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  • richardmitnick 9:30 am on February 8, 2016 Permalink | Reply
    Tags: , Cancer, Georgetown University   

    From Georgetown: “Gene family turns cancer cells into aggressive stem cells that keep growing” 

    Georgetown University bloc

    Georgetown

    February 5, 2016
    Karen Teber
    km463@georgetown.edu

    An examination of 130 gene expression studies in 10 solid cancers has found that when any of four related genes is overexpressed, patients have much worse outcomes, including reduced survival.

    Researchers from Georgetown Lombardi Comprehensive Cancer Center say their study, published Feb. 5 in Oncotarget, shows that this Ly6 family of genes allows cancer cells to act like cancer stem cells — which keep dividing and growing without pause.

    Ly6 gene oncogene
    MedicalXpress from Oncotarget

    “These are remarkable findings. We believe this family of genes produces cancer that easily metastasizes, is drug resistant and very difficult to destroy,” says the study’s senior investigator, Geeta Upadhyay, PhD, research assistant professor of oncology at Georgetown Lombardi.

    Upadhyay and her collaborators are currently working on novel agents that can inhibit Ly6 gene expression.

    Upadhyay’s research was initially based on Sca1, a mouse gene investigators use to check for the presence of cancer stem cells in animals. In 2011, she found that Sca1 was more than just a biomarker — it played a key role in creating and maintaining the stem-like quality in cancer stem cells.

    She then looked to see if Sca1 works the same way in humans, and found a family of Ly6 genes that mapped to the same chromosomal location in humans where Sca1 resides in the mouse genome. The Ly6 family of genes was structurally similar to Sca1 as well.

    This study was designed to determine if any of the genes in the Ly6 family are important in human cancer.

    The researchers used 130 published, publicly available studies that included information on patients’ genes and their cancer outcomes. Some studies were from the Georgetown Database of Cancer; others were available at the National Institutes of Health.

    They discovered that four different members of the family — Ly6D, Ly6E, Ly6H, or Ly6K — are not active in normal tissue but are expressed in bladder, brain and central nervous system, colorectal, cervical, ovarian, lung, head and neck, pancreatic and prostate cancers. Investigators also found that high expression of these genes are linked to poor outcomes and reduced survival in ovarian, colorectal, gastric, lung, bladder and brain and central nervous system cancers.

    “Correlation between Ly6 gene expression and poor patient survival in multiple cancer types indicate that this family of genes will be important in clinical practice — not only as a marker of poor prognosis, but as targets for new drugs,” Upadhyay says.

    This study of big data supports the “cancer moonshot” proposal to speed up research announced by President Obama at this year’s State of the Union address, Upadhyay says. “The cancer field makes rapid progress when researchers share data and this study, which examines the work of scores of research teams, illustrates what can be done.”

    “We applied bioinformatic tools to explore the clinical significance of increased LY6 in survival outcome in multiple cancer types. Systems biology tools are critical for steering basic research to solve critical clinical challenges and identify novel signaling nodes such as this one,” says co-author Subha Madhavan, PhD, director of the Innovation Center for Biomedical Informatics at Georgetown.

    Other researchers participating in the study are Georgetown researchers Linlin Luo, Peter McGarvey PhD, and Yuriy Gusev, PhD, all from the Innovation Center for Biomedical Informatics, and Rakesh Kumar, PhD.

    This work was supported by a grant from the National Cancer Institute (1R21CA175862-01A1) and an American Cancer Society Institutional Research Grant.

    See the full article here .

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    Georgetown University campus

    Georgetown University is one of the world’s leading academic and research institutions, offering a unique educational experience that prepares the next generation of global citizens to lead and make a difference in the world. We are a vibrant community of exceptional students, faculty, alumni and professionals dedicated to real-world applications of our research, scholarship, faith and service.

    Established in 1789, Georgetown is the nation’s oldest Catholic and Jesuit university. Drawing upon the 450-year-old legacy of Jesuit education, we provide students with a world-class learning experience focused on educating the whole person through exposure to different faiths, cultures and beliefs. Students are challenged to engage in the world and become men and women in the service of others, especially the most vulnerable and disadvantaged members of the community.

    These values are at the core of Georgetown’s identity, binding members of the community across diverse backgrounds.

     
  • richardmitnick 12:29 pm on February 6, 2016 Permalink | Reply
    Tags: , Cancer, Nature Genetics   

    From Nature: “The many ways MYB drives cancer” 

    Nature Mag
    Nature

    free association
    free association from Nature Genetics

    Nature Genetics | Free Association

    05 Feb 2016
    Posted by Brooke LaFlamm

    Two papers published online this week in Nature Genetics demonstrate that MYB, long known as a cancer gene, has many different strategies for driving tumorigenesis.

    Fruitfly eye signals about cancer
    Fruitfly eye, evidence of cancer

    Bradley Bernstein, Birgit Knoechel and colleagues studied the role of MYB translocations in adenoid cystic carcinoma (ACC) and found that MYB translocations can reposition the gene to be driven by super-enhancers—which themselves are bound by MYB to drive its own expression even higher. In an interesting twist, they also found that MYB drives different regulatory programs in different ACC cell lineages: MYB’s oncogenic function is mediated by TP63 in myoepithelial cells, while in luminal epithelial cells, MYB appears to act through the Notch signaling pathway.

    In an independent study focused on pediatric angiocentric gliomas, Keith Ligon, Rameen Beroukhim, Adam Resnick and colleagues found that MYB translocations resulting in MYB-QKI fusion genes are the most common MYB alteration in this cancer type. The fusion results in higher expression of MYB and loss of QKI expression, both of which contribute to the development of these gliomas. As in the ACC study, this translocation resulted in repositioning of MYB near enhancers that help drive its expression up. At the same time, the translocation caused loss of some regulatory elements, also leading to aberrant expression of MYB, and loss of function of QKI, a tumor suppressor. Thus, MYB-QKI uses three different mechanisms to drive gliomagenesis.

    Both cancer types are relatively rare but aggressive, and new treatment options are sorely needed. Adenoid cystic carcinoma (ACC) occurs in secretory glands, mainly the salivary glands in the head and neck, and can spread to the nerves as well as metastasizing to distant sites, such as the lungs. The tumors are often resistant to therapy and can recur many years after the primary tumor has been removed surgically. Angiocentric gliomas are very rare brain tumors that generally affect children and young adults. Very little is known about the genetic changes that occur in this tumor type and, prior to this study, there were no known recurrent driver mutations, which are often good candidates for new targeted drug therapies. “The discovery of a recurrent rearrangement in angiocentric glioma provides a clinically relevant diagnostic marker, and insights into the biology that drives these tumors,” said Pratiti Bandopadhayay, one of the lead authors of the study.

    We asked some of the authors from both studies to tell us a little more about the work and why it is important. Yotam Drier and Birgit Knoechel talked to us about the study in ACC. Pratiti Bandopadhayay, Lori Ramkissoon, Guillaume Bergthold and Payal Jain talked to us about the study in angiocentric gliomas.

    How do your findings clarify earlier results showing a role for MYB in ACC? Do you think these findings are relevant for other cancer types?

    Yotam Drier and Birgit Knoechel (Broad Institute):

    Our work identified a unifying mechanism for MYB over-expression in ACC. Persson et al. suggested in 2009 that MYB over-expression occurs where the MYB 3′ untranslated region (UTR) is lost. However, in most cases of ACC the MYB 3′ UTR remains intact, and we now describe that in all cases of detected MYB rearrangements in this cancer–independent of whether the 3′ UTR is retained or lost–MYB is being driven by hijacking MYB bound super-enhancers, thus creating a positive feedback loop. This is complementary to the previous model, and we believe that in those cases where the MYB 3′ UTR is lost, both mechanisms would contribute to increased MYB expression.

