tbuckley/cabot-search huggingface dataset:
Association of Late Adolescent Personality With Risk for Subsequent Serious Mental Illness Among Men in a Swedish Nationwide Cohort Study
Authors: Joseph F. Hayes, David P. J. Osborn, Glyn Lewis, Christina Dalman, Andreas Lundin
Journal: JAMA Psychiatry (2017)

Understanding of personality as an independent risk factor for serious mental illness (SMI) remains limited. Recently, overlap between the polygenic basis for specific personality traits and specific SMIs has been identified.To determine the association of the adolescent personality domains of social maturity, mental energy, and emotional stability with later diagnosis of SMI.This longitudinal cohort study enrolled Swedish male military conscripts aged 18 or 19 years from January 1, 1974, through December 31, 1997. The diagnosis of an SMI was extracted from the National Patient Register for all inpatient treatment episodes in Sweden from January 1, 1974, through December 31, 2011. Data were analyzed from May 3 to September 16, 2016.Social maturity, mental energy, and emotional stability assessed at conscription interview.Inpatient diagnoses of bipolar disorder, schizoaffective disorder, schizophrenia, and other nonaffective psychoses occurring until December 31, 2011.Of the 1 017 691 men included in the cohort, 4310 developed bipolar disorder; 784, schizoaffective disorder; 4823, schizophrenia; and 5013, other nonaffective psychoses. After adjustment, with use of mean scores as a reference, low social maturity (hazard ratio [HR], 1.61; 95% CI, 1.48-1.74), low mental energy (HR, 1.34; 95% CI, 1.24-1.44), and low emotional stability (HR, 1.51; 95% CI, 1.40-1.63) were inversely associated with schizophrenia in a dose-dependent fashion. Other nonaffective psychoses displayed a similar pattern. Bipolar disorder was associated with high (HR, 1.21; 95% CI, 1.09-1.35) and low (HR, 1.12; 95% CI, 1.01-1.25) social maturity and low emotional stability (HR, 1.62; 95% CI, 1.46-1.78). Schizoaffective disorder was associated with low emotional stability (HR, 1.53; 95% CI, 1.26-1.85).Emotional stability is inversely associated with all SMI. Bipolar disorder has a unique U-shaped association with social maturity. Premorbid personality may reflect subtle changes in cerebral function, may combine with symptoms and other neurocognitive deficits to influence illness presentation, and/or may be owing to shared genetic architecture.
Health-related quality of life and risk factors associated with spirometric restriction
Authors: Stefano Guerra, Anne-Elie Carsin, Dirk Keidel, Jordi Sunyer, Bénédicte Leynaert, Christer Janson, Debbie Jarvis, Daiana Stolz, Thomas Rothe, Marco Pons, Alexander Turk, Josep M. Anto, Nicole Probst-Hensch
Journal: European Respiratory Journal (2017)

The restrictive spirometric pattern is associated with a substantial morbidity and mortality burden. We sought to determine to what extent spirometric restriction is associated with impaired quality of life. We used data from two large population-based European cohorts: 6698 European Community Respiratory Health Survey (ECRHS) and 6069 Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) adult participants. The restrictive pattern was defined as forced expiratory volume in 1 s (FEV 1 )/forced vital capacity (FVC) ≥lower limit of normal (LLN) and FVC &lt;LLN; an obstructive pattern was defined as FEV 1 /FVC &lt;LLN independent of FVC. The Physical Component Summary and Mental Component Summary of quality of life were computed using the Short Form-36 questionnaire. In both cohorts, the restrictive pattern was associated with heavy smoking, being underweight or obese and the coexistence of respiratory symptoms. In univariate analyses, compared with the normal group, both the restrictive and obstructive pattern had significant Physical Component Summary deficits (−2.77 and −2.08, respectively, in ECRHS; −3.25 and −2.14, respectively, in SAPALDIA; all p-values &lt;0.001). However, in models adjusted for sex, age, education, body mass index, smoking, comorbidities and respiratory symptoms, only the restrictive pattern remained significantly associated with Physical Component Summary deficits (p=0.004 in ECRHS; p=0.001 in SAPALDIA). The restrictive spirometric pattern is associated with deficits in the physical component of quality of life that are partly independent of the presence of respiratory symptoms.
Iconic enrichments: Signs vs. gestures
Authors: Philippe Schlenker
Journal: Behavioral and Brain Sciences (2017)

