few minutes.

    “We are investigating various aspects of hardware design to get the frame rate that we need. Pixel size and bit-depth are factors,” says Poludniowski. “Substantial innovations are [also] being made in the read-out design and electronics.”

    First scans in late 2015

    Investigations into the effects of telescope geometry on performance and the radiation hardness of the sensor are also in progress. The consortium plans to build a device and perform the first scans by the end of 2015, and then commercialize the technology with an industrial partner.

    The research is described in Physics in Medicine and Biology.

    See the full article here.

    PhysicsWorld is a publication of the Institute of Physics. The Institute of Physics is a leading scientific society. We are a charitable organisation with a worldwide membership of more than 50,000, working together to advance physics education, research and application.

    We engage with policymakers and the general public to develop awareness and understanding of the value of physics and, through IOP Publishing, we are world leaders in professional scientific communications.
    IOP Institute of Physics


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  • richardmitnick 3:45 pm on June 6, 2014 Permalink | Reply
    Tags: , , , Cancer,   

    From Brookhaven LAB: “Scientists Reveal Details of Calcium ‘Safety-Valve’ in Cells” 

    Brookhaven Lab

    Structure of membrane protein that plays a role in signaling cell death could be new target for anticancer drugs

    June 6, 2014
    Karen McNulty Walsh

    Sometimes a cell has to die—when it’s done with its job or inflicted with injury that could otherwise harm an organism. Conversely, cells that refuse to die when expected can lead to cancer. So scientists interested in fighting cancer have been keenly interested in learning the details of “programmed cell death.” They want to understand what happens when this process goes awry and identify new targets for anticancer drugs.

    The details of one such target have just been identified by a group of scientists from the U.S. Department of Energy’s Brookhaven National Laboratory, Columbia University, New York University, Baylor College of Medicine, Technical University of Munich, and the New York Structural Biology Center. The group, known as the New York Consortium on Membrane Protein Structure (NYCOMPS), used x-rays at Brookhaven Lab’s National Synchrotron Light Source (NSLS) to decipher the atomic level structure of a protein that regulates the level of calcium in cells. The work is described as a research article published in Science June 6, 2014.

    “The accumulation of calcium is a key signaling agent that can trigger programmed cell death, or apoptosis,” explained Wayne Hendrickson of Columbia and Brookhaven, and the director of NYCOMPS as well as a senior author on the paper. “Our study reveals how this protein, embedded in a cellular membrane structure called the endoplasmic reticulum, serves as a molecular safety valve for keeping calcium levels steady. Designing drugs that inhibit this protein would promote cell death, which could be a promising strategy for fighting cancers in which such proteins are overexpressed.”

    cal
    A calcium-leak channel prevents calcium overload in cellular organelles for protection of life. Viewing from within the membrane, the structure is shown as ribbons for the closed-conformation. The di-aspartyl pH-sensor unit and the arginine/aspartate lock are shown as sticks covered by electron densities in magenta.

    3-D Model for Rational Drug Design

    The protein that the scientists studied is a prokaryotic homolog of human “Transmembrane Bax Inhibitor Motif” (TMBIM) proteins, which come in six varieties. TMBIM6 is overexpressed in various cancers—including prostate, breast, glioma, uterine, ovarian, and lung.

    “Our work using the prokaryotic version of this protein has enabled us to construct a three-dimensional model that can be used as a basis for the rational design of possible inhibitor molecules,” said Qun Liu, a scientist at NSLS and NYCOMPS and the lead author on the paper.

    The atomic-level structures were determined using x-ray crystallography at NSLS beamlines X4A and X4C. Interactions of x-rays with the 3-D lattices of the protein molecules produce diffraction patterns from which the 3-D molecular images were derived. The images reveal a novel structure consisting of a centralized helix wrapped by two novel triple-helix sandwiches that traverse the membrane. The central portion can take on an open or closed conformation dependent on the acidity level, or pH. At physiological pH, open and closed conformations exist in equilibrium, maintaining a steady of state of calcium in the cell by allowing gradual leakage of calcium across the membrane through a transient transmembrane pore.