    We believe that similar rearrangements involving enhancer translocations may contribute to MYB overexpression in other cancer types. For example, our colleagues at Dana Farber simultaneously report a similar mechanism of MYB activation in angiocentric gliomas.

    How do the mechanisms described in your paper compare to what is described in the related paper by Drier et al.?

    Pratiti Bandopadhayay, Lori Ramkissoon and Guillaume Bergthold (Dana-Farber Cancer Institute) and Payal Jain (Children’s Hospital of Philadelphia):

    We were excited to learn about the findings from the Bernstein group as their findings compliment ours, in a completely different tumor type. We found that angiocentric gliomas harbor rearrangements involving the MYB and QKI genes, while Dr. Bernstein’s team focused on adenoid cystic carcinomas, which frequently have similar MYB rearrangements. Both papers show that MYB rearrangements result in aberrant activation of the MYB promoter to drive expression of the oncogenic fusion proteins, and that these fusion proteins then participate in auto-regulatory feedback loops to drive their own expression.

    From your perspective, what was the most unexpected finding in this study?

    Yotam Drier and Birgit Knoechel:

    We were surprised by our finding that MYB orchestrates 2 opposing epigenetic states—a TP63-dependent program in myoepithelial cells and a NOTCH-dependent program in luminal cells. Thus, overexpression of a single transcription factor can drive distinct epigenetic states that depend on the cellular context in which the overexpression occurs.

    Pratiti Bandopadhayay, Lori Ramkissoon, Guillaume Bergthold and Payal Jain:

    The unexpected result of our study that we find very exciting is that this one single driver rearrangement contributes to tumor growth through multiple mechanisms. MYB-QKI rearrangements simultaneously drive expression of a fusion protein that causes cells to grow faster and form tumors, it changes the regulatory landscape of the gene to promote expression of this protein and it simultaneously disrupts a tumor suppressor gene (QKI) that in turn also makes the cells divide faster. We feel that this finding is likely relevant to a number of other pediatric and adult cancers.

    How does the fusion with QKI impact the function of the translocated MYB and do you think it is necessary for its role in driving gliomagenesis?

    Pratiti Bandopadhayay, Lori Ramkissoon, Guillaume Bergthold and Payal Jain:

    The rearrangement with QKI results in displacement of regulatory elements on QKI towards MYB and these elements help drive expression of MYB-QKI. In addition, it disrupts the function of QKI itself, which is a tumor suppressor gene. We feel that the association with QKI is important in angiocentric glioma since the rearrangement between MYB and QKI occurred with such high frequency in our study.

    What are the additional steps needed before your findings can be implemented in the clinic?

    Yotam Drier and Birgit Knoechel:

    Interestingly, while BET inhibition can slow tumor growth in low grade ACCs, high grade ACCs often show genetic activation of NOTCH and are thus amenable to treatment with gamma secretase inhibitors or other NOTCH targeting therapies. It will be important to evaluate whether combining BET inhibition with NOTCH inhibition may show additional effects over BET inhibition alone. It is conceivable that by adding the NOTCH inhibitor one might preferentially target the luminal epithelial cells which are characterized by a NOTCH driven regulatory program. This will need to be tested further in preclinical models. Moreover, the fact that grade 3 tumors failed to respond to BET inhibition requires further preclinical analyses. Identifying mechanisms of BET inhibitor failure which are just entering clinical trials will be of utmost importance in order to predict which patients may benefit from these.

    Pratiti Bandopadhayay, Lori Ramkissoon, Guillaume Bergthold and Payal Jain:

    We are excited that our results provide us with novel possibilities to treat angiocentric gliomas. As MYB is a transcription factor the likelihood of targeting it or the MYB-QKI fusion is challenging; however we identified several downstream targets that represent potential therapeutic strategies. In addition, the finding of altered regulatory elements represents another exciting therapeutic strategy. Our findings directly impact clinical care for children with angiocentric glioma through development of two diagnostic tests that will be used to support the diagnosis of angiocentric glioma. We also feel our findings are likely relevant to other pediatric and adult cancers that are driven by driver rearrangements.

    Finally we would like to highlight that multiple institutions and funding sources helped facilitate this study. We would also like to acknowledge the families whose children have been afflicted with Pediatric Low-Grade Glioma.

    See the full article here .

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    Nature is a weekly international journal publishing the finest peer-reviewed research in all fields of science and technology on the basis of its originality, importance, interdisciplinary interest, timeliness, accessibility, elegance and surprising conclusions. Nature also provides rapid, authoritative, insightful and arresting news and interpretation of topical and coming trends affecting science, scientists and the wider public.

     
  • richardmitnick 6:50 am on February 6, 2016 Permalink | Reply
    Tags: , Cancer, , SPIE   

    From SPIE: “Tracking DNA damage with electrochemical sensing” 

    SPIE

    SPIE

    2.6.16
    Jason D. Slinker
    The University of Texas at Dallas
    Richardson, TX

    DNA, the fundamental biomolecule of life, is constantly subject to damage that threatens the vitality of cells and the integrity of the genome. Without enzymatic intervention, this damage can produce mutations that lead to cancerous tumors. Furthermore, many current and developing treatments of cancer and disease rely on the generation of DNA damage products, which—from a chemical standpoint—are very subtle. For example, 8-oxoguanine, the most prevalent oxidative DNA damage product, involves the addition of a single oxygen bond to a guanine base. Remarkably, enzymes in cells recognize and remove this damage and other products of degradation. Biological assays that follow repair of this subtle DNA damage assist cancer studies by advancing fundamental understanding of DNA-protein interactions, connecting damage to diagnosis, and informing options for treatment.

    We have demonstrated devices that follow DNA damage repair in real time, with a convenient, low-cost package (see Figure 1).1 In this device, DNA is bound to the circular electrodes of multielectrode chips, and a redox probe at the top of the DNA reports charge transfer through it. DNA is the natural recognition element not only for the binding of repair proteins but also for their repair activity, and it can be synthesized with or without damage/lesion sites to establish controls. Furthermore, DNA can also serve as an electrical transducing element when modified with a redox-active probe and self-assembled on a working electrode, as first demonstrated by the Barton group.2 We have combined these features of DNA, using them to form devices capable of selectively detecting oxidative DNA damage repair (see Figure 1) and changes in DNA stability.1 The devices give a direct measure of molecular-level repair, providing a window into intracellular DNA repair by DNA-binding proteins.

    DNA Device
    Figure 1. Top: Schematic of detection of oxidative damage removal. Bottom: Image of the device used to study DNA-damaging drugs. (Photo by Randy Anderson). FPG: Formamidopyrimidine DNA glycosylase. e-: Electron.

    Specifically, we have used our approach to show sensitive and selective electrochemical sensing of 8-oxoguanine and uracil repair glycosylase activity. We produced sensors on electrospun fibers as low-cost devices with improved dynamic range. Our experiments compared electroactive, probe-modified DNA monolayers containing a base defect with the rational control of defect-free monolayers. We found damage-specific limits of detection on the order of femtomoles of proteins, corresponding to mere nanograms of the enzymes. The DNA chips enabled the real-time observation of protein activity, and we observed base excision activity on the order of seconds. We also demonstrated damage-specific detection in a mixture of enzymes and in response to environmental oxidative damage. We showed how nanofibers may behave similarly to conventional gold-on-silicon devices, revealing the potential of these low-cost devices for sensing applications. This device approach enables sensitive, selective, and rapid assay of repair protein activity, allowing biological interrogation of DNA damage repair.

    Given the ability of these devices to follow induced oxidative damage, we are further using them to follow DNA-damaging anticancer drug activity. We are working with the group of David Boothman of the University of Texas Southwestern Medical Center to sense DNA repair activity in conjunction with a novel drug therapy that selectively produces oxidative damage of DNA in cancer cells, bringing about selective cancer cell death. We represent key features of a living system to reproduce DNA damaging and repair activity pathways on the chip. Recent results have shown that we can follow specific drug-induced DNA damage excision and subsequent DNA repair with our devices. Furthermore, the multiple electrodes of the chip allowed us to perform controls of each associated enzyme and to obtain high statistical confidence of results. Given this success, we have launched studies of other DNA damaging drugs to explore the generality of this technique.

