tbuckley/cabot-search huggingface dataset:
TMOD-01. CMYC OVEREXPRESSION INDUCES CHOROID PLEXUS TUMOURS THROUGH MODULATION OF INFLAMMATORY PATHWAYS
Authors: Ashirwad Merve, Serena Acquati, Joerg Hoeck, Jennie Jeyapalan, Axel Behrens, Silvia Marino
Journal: Neuro-Oncology (2017)

Choroid plexus tumours (CPTs) account for up to 20% of brain tumours in children under 2 years of age. They can spread along the neuraxis and can recur after treatment. Little is known about the molecular mechanisms underlying their formation and only one high fidelity mouse model of p53-deficient CPTs is available. c-Myc is a proto-oncogene deregulated in various malignancies, including paediatric brain tumours. Here, we conditionally overexpressed c-Myc in neural progenitor cells to assess its role in brain tumour pathogenesis. We show that c-Myc overexpression increased proliferation of neural progenitor cells both in vitro and in vivo during brain development while at the same time inducing apoptosis in a dosage-dependent manner. Interestingly, a high incidence (84%) of CPTs was observed in the compound mutant mice. We used a publicly available gene expression dataset of 40 human CPTs to assess the translational value of this novel mouse model. We show that a proportion of human CPTs expressed c-Myc and this discovery platform revealed a specific molecular signature of this CPT subgroup associated with inflammatory pathways, including TNF, Interleukins and Cytokine-Cytokine receptor pathways. An independent cohort of 42 human CPT (Brain UK) was used to validate overexpression of c-Myc in these tumours. 43% of cases overexpressed c-Myc and in these cases the CD3+ T-lymphocyte and the CD68+ macrophage infiltrates were increased. Deregulation of inflammatory pathways and increased intratumoural inflammation were key to the development of the tumours in the mouse model. Overexpression of c-Myc identifies a proportion of human CPTs, which can be modelled by overexpressing c-Myc in chroroid plexus cells. The underlying pathogenetic mechanism is mediated by c-Myc induced pro-inflammtory role in the murine model, which reflects the histopathological phenotype observed in human c-Myc overexpressing CPTs.
Efficacy of a football rule to prevent concussion
Authors: Florian Beaudouin, Claus Reinsberger, Tim Meyer
Journal: British Journal of Sports Medicine (2017)

Objective Although the incidence of concussion per athlete exposure is relatively low in comparison to high risk sports, absolute numbers of concussions are considerable in football, because of its high popularity and high number of athletes. In 2006, the International Football Association Board (IFAB) employed a modification of football rules to protect the brain and reduce head injuries. Starting during the season 2006/2007, an attack towards the head (e.g. by elbow check) was punished more consequently and can even lead to an elimination from the game, if performed on purpose. The objective of our study is to examine, whether the rule change resulted in a lower incidence of concussion in professional German football. Design Based on data of a German football magazine (obtained by in depth coverage on each club of the German Bundesliga), a database of all head injuries in the German football Bundesliga between 2000/2001 and the current season was created. The incidence of concussion during six years before and six years after the initiation of the rule change was then calculated and compared. Furthermore, the number of missed days of practice and/or games and the mechanism of injury (based on player’s position and club) was analysed. Main results The incidence of concussion during the seasons 2006/07 – 2012/13 is lower than the incidence during 2000/01 – 2005/06. Conclusions A rule change with the intention to punish attacks to the head more consequently to protect the brain might be an effective means to prevent concussion in football. Competing interests This work was funded by a grant of the Federal Institute of Sports Science (Federal Ministry of the Interior).
Histone H3 lysine 36 methylation affects temperature-induced alternative splicing and flowering in plants
Authors: A. Pajoro, E. Severing, G. C. Angenent, R. G. H. Immink
Journal: Genome biology (2017)