    “This leak is intrinsic to all kinds of cells and is cytoprotective for life, similar to a pressure safety value used in a standard steam boiler for safety assurance,” said Liu.

    The studies reveal in detail how the TMBIM protein senses and responds to changes in acidity to precisely regulate the mechanism.

    “The next step will be to solve crystal structures of the human TMBIM proteins to refine the design of possible inhibitor drugs,” said Liu.

    That work will take place at a new light source nearing completion at Brookhaven known as NSLS-II. That facility, set to start early experiments later this year, will be 10,000 times brighter than NSLS, making it particularly suitable for studies of membrane proteins, which are difficult to crystallize.

    Brookhaven NSLS II Photo
    Brookhaven NSLS II

    The New York Structural Biology Center is working in partnership with Photon Sciences at Brookhaven to build a microdiffraction beamline, called NYX, for advanced studies of biological molecules at NSLS-II.

    This research was supported in part by the National Institutes of Health (NIH) grant GM095315 and GM107462. The NSLS at Brookhaven Lab is a DOE Office of Science user facility, with beamlines X4A and X4C supported by the New York Structural Biology Center.

    See the full article here.

    One of ten national laboratories overseen and primarily funded by the Office of Science of the U.S. Department of Energy (DOE), Brookhaven National Laboratory conducts research in the physical, biomedical, and environmental sciences, as well as in energy technologies and national security. Brookhaven Lab also builds and operates major scientific facilities available to university, industry and government researchers. The Laboratory’s almost 3,000 scientists, engineers, and support staff are joined each year by more than 5,000 visiting researchers from around the world.Brookhaven is operated and managed for DOE’s Office of Science by Brookhaven Science Associates, a limited-liability company founded by Stony Brook University, the largest academic user of Laboratory facilities, and Battelle, a nonprofit, applied science and technology organization.
    i1


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  • richardmitnick 1:42 pm on May 22, 2014 Permalink | Reply
    Tags: , , Cancer, , ,   

    From Berkeley Lab: “New Details on Microtubules and How the Anti-Cancer Drug Taxol Works” 

    Berkeley Logo

    Berkeley Lab

    May 22, 2014
    Lynn Yarris (510) 486-5375 lcyarris@lbl.gov

    A pathway to the design of even more effective versions of the powerful anti-cancer drug Taxol has been opened with the most detailed look ever at the assembly and disassembly of microtubules, tiny fibers of tubulin protein that form the cytoskeletons of living cells and play a crucial role in mitosis. Through a combination of high-resolution cryo-electron microscopy (cryo-EM) and new methodology for image analysis and structure interpretation, researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley have produced images of microtubule assembly and disassembly at the unprecedented resolution of 5 angstroms (Å). Among other insights, these observations provide the first explanation of Taxol’s success as a cancer chemotherapy agent.

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    The most detailed look ever at the assembly and disassembly of microtubules, tiny fibers of tubulin protein that play a crucial role in cell division, provides new insight into the success of the anti-cancer drug Taxol.

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    The eukaryotic cytoskeleton. Actin filaments are shown in red, microtubules are in green, and the nuclei are in blue.

    “This is the first experimental demonstration of the link between nucleotide state and tubulin conformation within the microtubules and, by extension, the relationship between tubulin conformation and the transition from assembled to disassembled microtubule structure,” says Eva Nogales, a biophysicist with Berkeley Lab’s Life Sciences Division who led this research. “We now have a clear understanding of how hydrolysis of guanosine triphosphate (GTP) leads to microtubule destabilization and how Taxol works to inhibit this activity.”

    Nogales, who is also a professor of biophysics and structural biology at UC Berkeley, as well as an investigator with the Howard Hughes Medical Institute, is the corresponding author of a paper describing this research in the journal Cell. The paper is entitled High resolution αβ microtubule structures reveal the structural transitions in tubulin upon GTP hydrolysis. Co-authors are Gregory Alushin, Gabriel Lander, Elizabeth Kellogg, Rui Zhang and David Baker.