    In summary, we have designed and fabricated low-cost devices that are capable of electrochemical sensing of 8-oxoguanine and uracil repair glycosylase activity. Ultimately, in addition to their utility in bioassays of DNA-protein interactions, our devices have potential in a number of applications for public health, and our future work will focus on realizing these. The prevalence of high damage repair sites can be an indication of cancers and disease states, and these devices could provide statistically significant diagnosis. Additionally, as a number of cancer treatments involve DNA-damaging agents, our devices can be used to improve treatment outcomes. These devices could be used to sample the activity of multiple drugs with a small volume patient sample, enabling a tailored treatment based on DNA-damaging effectiveness. Similarly, they may also be used to follow the course of cancer treatment through characteristic measures of enzymatic activity of cancer cells versus healthy cells.

    See the full article here.

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  • richardmitnick 5:46 pm on February 5, 2016 Permalink | Reply
    Tags: , Cancer,   

    From Princeton: “Antibiotic’s killer strategy revealed (PNAS)” 

    Princeton University
    Princeton University

    February 4, 2016
    Tien Nguyen, Department of Chemistry

    Using a special profiling technique, scientists at Princeton have determined the mechanism of action of a potent antibiotic, known as tropodithietic acid (TDA), leading them to uncover its hidden ability as a potential anticancer agent.

    TDA is produced by marine bacteria belonging to the roseobacter family, which exist in a unique symbiosis with microscopic algae. The algae provide food for the bacteria, and the bacteria provide protection from the many pathogens of the open ocean.

    “This molecule keeps everything out,” said Mohammad Seyedsayamdost, an assistant professor of chemistry at Princeton and corresponding author on the study published in the Proceedings of the National Academy of Science. “How could something so small be so broad spectrum? That’s what got us interested,” he said.

    In collaboration with researchers in the laboratory of Zemer Gitai, an associate professor of molecular biology at Princeton, the team used a laboratory technique referred to as bacterial cytological profiling to investigate the mode of action of TDA. This method involves destroying bacterial cells with the antibiotic in the presence of a set of dyes, and then visually assessing the aftermath. “The key assumption is that dead cells that look the same probably died by the same mechanism,” he said.

    The team used three dyes to evaluate 13 different features of the deceased cells, such as cell membrane thickness and nucleoid area, comprising TDA’s cytological profile. By comparing to profiles of known drugs, the researchers found a match with a class of compounds called polyethers, which possess anticancer activity.

    Given their similar profiles, Seyedsayamdost and coworkers hypothesized that TDA might exhibit anticancer properties as well, and indeed observed its strong anticancer activity in a screen against 60 different cancer cell lines. “The strength of this profiling technique is that it tells you how to repurpose molecules,” Seyedsayamdost said.

    The researchers were surprised by the compounds’ shared mode of action because unlike the small sized TDA, polyether compounds are quite large. But through different chemical reactions, they are both able to cause chemical disruptions in the cell membrane that render the bacterium unable to produce the energy needed to perform critical tasks, such as cell division and making proteins.

    In addition to TDA’s killing mechanism, the researchers were interested in understanding the mechanism by which a bacterial strain could become resistant to the antibiotic. Particularly, they wondered how the marine roseobacter kept itself safe from the deadly antibiotic weapon that it produced.

    The research team approached the task by probing the genes in roseobacter that synthesize TDA as well as the surrounding genes. They identified three nearby genes responsible for transport in and out of the cell, and upon transferring these specific genes to E. coli, were able to produce an elusive TDA resistant bacterial strain.

    “We often look at natural products as black boxes,” said Seyedsayamdost, “but these molecules have evolved for millennia to fulfill a certain function. By linking the unusual structural features of TDA to its mode of action, we have begun to explain why TDA looks the way it does.”

    Read the abstract:

    Wilson, M. Z.; Wang, R.; Gitai, Z.; Seyedsayamdost, M. R. Tropodithietic Acid: Mode of Action and Mechanism of Resistance. Proc. Natl. Acad. Sci. 2016, Published online on January 22, 2016.

    This work was supported by grants from the National Institutes of Health

    See the full article here .

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    About Princeton: Overview

    Princeton University is a vibrant community of scholarship and learning that stands in the nation’s service and in the service of all nations. Chartered in 1746, Princeton is the fourth-oldest college in the United States. Princeton is an independent, coeducational, nondenominational institution that provides undergraduate and graduate instruction in the humanities, social sciences, natural sciences and engineering.

    As a world-renowned research university, Princeton seeks to achieve the highest levels of distinction in the discovery and transmission of knowledge and understanding. At the same time, Princeton is distinctive among research universities in its commitment to undergraduate teaching.

    Today, more than 1,100 faculty members instruct approximately 5,200 undergraduate students and 2,600 graduate students. The University’s generous financial aid program ensures that talented students from all economic backgrounds can afford a Princeton education.

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  • richardmitnick 2:39 pm on February 2, 2016 Permalink | Reply
    Tags: , Cancer,   

    From DLR: “Cancer research in microgravity with TEXUS 53” 

    DLR Bloc

    German Aerospace Center

    23 January 2016

    Diana Gonzalez
    Deutsches Zentrum für Luft- und Raumfahrt (DLR) – German Aerospace Center
    Corporate Communications
    Tel.: +49 228 447-388
    Fax: +49 228 447-386

    Dr Otfried Joop
    German Aerospace Center (DLR)
    Space Administration, Microgravity Research and Life Sciences
    Tel.: +49 228 447-204
    Fax: +49 228 447-735

    Thyroid cells under the microscope
    Thyroid cells under the microscope. Cell nucleii ar blue, cytoskeleton is red.

    On 23 January 2016, five German science experiments travelled on board a German Aerospace Center (Deutsches Zentrum für Luft- und Raumfahrt; DLR), TEXUS sounding rocket, to take a ‘short trip’ in microgravity. These experiments in biology, physics and materials research were able to proceed without the influence of Earth’s gravity for approximately six minutes. The experiments were aimed at, among other things, answering questions in the field of cancer research and optimising solar cells. The TEXUS 53 rocket was launched at 09:30 CET from the Esrange Space Center in Kiruna, northern Sweden, and carried the experiments to an altitude of 253 kilometres.

    Researchers at the University of Magdeburg are interested in tracing the mechanisms involved in the functioning of cancer cells. In the THYROID experiment, they are examining the influence of microgravity on isolated human thyroid cancer cells. “The results will mean that we are better capacitated to detect early genetic changes and assess their significance for metabolism in cells,” explains Principal Investigator Daniela Grimm. Earlier experiments have already demonstrated that short periods of microgravity affect both the structure and genetic material of the cells. In addition, it would seem that long-term microgravity is able to cause changes in cell growth and mitigate the malignancy of these cells. These results indicate that microgravity cancer cell research is enabling new insights, which may be helpful in the development of new approaches for anticancer agents. On the TEXUS 53 flight, scientists wanted, above all, to determine details of the genes and proteins in cancer cells.

    How can solar cells make a better contribution to energy in the future?

    Whether solar energy can play an increasingly important role in global energy production in the future depends – in addition to storage capabilities – primarily on the efficiency and quality of the individual solar cells. Optimising this is the aim of the experiment by researchers from the Fraunhofer Institute for Integrated Systems and Device Technology (Fraunhofer-Institut für Integrierte Systeme und Bauelementetechnologie; IISB) in Erlangen and the University of Freiburg. ‘ParSiWal-2’ (Bestimmung der kritischen Einfanggeschwindigkeit von Partikeln bei der gerichteten Erstarrung von Solarsilizium im Weltall – determination of the critical capture speed of particles during the directional solidification of solar grade silicon in space) examines the undesirable incorporation of silicon nitride (Si3N4) particles that can occur during the crystallisation of silicon. As this contamination reduces the quality of solar cells, it is important to understand how it can be prevented during production. On the TEXUS 51 flight in April 2015, scientists successfully studied the incorporation of silicon carbide (SiC) particles with the precursor ParSiWal experiment.