Global warming severely affects flowering time and reproductive success of plants. Alternative splicing of pre-messenger RNA (mRNA) is an important mechanism underlying ambient temperature-controlled responses in plants, yet its regulation is poorly understood. An increase in temperature promotes changes in plant morphology as well as the transition from the vegetative to the reproductive phase in Arabidopsis thaliana via changes in splicing of key regulatory genes. Here we investigate whether a particular histone modification affects ambient temperature-induced alternative splicing and flowering time. We use a genome-wide approach and perform RNA-sequencing (RNA-seq) analyses and histone H3 lysine 36 tri-methylation (H3K36me3) chromatin immunoprecipitation sequencing (ChIP-seq) in plants exposed to different ambient temperatures. Analysis and comparison of these datasets reveal that temperature-induced differentially spliced genes are enriched in H3K36me3. Moreover, we find that reduction of H3K36me3 deposition causes alteration in temperature-induced alternative splicing. We also show that plants with mutations in H3K36me3 writers, eraser, or readers have altered high ambient temperature-induced flowering. Our results show a key role for the histone mark H3K36me3 in splicing regulation and plant plasticity to fluctuating ambient temperature. Our findings open new perspectives for the breeding of crops that can better cope with environmental changes due to climate change.
TRTH-06. CHILDREN’S BRAIN TUMOUR DRUG DELIVERY CONSORTIUM
Authors: Ruman Rahman, Richard Grundy, Emma Campbell, Henry Brem, Monica Pearl, Jordan Green, Miroslav Janowski, Kenneth Cohen, Piotr Walczak, Katherine Warren, Stephen Lowis, Alexander Mullen, Marie Boyd, Gareth Veal, Darren Hargrave, Dannis van Vuurden, Stephen Powell, David Walker
Journal: Neuro-Oncology (2017)

INTRODUCTION: Whilst there is an urgent need to expedite the development of new or repurposed drugs for children’s cancer, the additional challenge in the developing brain is to ensure the drug is delivered to the tumour at therapeutic and non toxic concentrations for sufficient duration to achieve the biological effect. This is the necessary focus for personalised medicine agendas in children’s brain tumours as they account for over 20% of childhood cancer and differ significantly in their biological characteristics from their adult counterparts. METHODS: The authors took part in an international CNS drug delivery London workshop funded by the charity Children with Cancer UK (CwC) in February 2016 where different experimental techniques aimed at optimising CNS drug delivery in children’s brain tumours were presented and discussed. RESULTS: The workshop was reported (1) and promoted through e-cancer (2). We were encouraged to develop a proposal, to establish an international research consortium to raise awareness and promote collaboration in the field. This is now to be funded for two years by Children with Cancer. The Children’s Brain Tumour Drug Delivery Consortium will organise and host discussions between an international, multi-disciplinary network of clinicians and researchers within pharma and academia as well as a range of funders and stakeholders. This Consortium seeks to strengthen collaborative developments by working closely with the international children’s brain tumour community. CONCLUSION: We present this abstract to the SNO Pediatric conference to launch this initiative in North America and invite collaborators to promote this research priority for children across the world and to consider joining the consortium, which will be presented at the conference. 1. NAILOR,A, WALKER,DA and ET AL, 2016. Highlights of Children with Cancer UK’s Workshop on Drug Delivery in Paediatric Brain Tumours eCancer. 10, 630. 2. http://ecancer.org/conference/831-drug-delivery-in-paediatric-brain-tumours.php
Transparency of Conflicts of Interest: A Mixed Blessing? The Patients' Perspective
Authors: Cora Koch, Marlene Stoll, David Klemperer, Klaus Lieb
Journal: The American Journal of Bioethics (2017)