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    Gregory Alushin and Eva Nogales led a team of researchers that produced images of microtubule assembly and disassembly at the unprecedented resolution of 5 angstroms. (Photo by Roy Kaltschmidt)

    During mitosis, the process by which a dividing cell duplicates its chromosomes and distributes them between two daughter cells, microtubules disassemble and reform into spindles across which the duplicate sets of chromosomes migrate. For chromosome migration to occur, the microtubules attached to them must disassemble, carrying the chromosomes in the process. The crucial ability of microtubules to transition from a rigid polymerized or “assembled” state to a flexible depolymerized or “disassembled” state – called “dynamic instability” – is driven by GTP hydrolysis in the microtubule lattice. Taxol prevents or dramatically slows down the unchecked cell division that is cancer by binding to a microtubule in such a manner as to block the effects of hydrolysis. However, until now the atomic details as to how microtubules transition from polymerized to depolymerized structures and the role that Taxol can play have been sketchy.

    “Uncovering the atomic details of the conformational cycle accompanying polymerization, nucleotide hydrolysis, and depolymerization is essential for a complete description of microtubule dynamics,” Nogales says. “Such details should significantly aid in improving the potency and selectivity of existing anti-cancer drugs, as well as facilitate the development of novel agents.”

    To find these details, Nogales, an expert in electron microscopy and image analysis and a leading authority on the structure and dynamics of microtubules, employed cryo-EM, in which protein samples are flash-frozen at liquid nitrogen temperatures to preserve their natural structure. Using an FEI 300 kV Titan cryo-EM from the laboratory of Robert Glaeser, she and her colleagues generated cryo-EM reconstructions of tubulin proteins whose structures were either stabilized by GMPCPP, a GTP analogue, or were unstable and bound to guanosine diphosphate (GDP), or were bound to GDP but stabilized by the presence of Taxol.

    Alushin-Fig7_revisedThe tubulin protein is a heterodimer consisting of alpha (α) and beta (β) monomer subunits. It features two guanine nucleotide binding sites, an “N-site” on the α-tubulin that is buried, and an “E-site” on the β-tubulin that is exposed when the tubulin is depolymerized. Previous microtubule reconstruction studies were unable to distinguish the highly similar α-tubulin and β-tubulin from each other.

    “To be able to distinguish the α-tubulin from the β-tubulin, we had to resolve our images at better than 8 Å, which most prior cryo-EM studies were unable to do,” Nogales says. “For that, we marked the subunits with kinesin, a protein motor that distinguishes between α- and β-tubulin.”

    Nogales and her colleagues found that GTP hydrolysis and the release of the phosphate (GTP becomes GDP) leads to a compaction of the E-site and a rearrangement of the α-tubulin monomer that generates a strain on the microtubule that destabilizes its structure. Taxol binding leads to a reversal of this E-site compaction and α-tubulin rearrangement that restores structural stabilization.

    “Remarkably, Taxol binding globally reverses the majority of the conformational changes we observe when comparing the GMPCPP and GDP states,” Nogales says. “We propose that GTP hydrolysis leads to conformational strain in the microtubule that would be released by bending during depolymerization. This model is consistent with the changes we observe upon taxol binding, which dramatically stabilizes the microtubule lattice. Our analysis supports a model in which microtubule-stabilizing agents like Taxol modulate conformational strain and longitudinal contacts in the microtubule lattice.”

    This research was supported by NIH’s National Institute of General Medical Sciences, the Damon Runyon Cancer Research Foundation, and the Howard Hughes Medical Institute.

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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  • richardmitnick 9:25 am on April 20, 2014 Permalink | Reply
    Tags: , Cancer, , ,   

    From M.I.T.: “Targeting cancer with a triple threat” 

    April 15, 2014
    Anne Trafton | MIT News Office

    MIT chemists design nanoparticles that can deliver three cancer drugs at a time.

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    The new MIT nanoparticles consist of polymer chains (blue) and three different drug molecules — doxorubicin is red, the small green particles are camptothecin, and the larger green core contains cisplatin.

    Image courtesy of Jeremiah Johnson

    Delivering chemotherapy drugs in nanoparticle form could help reduce side effects by targeting the drugs directly to the tumors. In recent years, scientists have developed nanoparticles that deliver one or two chemotherapy drugs, but it has been difficult to design particles that can carry any more than that in a precise ratio.