    Laser technology for space

    Optical lasers are already being applied in many areas of research, such as in climate research, to detect trace gases in the atmosphere, or in astrophysics. In the ‘FOKUS-1B’ (Faserlaser-basierter optischer Kammgenerator unter Schwerelosigkeit – fibre-laser-based optical comb generator under microgravity conditions) experiment, an optical laser (frequency comb) developed at the Max-Planck Institute for Quantum Optics, will be tested for its suitability for applications in space.

    In the University of Berlin KALEXUS experiment (Kalium-Laser-Experimente unter Schwerelosigkeit – potassium laser experiment under microgravity conditions), scientists are studying the properties of miniaturised laser systems (External Cavity Diode Lasers; ECDL) for potassium spectroscopy. This experiment was designed to test whether this technology can be used on rocket flights. This is an important step in terms of its use in future space missions.

    Plants can sense microgravity

    How do living things sense microgravity? This is the question being asked by scientists at the University of Tübingen in their CAMELEON experiment. For this they measured the content of calcium ions in a model plant, thale cress (Arabidopsis thaliana), during the TEXUS flight. Plants use calcium signalling chains, for example, in their perception of gravity or microgravity. It is known from previous studies on parabolic flights that under microgravity conditions, after a few seconds, an increase in calcium content occurs and could be observed for more than 20 seconds. As six minutes of experimentation time in microgravity is available on a TEXUS flight, the scientists wanted to check how long the increased calcium values last and whether there is a specific microgravity-related variation in calcium content.

    Approximately 320 scientific experiments have been conducted since 1977 in the TEXUS programme – 70 percent of them on behalf of DLR and about 30 percent within the framework of participation by the European Space Agency (ESA). The DLR Space Administration contracted with Airbus Defence and Space GmbH in Bremen for the launch preparations and implementation of the TEXUS 53 campaign. OHB-System AG in Munich and the DLR Mobile Rocket Base (MObile RAketenBAsis; MORABA) also remain involved. The two-stage VSB-30 launcher was jointly developed by the Brazilian space agencies DCTA (Departamento de Ciência e Tecnologia Aeroespacial) and IAE (Instituto de Aeronáutica e Espaço), MORABA and the Swedish Space Corporation (SSC).

    See the full article here .

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    DLR Center

    DLR is the national aeronautics and space research centre of the Federal Republic of Germany. Its extensive research and development work in aeronautics, space, energy, transport and security is integrated into national and international cooperative ventures. In addition to its own research, as Germany’s space agency, DLR has been given responsibility by the federal government for the planning and implementation of the German space programme. DLR is also the umbrella organisation for the nation’s largest project management agency.

    DLR has approximately 8000 employees at 16 locations in Germany: Cologne (headquarters), Augsburg, Berlin, Bonn, Braunschweig, Bremen, Goettingen, Hamburg, Juelich, Lampoldshausen, Neustrelitz, Oberpfaffenhofen, Stade, Stuttgart, Trauen, and Weilheim. DLR also has offices in Brussels, Paris, Tokyo and Washington D.C.

     
  • richardmitnick 11:51 am on January 30, 2016 Permalink | Reply
    Tags: , Cancer,   

    From Harvard: “A cancer’s surprise origins, caught in action” 

    Harvard University

    Harvard University

    January 28, 2016
    Nancy Fliesler, Boston Children’s Hospital Communications

    Melanoma Onset
    Most of the time skin moles are harmless, but they occasionally turn into melanoma, a life-threatening skin cancer. Leonard Zon and colleagues found that this happens when a single cell regresses back to a stem cell state and starts to divide and invade the surrounding tissue. Courtesy of Boston Children’s Hospital

    First demonstration of a melanoma arising from a single cell

    Researchers at Harvard-affiliated Boston Children’s Hospital have, for the first time, visualized the origins of cancer from the first affected cell and watched its spread in a live animal. Their work, published in the Jan. 29 issue of Science, could change the way scientists understand melanoma and other cancers and lead to new, early treatments before the cancer has taken hold.

    “An important mystery has been why some cells in the body already have mutations seen in cancer, but do not yet fully behave like the cancer,” says the paper’s first author, Charles Kaufman, a postdoctoral fellow in the Zon Laboratory at Boston Children’s Hospital. “We found that the beginning of cancer occurs after activation of an oncogene or loss of a tumor suppressor, and involves a change that takes a single cell back to a stem cell state.”

    That change, Kaufman and colleagues found, involves a set of genes that could be targeted to stop cancer from ever starting.

    The study imaged live zebrafish over time to track the development of melanoma. All the fish had the human cancer mutation BRAFV600E — found in most benign moles — and had also lost the tumor suppressor gene p53.


    Download mp4 video here .
    A zebrafish melanoma model revealed the emergence of neural crest identity during melanoma initiation. With further research, these cancer-originating cells may offer scientists the ability to stop cancer before it even begins. Credit: The Zon Laboratory/Boston Children’s Hospital

    Kaufman and colleagues engineered the fish to light up in fluorescent green if a gene called crestin was turned on — a “beacon” indicating activation of a genetic program characteristic of stem cells. This program normally shuts off after embryonic development, but occasionally, in certain cells and for reasons not yet known, crestin and other genes in the program turn back on.

    “Every so often we would see a green spot on a fish,” said Leonard Zon, director of the Stem Cell Research Program at Boston Children’s and senior investigator on the study. “When we followed them, they became tumors 100 percent of the time.”

    The cell that caused melanoma

    When Kaufman, Zon, and colleagues looked to see what was different about these early cancer cells, they found that crestin and the other activated genes were the same ones turned on during zebrafish embryonic development — specifically, in the stem cells that give rise to the pigment cells known as melanocytes, within a structure called the neural crest.

    “What’s cool about this group of genes is that they also get turned on in human melanoma,” said Zon, who is also a member of the Harvard Stem Cell Institute and a Howard Hughes Medical Institute investigator. “It’s a change in cell fate, back to neural crest status.”

    Finding these cancer-originating cells was tedious. Wearing goggles and using a microscope with a fluorescent filter, Kaufman examined the fish as they swam around, shooting video with his iPhone. Scanning 50 fish could take two to three hours. In 30 fish, Kaufman spotted a small cluster of green-glowing cells about the size of the head of a Sharpie marker — and in all 30 cases, these spots grew into melanomas. In two cases, he was able to see on a single green-glowing cell and watch it divide and ultimately become a tumor mass.

    “It’s estimated that only one in tens or hundreds of millions of cells in a mole eventually becomes a melanoma,” says Kaufman, who is also an instructor at the Harvard-affiliated Dana-Farber Cancer Institute. “Because we can also efficiently breed many fish, we can look for these very rare events. The rarity is very similar in both humans and fish, which suggests that the underlying process of melanoma formation is probably much the same in humans.”

    Zon, the Grousbeck Professor of Pediatric Medicine at Harvard Medical School, and Kaufman believe that their findings could lead to a new genetic test for suspicious moles to see whether the cells are behaving like neural crest cells, indicating that the stem-cell program has been turned on. They are also investigating the regulatory elements that turn on the genetic program (known as super-enhancers). These DNA elements have epigenetic functions that are similar in zebrafish and human melanoma, and could potentially be targeted with drugs to stop a mole from becoming cancerous.

    A paradigm shift for cancer?