Chimonas, DeVito, and Rothmann (2017) report interesting aspects of physicians' views of the Physician Payments Sunshine Act and the Open Payments website. In this context, it is important to also ...
FREQUENCY IN EGFR, K-RAS, BRAF AND ALK MUTATIONS IN A COHORT OF CANCERS: ALK TRANSLOCATIONS ARE MORE FREQUENTLY SEEN IN ADVANCED DISEASE
Authors: E. Lim, D.G. De Castro, S. Popat, E. Shaw, I. Walker, P. Johnson, O. Bamsey, A. Higgins, T. Osadolor, L. Renouf, A.G. Nicholson
Journal: Journal of Thoracic Oncology (2013)
LGG-13. SYNERGISTIC TREATMENT FOR PEDIATRIC LOW GRADE GLIOMA WITH THE DUAL MTORC1/2 INHIBITOR TAK-228 AND MEK INHIBITOR TRAMETINIB
Authors: Antje Arnold, Fausto Rodriguez, Charles Eberhart, Eric Raabe
Journal: Neuro-Oncology (2017)

Pediatric low-grade glioma (PLGG) is one of the most common childhood tumors. If the tumor is located in a brain region that is not accessible for surgical resection, additional therapies are needed. Recent studies highlighted the important role of mTORC and MEK-activation in PLGG. The dual mTORC1/2-inhibitor, TAK-228, and MEK-inhibitor, trametinib, are promising candidates for targeted therapy. We hypothesized that TAK-228 and trametinib would show synergistic effects in vitro and in vivo in PLGG models. We treated the PLGG-derived cell lines Res186 and Res259 and our human MAP-kinase-driven glioma model with TAK-228 and trametinib. Cell growth was investigated using MTT-assay, DNA replication with bromodeoxyuridine (BrdU) assay, and apoptosis through cleaved-caspase-3 (CC-3) staining. Activation of MAPK pathway was detected via Western Blot by pERK and mTOR pathway by pAKT, pS6, and p4E-BP1 to total protein amount, and β-actin. Synergy was calculated with the Chou-Talalay method. Treatment of Res186 and Res259 with TAK-228 or trametinib reduced cell growth and proliferation in a dose- and time-depended manner. The combination of TAK-228 (20nM) and trametinib (100nM) resulted in a synergistic effect in Res259. No synergy was detected for Res186. Staining for CC-3 showed a significant increase for apoptosis in Res259 after treatment with TAK-228 or trametinib (**p<0.01). No positive CC-3 staining was detected in Res186 after drug treatment. MAPK pathway was inactivated in a dose-depend manner after trametinib and mTOR pathway was inactivated after treatment with TAK-228 in both cell lines. Our human neural stem cells similarly showed similar reductions in BrdU incorporation (**p<0.01) and CC-3 (*p<0.05). Our preliminary results show that our used PLGG-models are sensitive to TAK-228 and trametinib treatment. All cell lines showed decreased proliferation at various doses of either inhibitor. Synergy was seen for Res259 cells. We will now investigate both drugs in vivo using a BRAFV600E mutation glioma xenograft.
Abstract P317: Acute Exercise Stress and ROS Signaling: Activation of Nrf2/ARE-Dependent Antioxidant Defense Mechanisms in the Mouse Myocardium
Authors: Corey J Miller, Kalavathy Ramachandran, Gayatri D Khanderao, Sankaranarayanan Kannan, Vasanthi Rajasekaran, Christoph Boheme, J David Symons, Christopher J Davidson, Rajasekaran Namakkal Soorappan
Journal: Circulation Research (2011)