    Now MIT chemists have devised a new way to build such nanoparticles, making it much easier to include three or more different drugs. In a paper published in the Journal of the American Chemical Society, the researchers showed that they could load their particles with three drugs commonly used to treat ovarian cancer.

    “We think it’s the first example of a nanoparticle that carries a precise ratio of three drugs and can release those drugs in response to three distinct triggering mechanisms,” says Jeremiah Johnson, an assistant professor of chemistry at MIT and the senior author of the new paper.

    Such particles could be designed to carry even more drugs, allowing researchers to develop new treatment regimens that could better kill cancer cells while avoiding the side effects of traditional chemotherapy. In the JACS paper, Johnson and colleagues demonstrated that the triple-threat nanoparticles could kill ovarian cancer cells more effectively than particles carrying only one or two drugs, and they have begun testing the particles against tumors in animals.

    Longyan Liao, a postdoc in Johnson’s lab, is the paper’s lead author.

    Putting the pieces together

    Johnson’s new approach overcomes the inherent limitations of the two methods most often used to produce drug-delivering nanoparticles: encapsulating small drug molecules inside the particles or chemically attaching them to the particle. With both of these techniques, the reactions required to assemble the particles become increasingly difficult with each new drug that is added.

    Combining these two approaches — encapsulating one drug inside a particle and attaching a different one to the surface — has had some success, but is still limited to two drugs.

    Johnson set out to create a new type of particle that would overcome those constraints, enabling the loading of any number of different drugs. Instead of building the particle and then attaching drug molecules, he created building blocks that already include the drug. These building blocks can be joined together in a very specific structure, and the researchers can precisely control how much of each drug is included.

    Each building block consists of three components: the drug molecule, a linking unit that can connect to other blocks, and a chain of polyethylene glycol (PEG), which helps protect the particle from being broken down in the body. Hundreds of these blocks can be linked using an approach Johnson developed, called “brush first polymerization.”

    “This is a new way to build the particles from the beginning,” Johnson says. “If I want a particle with five drugs, I just take the five building blocks I want and have those assemble into a particle. In principle, there’s no limitation on how many drugs you can add, and the ratio of drugs carried by the particles just depends on how they are mixed together in the beginning.”

    Varying combinations

    For this paper, the researchers created particles that carry the drugs cisplatin, doxorubicin, and camptothecin, which are often used alone or in combination to treat ovarian cancer.

    Each particle carries the three drugs in a specific ratio that matches the maximum tolerated dose of each drug, and each drug has its own release mechanism. Cisplatin is freed as soon as the particle enters a cell, as the bonds holding it to the particle break down on exposure to glutathione, an antioxidant present in cells. Camptothecin is also released quickly when it encounters cellular enzymes called esterases.

    The third drug, doxorubicin, was designed so that it would be released only when ultraviolet light shines on the particle. Once all three drugs are released, all that is left behind is PEG, which is easily biodegradable.

    This approach “represents a clever new breakthrough in multidrug release through the simultaneous inclusion of different drugs, through distinct chemistries, within the same … platform,” says Todd Emrick, a professor of polymer science and engineering at the University of Massachusetts at Amherst who was not involved in the study.

    Working with researchers in the lab of Paula Hammond, the David H. Koch Professor of Engineering and a member of MIT’s Koch Institute for Integrative Cancer Research, the team tested the particles against ovarian cancer cells grown in the lab. Particles carrying all three drugs killed the cancer cells at a higher rate than those that delivered only one or two drugs.

    Johnson’s lab is now working on particles that carry four drugs, and the researchers are also planning to tag the particles with molecules that will allow them to home to tumor cells by interacting with proteins found on the cell surfaces.

    Johnson also envisions that the ability to reliably produce large quantities of multidrug-carrying nanoparticles will enable large-scale testing of possible new cancer treatments. “It’s important to be able to rapidly and efficiently make particles with different ratios of multiple drugs, so that you can test them for their activity,” he says. “We can’t just make one particle, we need to be able to make different ratios, which our method can easily do.”

    Other authors of the paper are graduate students Jenny Liu and Stephen Morton, and postdocs Erik Dreaden and Kevin Shopsowitz.

    See the full article here.


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