    Zon and Kaufman posit a new model for cancer formation, going back to a decades-old concept of “field cancerization.” They propose that normal tissue becomes primed for cancer when oncogenes are activated and tumor suppressor genes are silenced or lost, but that cancer develops only when a cell in the tissue reverts to a more primitive, embryonic state and starts dividing. They believe this model may apply to most if not all cancers, not just melanoma.

    The study was supported by the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Ellison Foundation, the Melanoma Research Alliance, the V Foundation, and the Howard Hughes Medical Institute. Zon is a founder and stockholder of Fate, Inc., and Scholar Rock.

    Co-authors on the study were Christian Mosimann (University of Zürich), Zi Peng Fan (Whitehead Institute and MIT), Justin Tan (Genome Institute of Singapore), Richard White (Memorial Sloan Kettering Cancer Center), Dominick Matos (Massachusetts General Hospital), Ann-Christin Puller (University Medical Center Hamburg-Eppendorf, Germany), Eric Liao (Harvard Stem Cell Institute and MGH), Richard Young (Whitehead Institute and MIT), and, at Boston Children’s Hospital, Song Yang, Andrew Thomas, Julien Ablain, Rachel Fogley, Ellen van Rooijen, Elliott Hagedorn, Christie Ciarlo, and Cristina Santoriello.

    See the full article here .

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    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 10:12 am on January 28, 2016 Permalink | Reply
    Tags: , Cancer, Moonshot 2020,   

    From Nautilus: “The Man Who Would Tame Cancer” 

    Nautilus

    Nautilus

    January 28, 2016
    John Steele

    Fruitfly eye signals about cancer
    Fruitfly eye signals about cancer

    Mapping Cancer Markers
    Mapping Cancer Markers at World Community Grid

    “For the loved ones we’ve all lost, for the families that we can still save, let’s make America the country that cures cancer once and for all.”
    —President Barack Obama, State of the Union Address (2016)

    Patrick Soon-Shiong wants to turn cancer treatment upside down. On January 12, Soon-Shiong and a consortium of industry, government, and academia announced the launch of the Cancer MoonShot 2020, an ambitious program aiming to replace a long history of blunt trial-and-error treatment with what amounts to a training regiment for the body’s own immune system. That system, Soon-Shiong argues, is perfectly adept at finding and eliminating cancer with exquisite precision—if it can recognize the mutated cells in the first place. Helping it to do so could represent a powerful new treatment for the disease, akin to a flu vaccine.

    Soon-Shiong has hit home runs before. This past July, one of his firms underwent the highest-value biotech IPO in history. A cancer drug he developed, called Abraxane, is approved to fight breast, lung, and pancreatic cancers in more than 40 countries. Soon-Shiong’s path from medical school in South Africa through residency in Canada, to UCLA professor, NASA researcher and corporate CEO has given him the bird’s-eye view necessary to take on a project this ambitious, as well as the resources to marshal the world-class computing and genome-sequencing facilities that it requires.

    When I sat down with him after the MoonShot announcement, I found him enthralled by the power and aesthetics of newly emerging cancer science, and deeply optimistic about near-term outcomes. This, it seems, is an exciting time to tackle cancer anew.

    What’s wrong with how we treat cancer today?

    We handle cancer based on empirical trial and error and imperfect information. We now have more information than we have ever had in the history of science. And that data reinforces a belief I have always had as a young doctor, which is that we are born with inherent protective mechanisms that fight cancer, infection, and infectious diseases. The way our body reacts when we are infected by a virus, or tear an Achilles, involves the same biology as when we fight cancer.

    Have we been too simplistic in our thinking about cancer?

    Yes, I think that’s why we’ve been losing the war. As physicians we’re trained to be reductionist. We rigidly follow protocol. But life is not that way. Cancer is not linear—it is completely non-linear. It lives in the science of chaos. There’s no single point of control. You need to attack it in a non-linear fashion across time and space, monitoring it and truly dancing with it. I know this sounds philosophical and silly and esoteric but it’s not. If you biopsy a patient with breast cancer twice in the same day, once in the breast and once in the lymph node, you can get cancer cells with different sequences. Even if you biopsy two different points in the breast, the sequence can be different. This heterogeneity has really only come to light recently. Which breaks all these reductionist assumptions, because which target are you hitting and what made you choose it? Is it just because you biopsied here instead of there? You’re whacking a mole, but you have no idea which one you’re whacking. You whack this one, this other one wakens. The only chance we have, in my opinion, is to do what I call micro killing and macro killing at the same time. Micro killing meaning you go after these little targets, maybe even using a little chemotherapy. And macro killing meaning either surgery, radiation, or immunotherapy.

    How do you see cancer?

    I see it as a bunch of rare diseases. Every cancer has its own molecular profile. There are many different sub-types just in lung cancer. They all hijack the immune system, tricking your body into believe they are not there. If we can teach your immune system to outsmart cancer by realizing that these cells in your body need to be killed, and if we can mobilize our immune system, then we have a completely new shot at treating cancer. The flip side of this hypothesis is, why would you give yourself chemotherapy at the highest doses, which wipes out the immune system? That’s what we’ve been doing for 40 years. I’m not saying you shouldn’t give yourself chemotherapy at all—but why would you give yourself such a high dose that you actually wipe out whatever protective mechanisms that you already have? Let’s understand the biological complexity of cancer, and use that understanding and trick the cancer to kill itself. And I think we have figured out a way to do that.

    Is cancer a normal part of life?

    Yes, I think cancer is actually a part of your physiological normal self. There’s a process called apoptosis by which your normal cells die, like the autumn leaves going brown. Cancer is actually not just an out-of-control growth—it’s a prevention of death, meaning the cells refuse to die when they should. You are right now as we’re doing this interview producing cancer cells in your body. What normally happens with these abnormal mutations is that your immune system’s natural killer cells are recognizing them and killing them. I don’t think mankind could have been born without natural killer cells having evolved to protect us against infection and cancer. So cancer is the flipside of regenerative medicine and stem cells. You know for many years people didn’t believe a cancer stem cell even existed. But it does—it’s just your normal stem cells gone amuck. Cancer represents a breaking of the contract with the human body.

    Do the cells that you’re talking about have a kind of intelligence?

    If you watch the motion of cells interacting with each other, you realize that they are exquisitely intelligent. They perform what I call the dance of proteins. The natural killer cell itself has something like 30,000 receptors on it. It is just one cell but it actually sees what’s around it, and turns on, turns off, activates, de-activates. And you know the amazing thing about the immune system is that it’s incredibly beautiful in its orchestration. Once you understand that orchestration, the simplicity of using that for the treatment of cancer is so amazing.

    What is the Cancer MoonShot 2020?

    The Cancer MoonShot 2020 is a project that seeks to exploit the body’s own immune system to fight cancer. Around 2015 Vice President Biden called me about his son’s brain cancer, and I got involved with some of the diagnostics. His son passed away in May of this year. By October I had written a two-page white paper talking about accelerating cancer immunotherapy using genomic sequencing and big data. That white paper became the mission statement of the MoonShot. My job as a physician, a surgeon, a cancer oncologist, immunologist, NASA ex-scientist, and former CEO is to orchestrate all of this. We are pursuing a very, very ambitious program. I’m not saying we’re going to cure cancer by 2020, but maybe we’ll be able to activate the body’s T cells to fight it. Just this week we’re going to present the first neoepitope targeting antibody, which will target mutant cancer proteins. We have treated metastatic colon cancer patients that have failed every line of chemotherapy and every line of standard therapy. All they got is this one antibody as an injection. Thirty percent are alive today. Some patients have been alive for two years. The average survival for these patients should have been five months. The promise of this program is not some hypothetical promise, but it is here now, tangible but very complex.

    How do modern genetics fit into the MoonShot?