Background: Cellular defense mechanisms are crucial for maintaining intracellular redox state and mitigating free radical accumulation with aging. Nuclear Erythroid 2 p45 related factor-2 (Nrf2) regulates basal and inducible expression of numerous cytoprotective/antioxidant genes. We hypothesize that acute exercise will induce ROS, which triggers Nrf2/ARE signaling and promotes myocardial defense mechanisms. Methods: Age-matched wild-type (WT) and Nrf2−/− (KO) mice at 2 and &gt;20 months were subjected to acute exercise stress (AES) and then we assessed the activation of Nrf2/ARE-dependent transcriptional mechanisms in the heart. Myocardial ROS was measured by electron paramagnetic resonance (EPR) analysis. Results: Under basal conditions, total ROS and GSH levels were identical at 2 months, whereas they were significantly impaired in Nrf2-KO when compared to Wt myocardium at ∼20 months indicating that Nrf2-deficiency is coupled with blemished redox potential. Upon AES, the young WT and KO mice exhibited oxidative stress (OS), but the WT were able compensate for the stress by increasing Nrf2 nuclear translocation and subsequent upregulation of cytoprotective genes. However, the aged (WT &amp; KO) mice developed OS in response to AES. The degree of OS was several fold higher in the aged Nrf2-KO mice when compared with WT, suggesting an important age dependent function for Nrf2 in the myocardium. Western blot analysis revealed significant down regulation of major antioxidants (GCS, Nqo1, Ho1, catalase, G6pd and Gsr) in KO mice, while WT mice exhibited compensatory antioxidant response to the AES. Gene expression (qPCR) analysis revealed profound upregulation of major antioxidants in WT, but there was no such response occurred in KO mice after AES, suggesting Nrf2 independent mechanisms are inadequate to protect the myocardium. Conclusions: Acute exercise induces ROS and thereby activates Nrf2 in the myocardium. However, disruption of Nrf2 increases susceptibility of the myocardium to OS induced damage. Thus Nrf2 signaling might be a potential therapeutic target to protect the heart from ROS and/or age dependent ischemia/reperfusion (I/R) injury and myocardial infarction (MI).
Nanopreparations for mitochondria targeting drug delivery system: Current strategies and future prospective
Authors: Zhenjie Wang, Weiling Guo, Xiao Kuang, Shanshan Hou, Hongzhuo Liu
Journal: Asian Journal of Pharmaceutical Sciences (2017)

Mitochondria are a novel and promising therapeutic target for diagnosis, treatment and prevention of a lot of human diseases such as cancer, metabolic diseases and neurodegenerative disease. Owing to the mitochondrial special bilayer structure and highly negative potential nature, therapeutic molecules have multiple difficulties in reaching mitochondria. To overcome multiple barriers for targeting mitochondria, the researchers developed various pharmaceutical preparations such as liposomes, polymeric nanoparticles and inorganic nanoparticles modified by mitochondriotropic moieties like dequalinium (DQA), triphenylphosphonium (TPP), mitochondrial penetrating peptides (MPPs) and mitochondrial protein import machinery that allow specific targeting. The targeted formulations exhibited enhanced pharmacological effect and better therapeutic effect than their untargeted counterpart both in vitro and in vivo. Nanocarriers may be used for bio-therapeutic delivery into specific mitochondria that possess a great potential treatment of mitochondria related diseases.
Anastomose œso-gastrique endoscopique par prothèse d'apposition tissulaire: un pas vers un «Lewis Santy» hybride?
Authors: A Culetto, JM Gonzalez, G Vanbiervliet, P Miranda Garcia, J Tellechea, E Garnier, S Berdah, M Barthet
Journal: Endoscopy (2016)

La prise en charge chirurgicale des pathologies tumorales de l'œsophage repose sur une oesophagectomie suivie d'une anastomose œsogastrique. Cette intervention présente une morbidité importante souvent liée à l'apparition de fistule anastomotique (9 à 12% des cas). Il est possible de réaliser des anastomoses gastrojéjunales de bonne qualité, grâce à l'utilisation de prothèse permettant une apposition tissulaire. Nous avons appliqué cette technique pour la réalisation d'anastomose œsogastrique endoscopique. Le but de notre travail a été de s'assurer de la faisabilité et de la sûreté de la réalisation d'une anastomose œsogastrique par technique hybride, chirurgicale et endoscopique, en utilisant une prothèse trans-luminale d'apposition tissulaire.
10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension
Authors: Henry G Bone, Rachel B Wagman, Maria L Brandi, Jacques P Brown, Roland Chapurlat, Steven R Cummings, Edward Czerwiński, Astrid Fahrleitner-Pammer, David L Kendler, Kurt Lippuner, Jean-Yves Reginster, Christian Roux, Jorge Malouf, Michelle N Bradley, Nadia S Daizadeh, Andrea Wang, Paula Dakin, Nicola Pannacciulli, David W Dempster, Socrates Papapoulos
Journal: The Lancet Diabetes & Endocrinology (2017)
Associations Between Adding a Radial Artery Graft to Single and Bilateral Internal Thoracic Artery Grafts and Outcomes
Authors: David P. Taggart, Douglas G. Altman, Marcus Flather, Stephen Gerry, Alastair Gray, Belinda Lees, Umberto Benedetto
Journal: Circulation (2017)