    In 2003 people said we’ve solved cancer because we’ve solved the human genome, but that was completely naïve because it’s not the gene that’s important at all. It’s the output from the gene. What we called junk DNA actually turns out to control gene expression. So it was a naïve, almost arrogant assumption that just by solving the genome we’re going to know what we’re doing. We needed to actually take this junk DNA, 3 billion base pairs that control 20,000 genes, and understand it. To do that we needed to what’s called whole-genome sequencing. Which we’ve now done for the first time. Then we found that it’s not the gene, stupid—it’s the protein that the genes make. These 20,000 genes and this junk DNA control something called transcription, which involves 200,000 rRNA (ribosomal DNA) molecules. Then this rDNA is involved in making 10 million proteins through 10,000 different pathways. So has the science actually evolved to be able to take 3 billion base pairs times 20,000 genes times 200,000 rRNA molecules times 10,000 pathways, and find the pathway that actually causes the cancer? Yes. We are there. But, again we had this arrogance of saying that’s all we need. We have this other thing called passenger genes, which we thought we weren’t interested in. It turns out those passenger genes are the ones that are tricking the body into believing that mutant cancer proteins are not foreign. What if we can isolate those mutants and bring them into the body in the form of a vaccine, like a flu vaccine? Then we can train the body’s T cells to recognize them and go after them. That is the approach we’ve tried with the colon cancer patients.

    Is gene editing technology also relevant?

    We understand more about mechanisms at the attomolar level and the cellular level than ever. We can interrogate cells in real time in a way we’ve been never ever been able to do by using CRISPR technology, which lets us turn cells on and turn cells off and actually test our hypothesis in the test tube. The ability to measure 123 little biomarkers just in the immune system has been demonstrated. We’re learning more about the mechanism of the interaction of proteins than ever before.

    How important is big data to the MoonShot?

    It’s one of the weapons but it’s information that you actually use in real time to test hypotheses. What frustrates me most when people talk of big data is that they’re really talking about retrospective registries—the stuff that’s going on at research institutions and even at the National Institutes of Health. All these big data registries look at claims data, backward in time. I’m talking about real world data that I’m capturing now dynamically, treating you, knowing that my treatments are actually affecting the relevant mutation. That’s big data. That’s real world data. That’s the data we’re talking about. The trouble is the amount of data that we generate just from one single patient alone is bigger than anything that you see in all of Facebook.

    How did you get interested in science?

    We grew up in South Africa without TV, so we’d listen to radio and we’d read. There were magazines called Knowledge and Look and Learn, with pictures of these cells and descriptions of how they worked, and I think I was 13 when I said okay that’s what I want to do. I was trained at a school called the Chinese High School—you couldn’t go to a white school and you couldn’t go to a black school, you went to a Chinese high school. Our science teacher was a priest who went through World War I who got terribly ill in my last year or second-to-last year of high school. There was no teacher for about six months. And I was nominated to teach the class. So I read these science textbooks and taught my own class science lessons for a while.

    What was your medical education like?

    I was trained as a doctor in South Africa. It was a six-year training course and one-year internship, and at the end of that there was no specialty training. I got a full generalist training, including deep physiology, deep pathology, deep microbiology, deep pediatrics, and internal medicine. We had to end up having delivered 100 babies. So the exposure that I got to this breadth of medicine was amazing. I then had the good fortune to come to Canada, where I earned a Master’s at night studying protein-protein interactions, while I was doing my surgical residency. My focus was on the gastric inhibitory polypeptide and its role in managing the pancreas in patients with diabetes. Then I get recruited to UCLA, where I was thrown into the cauldron of being a young resident in the department of surgery, where you’re up all night, you’re doing surgery. Then I got bored. I started out doing these minor surgical procedures but decided I wanted to do the most difficult procedure, which at that time was a thing called the Whipple. A Whipple is a procedure in a patient with pancreatic cancer, in which you basically remove the pancreas, the stomach, a piece of the liver, and the bowels. You remove 80 percent of the area around the pancreas and you have to hook it all up again. That excited me. Then as an assistant professor of surgery I went off to train to do pancreas transplants. I did UCLA’s first two pancreas transplants. If you look at my evolution of generalist to scientist to surgeon to surgical oncologist to pancreas transplants it looks discordant, but to me it was a continuation of understanding biology under different circumstances.

    What got you interested in cancer specifically?

    The first two pancreas transplant patients at UCLA did fabulously, except they both rejected their transplant. Pancreas transplant rejections are the most frightening thing, because you’ve hooked the pancreas to the bladder. When the organ rejects, port-wine blood pours out the uretary catheter. I said to myself, “wow, do I really believe this is the right thing to do to a patient?” Which led to me tell my chairman that I’m going to shut down the program of which I’m a director. I decided that I needed to understand regenerative medicine, where I can take cells representing only 2 percent of the gland, one thumbnail full, put them into a micro encapsulation, and prevent rejection. Then I could do a transplant with a single needle. Then I got exposed to the Jet Propulsion Lab at NASA, where they were planning to create stem cells for astronauts on Mars, and got involved with that program. I got interested in the immune system because I was trying to induce tolerance, to make your body believe that this cell I’m going to give you as a diabetic patient is actually your cell, even though it came from a pig, so please don’t reject it. Out of that work came two things. One was the invention of Abraxane, a cancer drug which is also the nation’s first protein-based nanoparticle. The other was the realization that cancer cells have figured out how to induce tolerance, to tell your body “don’t eat me because I’m actually you.” So the irony is that the first part of my career was to induce tolerance for transplants, and the second part was to break tolerance to actually tell the body to kill cancer cells.

    More information is available at http://www.cancermoonshot2020.org.

    See the full article here .

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    Welcome to Nautilus. We are delighted you joined us. We are here to tell you about science and its endless connections to our lives. Each month we choose a single topic. And each Thursday we publish a new chapter on that topic online. Each issue combines the sciences, culture and philosophy into a single story told by the world’s leading thinkers and writers. We follow the story wherever it leads us. Read our essays, investigative reports, and blogs. Fiction, too. Take in our games, videos, and graphic stories. Stop in for a minute, or an hour. Nautilus lets science spill over its usual borders. We are science, connected.

     
  • richardmitnick 8:59 pm on January 25, 2016 Permalink | Reply
    Tags: , Cancer, , Researchers Pinpoint Place Where Cancer Cells May Begin, The fruitful fruitfly   

    From Northwestern: “Researchers Pinpoint Place Where Cancer Cells May Begin” 

    Northwestern U bloc

    Northwestern University

    January 20, 2016
    Megan Fellman

    Fruitfly eye signals about cancer
    The fruit fly’s eye is an intricate pattern of many different specialized cells, and scientists use it as a workhorse to study what goes wrong in human cancer. In a new study of the fly’s eye, Northwestern University researchers have gained insight into how developing cells normally switch to a restricted, or specialized, state and how that process might go wrong in cancer. (Credit: Northwestern University)

    Cancer cells are normal cells that go awry by making bad developmental decisions during their lives. In a study involving the fruit fly equivalent of an oncogene implicated in many human leukemias, Northwestern University researchers have gained insight into how developing cells normally switch to a restricted, or specialized, state and how that process might go wrong in cancer.

    The fruit fly’s eye is an intricate pattern of many different specialized cells, such as light-sensing neurons and cone cells. Because flies share with humans many of the same cancer-causing genes, scientists use the precisely made compound eye of Drosophila melanogaster (the common fruit fly) as a workhorse to study what goes wrong in human cancer.

    A multidisciplinary team co-led by biologist Richard W. Carthew and engineer Luís A.N. Amaral studied normal cell behavior in the developing eye. The researchers were surprised to discover that the levels of an important protein called Yan start fluctuating wildly when the cell is switching from a more primitive, stem-like state to a more specialized state. If the levels don’t or can’t fluctuate, the cell doesn’t switch and move forward.

    “This mad fluctuation, or noise, happens at the time of cell transition,” said Carthew, professor of molecular biosciences in Northwestern’s Weinberg College of Arts and Sciences. “For the first time, we see there is a brief time period as the developing cell goes from point A to point B. The noise is a state of ‘in between’ and is important for cells to switch to a more specialized state. This limbo might be where normal cells take a cancerous path.”

    The researchers also found that a molecular signal received by a cell receptor called EGFR is important for turning the noise off. If that signal is not received, the cell remains in an uncontrolled state.

    By pinpointing this noise and its “off” switch as important points in the normal process of cell differentiation, the Northwestern researchers provide targets for scientists studying how cells can go out of control and transform into cancer cells.

    The study was published as the cover story Jan. 14 by the online life sciences and biomedicine journal eLife.

    The “noisy” protein the Northwestern researchers studied is called Yan in the fly and Tel-1 in humans. (The protein is a transcription factor.) The Tel-1 protein instructs cells to turn into white blood cells; the gene that produces the protein, oncogene Tel-1, is frequently mutated in leukemia.

    The EGFR protein that turns off the noise in flies is called Her-2 in humans. Her-2 is an oncogene that plays an important role in human breast cancer.

    “On the surface, flies and humans are very different, but we share a remarkable amount of infrastructure,” said Carthew, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “We can use fruit fly genetics to understand how humans work and how things go wrong in cancer and other diseases.”

    Fruit fly cells are small and closely packed together, making study of them challenging. Carthew and Amaral’s team of biologists, chemical and biological engineers, computer scientists and chemists together figured out how to identify and analyze thousands and thousands of individual cells in the flies’ eyes.

    “In the past, people have built models of regulatory networks that control cell differentiation mostly by genetically perturbing one or two components of the network at a time and then compiling those results into models,” said Amaral, professor of chemical and biological engineering at the McCormick School of Engineering. “We instead measured the retina as it developed and found the unexpected behavior of the key regulatory factors Yan and EGFR.”

    Nicolás Peláez, first author of the study and a Ph.D. candidate in interdisciplinary biological sciences working with Amaral and Carthew, built new tools to study this strange feature of noise in developing flies. His methods enabled the researchers to easily measure both the concentration of the Yan protein and its fluctuation (noise).

    It takes 15 to 20 hours for a fruit fly cell to go from being an unrestricted cell to a restricted cell, Carthew said. Peláez determined the Yan protein is noisy, or fluctuating, for six to eight of those hours.

    “Studying the dynamics of molecules regulating fly-eye patterning can inform us about human disease,” Peláez said. “Using model organisms such as fruit flies will help us understand quantitatively the basic biological principles governing differentiation in complex animals.”

    The Department of Energy (grant DE-NA0002520) and the National Institutes of Health (grants P50GM081892, R01GM80372 and R01GM077581) supported the research.

    The paper is titled Dynamics and Heterogeneity of a Fate Determinant During Transition Towards Cell Differentiation.

    In addition to Carthew, Amaral and Peláez, other authors are Bao Wang and Aggelos K. Katsaggelos, of Northwestern; Arnau Gavalda-Miralles and Heliodoro Tejedor Navarro, of the Howard Hughes Medical Institute; and Herman Gudjonson, Ilaria Rebay and Aaron R. Dinner, of the University of Chicago.

    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 4:50 pm on January 22, 2016 Permalink | Reply
    Tags: , , Cancer,   

    From Broad Institute: “The beauty of imbalance” 

    Broad Institute

    Broad Institute

    January 21st, 2016
    Angela Page

    Temp 1
    Broad researchers have found that asymmetrical mutational patterns on the two strands of the double helix could be implicated in cancer. Image by Madeleine Price Ball/Lauren Solomon

    Every day, every cell in the body picks up one or two genetic mutations. Luckily, cells have a whole battery of strategies for fixing these errors. But most of the time, even if a mutation doesn’t get fixed — or doesn’t get fixed properly — there are no obvious functional implications. That is, the mutation isn’t known to impair the function of the cell. Some mutations, however — called “driver” mutations — do impair the cell, leading to cancer, aging, or other types of diseases.

    Identifying new driver mutations (a few hundred genes that carry driver mutations are known so far) is a huge focus for most labs that study cancer, including that of Broad Cancer Genome Computational Analysis group director Gad Getz. But in new research recently published in Cell, Getz and computational biology group leader Michael Lawrence wanted to look at all those other mutations: the “passengers” that may or may not cause cancer. Doing so, they surmised, would not only help them understand the fundamental biology of cells, but may also point them toward new mechanisms for causing mutations associated with cancer.

    And that’s exactly what happened. The new work reveals the mechanism behind cancers associated with a family of enzymes called APOBEC, which had been rather enigmatic until now. The original purpose of APOBEC enzymes, according to Lawrence, was probably to fight viruses. But recent studies from Getz’s lab and others have shown that many cancers are enriched for genetic mutations caused by these enzymes.

    “Something that most cervical and bladder cancers, some breast cancers, many head and neck cancers, and a scattering of many other tumor types, all have in common is over-activity of APOBEC enzymes,” Lawrence said. People had been studying APOBEC cancers for years, trying to figure out what exactly was going wrong, but they had so far met with little success.

    One thing that had interested Lawrence and Getz about APOBEC was that while it introduces dozens of mutations all across the genome, it always affects the cytosine bases — the “Cs” in the famous DNA alphabet which also contains As, Ts, and Gs. This was interesting because it played right into a hypothesis about asymmetry that Getz and Lawrence had already begun to explore.

    “Every cell has two DNA strands that wrap around each other in a double helix. Both carry the same information, so each double helix has two copies of the information,” Lawrence said. “When damage happens to the DNA it might happen on just one strand.” Identifying the strand on which the damage originally occurred could give researchers clues about the mechanisms behind cancer mutations.

    “But because the cell so carefully maintains the matching of the two strands, a misplaced base on one strand quickly leads to a complementary misplaced base on the other,” said Nicholas Haradhvala, co-first author on the paper together with Paz Polak, both associated scientists at Broad and members of Getz’s lab at MGH. “By the time DNA sequencing is performed, it is impossible to tell which strand originally was damaged.”

    In order to identify the strand originally damaged, Haradhvala and his colleagues looked at asymmetrical processes such as DNA transcription and replication. DNA transcription is the first step in gene expression, whereby the genetic blueprints contained in the gene are read and translated into proteins. DNA replication is the process by which DNA is copied when cells divide. In transcription, a variety of cellular apparatuses unzip the two DNA strands and then make a mirror image copy of one of them. The other strand hangs out like a vulnerable flag in the wind, waiting for the process to complete, potentially getting blown over with mutations in the meantime. The strand that is being read is further protected from mutation because the process includes a step in which another apparatus comes in with the specific job of repairing any damage it finds. The non-transcribed strand — that vulnerable flag — doesn’t benefit from such a perk.

    After analyzing the mutational patterns of 590 tumors across 14 different cancer types, the team discovered that liver cancers seem to be riddled with mutations that stem from transcription-coupled damage. That is, mutations tend to pile up on the non-transcribed strand more frequently in liver tumors than expected. This is a novel phenomenon that is first described in this work.

    In replication, both strands are copied simultaneously, but since the machinery that does so only works in one direction, copying the strand with the opposite orientation is a bit of a stilted process. The copying apparatus, a protein called a polymerase, takes a step forward, copies everything behind it, and then moves another step forward and copies backwards again. The other strand is just happily copied in a continuous, (literally) straightforward manner. And since the backwards strand is so often hanging out alone, it is more vulnerable to damage just like the non-transcribed strand described above.

    So in both transcription and replication, cellular processes treat the two strands of DNA in an asymmetrical fashion. This asymmetry is what allowed Getz, Lawrence, and their colleagues to figure out the mechanism behind APOBEC cancers. It turns out, according to the team’s painstaking analysis of millions of data points, that the APOBEC enzyme most often introduces mutations to the lagging (or “backward”) strand during DNA replication.