Background: Whether the use of the radial artery (RA) can improve clinical outcomes in coronary artery bypass graft surgery remains unclear. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral internal thoracic artery (BITA) over single left internal thoracic artery (SITA). In the ART, a large proportion of patients (≈20%) also received an RA graft instead of a saphenous vein graft (SVG). We aimed to investigate the associations between using the RA instead of an SVG to supplement SITA or BITA grafts and outcomes by performing a post hoc analysis of the ART. Methods: Patients enrolled in the ART (n=3102) were classified on the basis of conduits actually received (as treated). The analysis included 2737 patients who received an RA graft (RA group; n=632) or SVG only (SVG group; n=2105) in addition to SITA or BITA grafts. The primary end point was the composite of myocardial infarction, cardiovascular death, and repeat revascularization at 5 years. Propensity score matching and stratified Cox regression were used to compare the 2 strategies. Results: Myocardial infarction, cardiovascular death, and repeat revascularization cumulative incidence was 2.3% (95% confidence interval [CI], 1.1–3.4), 3.5% (95% CI, 2.1–5.0), and 4.4% (95% CI, 2.8–6.0) in the RA group and 3.4% (95% CI, 2.0–4.8), 4.0% (95% CI, 2.5–5.6), and 7.6% (95% CI, 5.5–9.7) in the SVG group, respectively. The composite end point was significantly lower in the RA group (8.8%; 95% CI, 6.5–11.0) compared with the SVG group (13.6%; 95% CI, 10.8–16.3; P =0.005). This association was present when an RA graft was used to supplement both SITA and BITA grafts (interaction P =0.62). Conclusions: This post hoc ART analysis showed that an additional RA was associated with lower risk for midterm major adverse cardiac events when used to supplement SITA or BITA grafts. Clinical Trial Registration: URL: https://www.situ.ox.ac.uk/surgical-trials/art . Unique identifier: ISRCTN46552265.
TMOD-10. INTRACRANIAL PATIENT-DERIVED XENOGRAFT FROM A PEDIATRIC GLIOBLASTOMA RETAINS MOLECULAR CHARACTERISTICS AND GROWTH PATHWAYS
Authors: Angela R. White, Shiva Senthil Kumar, Amanda R. Smith, Annmarie Ramkissoon, Nicole Oatman, Biplab Dasgupta, Erin H. Breese, Charles Stevenson, Christine Fuller, Maryam Fouladi, Mariko D. DeWire, Rachid Drissi, Lionel M.L. Chow
Journal: Neuro-Oncology (2017)