    Both the liver and APOBEC findings are big news. After all, it’s not every day that a new mechanism for generating mutations comes along. But more importantly, they also offer insight into how DNA transcription and replication work from the perspective of mutations — findings that could have implications in understanding even more cancer types in the future.
    “It’s like having a computational microscope,” said Getz. “It allows us to see what’s going on inside the cell, where the action is happening while the DNA is being transcribed or replicated. That’s the beauty of this work.”

    Going forward, Getz, Lawrence, and their colleagues have big plans for their asymmetry work. They are already in the process of collaborating with dozens of labs around the globe to collect and analyze whole genome sequences of 2,800 tumors. Part of that work will include asymmetry analyses like those described here, to try to understand whether these processes have mechanistic implications for other cancer types as well. In the meantime, they are also collaborating with their benchtop biologist colleagues to carry out functional studies as follow up to the computational work done for this study, trying to recreate in a live setting what they saw in that computational microscope.

    Other Broad Researchers:

    Julian Hess, Esther Rheinbay, Jaegil Kim, Yosef Maruvka, Lior Braunstein, Atanas Kamburov, and Amnon Koren.

    Papers cited:

    Burns, et al. Evidence for APOBEC3B mutagenesis in multiple human cancers Nature Genetics. Online July 14, 2013. DOI: 10.1038/ng.2701

    Haradhvala, et al. Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair. Cell. Online January 21, 2016. DOI: 10.1016/j.cell.2015.12.050

    Roberts, et al. An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers. Nature Genetics. January 28, 2013. DOI: 10.1038/ng.2702

    See the full article here .

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    Broad Institute Campus

    The Eli and Edythe L. Broad Institute of Harvard and MIT is founded on two core beliefs:

    This generation has a historic opportunity and responsibility to transform medicine by using systematic approaches in the biological sciences to dramatically accelerate the understanding and treatment of disease.
    To fulfill this mission, we need new kinds of research institutions, with a deeply collaborative spirit across disciplines and organizations, and having the capacity to tackle ambitious challenges.

    The Broad Institute is essentially an “experiment” in a new way of doing science, empowering this generation of researchers to:

    Act nimbly. Encouraging creativity often means moving quickly, and taking risks on new approaches and structures that often defy conventional wisdom.
    Work boldly. Meeting the biomedical challenges of this generation requires the capacity to mount projects at any scale — from a single individual to teams of hundreds of scientists.
    Share openly. Seizing scientific opportunities requires creating methods, tools and massive data sets — and making them available to the entire scientific community to rapidly accelerate biomedical advancement.
    Reach globally. Biomedicine should address the medical challenges of the entire world, not just advanced economies, and include scientists in developing countries as equal partners whose knowledge and experience are critical to driving progress.

    Harvard University

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  • richardmitnick 1:54 pm on January 16, 2016 Permalink | Reply
    Tags: , Cancer,   

    From SA: “Can We Truly “Cure” Cancer?” NO. 

    Scientific American

    Scientific American

    January 14, 2016
    Dina Fine Maron

    Temp 1
    On January 12 Pres. Barack Obama laid out an aspirational plan in his final State of the Union to “cure cancer.”Credit: ©iStock

    In one well-known episode of The West Wing a line about an astronomical effort to “cure cancer” gets cut from the president’s State of the Union. In real life, however, someone wrote the speech that the fictional president Josiah Bartlet never got to give.

    On January 12 Pres. Barack Obama laid out an aspirational plan in his final State of the Union to “cure cancer.” He did not put forth a specific time line for this effort or the metrics that would measure success but did say that he was putting Vice Pres. Joe Biden in charge of “mission control.” And already, the White House released information about several meetings in the coming month that Biden will hold to get the ball rolling on the initiative.

    Yet is such a goal truly achievable in the near future? Patients and doctors know all too well that cancer is not one disease and there is no singular cure for the complex group of disorders. Biden did help secure a $264-million cash infusion in the most recent government spending bill that will support cancer work at the National Cancer Institute, but the obstacles to attacking cancer effectively are more than just financial. “A cure is a long way off,” but the prospect for some specific cancers does look bright, says James Allison, chair of the Department of Immunology at The University of Texas M. D. Anderson Cancer Center in Houston. For his part, at least Allison was not surprised about the announcement last night, he says, because the vice president himself called him and other researchers within the past two months to talk about cancer research. And now, unlike even five years ago, a 10-year remission is realistic for cancers like melanoma, which seemingly were unbeatable.

    These gains are largely thanks to historic breakthroughs in the past few years with a bevvy of methods to employ patients’ own immune systems, collectively known as immunotherapy. But still large obstacles remain when it comes to getting immunotherapy to work for many different types of tumors. Although some cancers—particularly those that are rife with mutations like lung cancer or melanoma—create more tangible targets on the surface of cells for the immune system to recognize and attack, other malignancies such as prostate and pancreatic cancers have proved more intransigent. As Scientific American reported earlier this year, more than half of the current cancer clinical trials do incorporate some form of immunotherapy but still oncologists are often only in the early stages of understanding how to use such treatment on a larger scale. Even with the cancers that are further along in their immunotherapy responses, a “certain fraction of those kinds of tumors, I don’t know we’ll ever cure,” Allison says.

    Monica Bertagnolli, chief of the Division of Surgical Oncology at Brigham and Women’s Hospital and chair of the Alliance for Clinical Trials in Oncology, a nationwide effort to test new therapies, says she was thrilled that the president used the word “cure” in his speech at all. “I don’t think any of us are naive and think there is some magic bullet sitting under our thumb that is going to miraculously turn into a cure, but that’s where we have to aim—to cure,” she says. “For that reason, I think it was perfect to use that terminology.” Like Allison, Bertagnolli believes cures will be difficult to achieve and questions if that will be possible for some cancers. But the next best thing, she says, is “making sure that it [cancer] doesn’t negatively impact a patient’s life” and laying out this aspirational goal may help provide the impetus to get there and beyond.

    Still, even agreeing on the definition of “cure” remains controversial. Cancer is often talked about in terms of years in remission rather than cure because there is still the creeping concern that the cancer will one day resurface. But whereas some “old school surgeons” would see potentially suspicious dark scar tissue on a CT (computed tomography) scan and say you cannot say cancer is “cured,” Allison maintains if there is no real evidence that a person still has cancer and they have been in remission for 10 years, “for all intents and purposes it is cured.”

    Clinicians’ recent gains against cancer are not just due to immunotherapies. The American Cancer Society’s recent annual report on cancer indicates that more than 1.7 million cancer deaths have been averted between 1991 and 2012 largely due to better preventative steps such as smoking cessation and screening for breast and colon cancers.

    Despite the progress against cancer, however, it is still the number-two killer in the U.S. after heart disease. Although more people are living or living longer with cancer than in years past, that is still not truly curing cancer. Cancer will certainly remain part of the human condition but the question is how best to tamp it down when it does appear. One of the biggest challenges that remains is making sure therapies continue to work with patients in the long term and pinpointing if that means cancer therapies should be administered in combination or deployed in a specific order for certain patients. “Unfortunately, we see some patients don’t respond to these wonderfully new therapies and some patients that do respond initially eventually develop resistance to those therapies and so the tumor returns,” Bertagnolli says. “Obviously that’s in the way of curing cancer because we want a treatment that a patient will never develop resistance to.”

    Indeed, the fight against cancer is a long one and the president only has one year left in office. In the 1970s Pres. Richard Nixon called for a “War on Cancer.” That effort, alongside its public relations campaign, fueled unrealistic expectations that cancer would be quickly extinguished. So what’s different here? For one thing, the base level of knowledge about cancers and their causes—and targets to combat them—is fundamentally different. “I hope people don’t think the cure is right around the corner but I do think there’s reason for optimism,” Allison says. “To use a Texas term, we finally have purchase on it.”

    See the full article here .

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