BACKGROUND: Pediatric glioblastomas (pGBM) are characterized by overlapping and unique molecular driver mutations compared to their adult counterparts. Primary cell cultures and patient-derived xenograft (PDX) models of pGBM are rare which may contribute to difficulty in advancing patient outcomes. We have established an orthotopic PDX mouse model from a pGBM resected from a 12 yo male with recurrent disease. The patient received focal radiation and several chemotherapy regimens prior to the recurrence leading to this tumor resection. METHODS: The surgical tumor specimen was dissociated and directly implanted into the brains of immunocompromised (NSG) mice. DNA and immunohistochemical analyses of the patient tumor and PDX were performed. Multiple in vitro culture conditions were tested on the dissociated primary tumor cells and PDX tumor cells. RESULTS: Implantation of the patient tumor cells in mice resulted in tumor growth after 120–250 days. Tumors were serially transplanted successfully. Attempts to establish in vitro cell cultures from primary tumor and from established PDX tumors failed. DNA sequencing of the patient tumor sample and tumors from each PDX generation revealed the H3F3A G34R mutation characteristic of cortical pGBM, and mutations in the TP53, PTEN and PIK3CA genes, all of which were conserved in PDX tumors. Interestingly, the patient tumor showed evidence of telomerase activity and alternative lengthening of telomeres (ALT) as did the PDX tumors. The combined PTEN and PIK3CA mutations in this tumor resulted in activation of the PI3K-mTOR pathway. Treatment of tumor-bearing mice with an mTOR or PI3K inhibitor resulted in suppression of the pathway and reduced proliferation. CONCLUSION: This pGBM PDX model conserved key driver mutations and pathways from the patient tumor. In vitro culture of pGBM can be extremely challenging to establish and more difficult methods such as orthotopic PDX may be required to study these tumors.
Blue card: referees’ perspectives of a rugby union concussion recognition and management programme
Authors: John Sullivan, Kyal Collins, Andrew Grey, Phil Handcock
Journal: British Journal of Sports Medicine (2017)

Objective The Northland (New Zealand) Rugby Union developed an innovative concussion recognition and management programme (Blue Card) as part of its player welfare responsibilities for club (community) players. The referee is empowered to issue a Blue Card (BC) to any player they suspect of being concussed, thus removing them from the game. The purpose of this descriptive study was to investigate the referees’ perspectives on having this added responsibility, and whether this detracted from their enjoyment of refereeing. Design Cross-sectional survey. Setting Northland Rugby Union headquarters Participants Twenty-one amateur male referees who officiated in club-level rugby matches covered by the Northland Rugby Union Blue (NRUBC) programme during the 2014 season volunteered to participate. Outcome measures Custom-designed survey instrument using both open and closed questions. Main results The referees had between 2 and 35 (mean=12.1) seasons of refereeing experience with 81% (17/21) claiming a good or average knowledge of concussion. The majority (20/21) reported that they had sufficient training for their expanded role. Two thirds (14/21) of the respondents did not think that the additional responsibility impacted on their refereeing satisfaction. Over the season nine (9) BCs were issued by 7 of the participating referees, with 5 indicating that they were “very confident” in their decision. Conclusions The referees indicated that they were well prepared to handle the added responsibility as on-field concussion gatekeepers, and this role did not detract from their enjoyment of refereeing the game. Additional insight into how the NRUBC programme is received by players, teammates and their families, needs investigation. Competing interests S.J Sullivan, A Gray and P Handcock: None. K Collins was involved in the development of the Northland Blue Card Programme but was not involved in the data analysis. None.
Rituximab Plus Lenalidomide Versus Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. First Analysis of Survival Endpoints of the Randomized Phase-2 Trial SAKK 35/10
Authors: Eva Kimby, Stephanie Rondeau, Anna Vanazzi, Bjorn Ostenstad, Ulrich J.M. Mey, Daniel Rauch, Björn E Wahlin, Felicitas Hitz, Micaela Hernberg, Ann-Sofie Johansson, Peter de Nully Brown, Hans Hagberg, Andres J.M. Ferreri, Andreas Lohri, Urban Novak, Thilo Zander, Hanne Bersvendsen, Mario Bergetzi, Walter Mingrone, Fatime Krasniqi, Stefan Dirnhofer, Hanne Hawle, Simona Berardi, Michele Ghielmini, Emanuele Zucca
Journal: Blood (2016)
The microRNA miR-31 inhibits CD8+ T cell function in chronic viral infection
Authors: Howell F Moffett, Adam N R Cartwright, Hye-Jung Kim, Jernej Godec, Jason Pyrdol, Tarmo Äijö, Gustavo J Martinez, Anjana Rao, Jun Lu, Todd R Golub, Harvey Cantor, Arlene H Sharpe, Carl D Novina, Kai W Wucherpfennig
Journal: Nature Immunology (2017)