Semantic work on sign language iconicity suggests, as do Goldin-Meadow & Brentari (G-M&B) in their target article, that "sign should be compared with speech-plus-gesture, not speech alone" (sect. 7.1). One key question is whether speech-plus-gesture and sign-with-iconicity really display the same expressive resources. This need not be the case, because gestural enrichments are typically not at-issue, whereas iconic enrichments in sign language can often be at-issue. Future research should thus focus on the "projection" properties of different sorts of iconic enrichment in both modalities.
TRTH-28. HIGH THROUGHPUT SCREENING OF NOVEL HISTONE DEACETYLASE INHIBITORS FOR EPIGENETIC THERAPY OF PRIMARY BRAIN TUMORS
Authors: Viktoria Marquardt, David Pauck, Finn K. Hansen, Daniel Picard, Jörg Felsberg, Guido Reifenberger, Arndt Borkhardt, Thomas Kurz, Marc Remke
Journal: Neuro-Oncology (2017)

BACKGROUND: Histone deacetylases (HDACs) are crucial regulators of epigenetic and posttranslational modifications and therefore represent a promising therapeutic target in cancer cells that harbor distinct epigenomes from normal cells. To exploit the therapeutic potential of HDAC inhibitors (HDACi) we synthesized a unique in-house library of more than 200 inhibitors. For the evaluation of the antitumor effects of the compound library in brain tumor cell lines, we successfully established an optimal screening workflow. METHODS: The screening procedure was streamlined by automated dispensing of cell lines, reagents and inhibitors using state of the art equipment. The drugs were evaluated for their effect on tumor cell viability in a panel of cell lines derived from different brain tumor entities (8 glioblastoma, 10 medulloblastoma and 6 atypical teratoid/rhabdoid tumor cell lines) and compared to 5 normal control tissues. Corresponding dose-response profiles were generated using an optimized bioinformatics workflow. In addition to our in-house library commercially available and clinically used HDACi (e.g. Vorinostat) were included. RESULTS: The semi-automated setup enabled the miniaturization of the assay format to 384-well plates. In combination with additional modifications, a remarkable increase of the overall throughput was realized, while generating accurate and reproducible results. Based on this workflow, we created a unique and comprehensive data set and could thereby identify various HDACi acting universally across brain tumors or being specifically active in distinct tumor entities. Promising candidates are currently being further characterized, e.g. Panobinostat showed activity in the majority of brain tumor models at low nanomolar concentrations. CONCLUSION: The growing importance of HDAC inhibitors is reflected by an increasing number of HDACi in clinical trials, with four HDACi already approved by the FDA for treating lymphomas and multiple myelomas. Our study supports the finding that HDACi are valid therapeutic agents and that selected inhibitors are promising candidates for future epigenetic therapy of primary brain tumors.
TRTH-09. PTT2.0: DEVELOPING PERSONALIZED PEDIATRIC ONCOLOGY
Authors: Till Milde, Jonas Ecker, Florian Selt, David Capper, Felix Sahm, Andrey Korshunov, Cornelis M. van Tilburg, Hendrik Witt, Andreas von Deimling, David Jones, Stefan Pfister, Olaf Witt
Journal: Neuro-Oncology (2017)

Individualized treatment approaches require precise and robust diagnostics concerning diagnosis and detection of actionable alterations. The “pediatric targeted therapy” (PTT) program aims to improve accuracy of disease diagnosis and detection of targetable alterations and evaluate the clinical benefit of a personalized treatment approach in relapsed or progressive tumors on an individual basis. The methods employed are DNA methylation array, a customized targeted gene panel sequencing, and immunohistochemistry (IHC) of selected markers. Pediatric patients with tumors independent of the histological diagnosis, with relapse or progression after treatment according to standard protocols are included. Only formalin fixed paraffin embedded (FFPE)-material and a blood sample for germline comparison are requested. A questionnaire-based follow-up is used to determine the clinical benefit of the PTT analysis. On average, n=12 cases / month are included, the most common entities being brain tumors. The transition from IHC only to a combination of next-generation diagnostics such as methylation arrays and targeted sequencing in addition to selected IHC markers adds robust information for clinical decision-making. Follow-up analyses are ongoing.
LGG-15. CARBOPLATIN IS SYNERGISTIC WITH MAPK INHIBITORS TRAMETINIB AND EVEROLIMUS IN LOW GRADE GLIOMA MODELS
Authors: Brad Poore, Antje Arnold
Journal: Neuro-Oncology (2017)

Pediatric lower grade glioma (LGG) can cause significant morbidity and mortality in patients. Tumors often initially respond to first line chemotherapies, such as carboplatin, but approximately 50% of the time tumors recur and require additional therapy. The discovery that aggressive LGG often have MAPK-ERK pathway, as well as mTOR activation, increases the number of treatment options available, such as trametinib, an ERK inhibitor, or everolimus, an mTORC1 inhibitor. Using preexisting and newly developed models for LGG, our lab sought to determine if there was synergy between carboplatin and the MAPK-ERK and mTOR inhibitors trametinib or everolimus. In the cell lines Res186 (derived from pilocytic astrocytoma grade I), and Res259 (derived from diffuse astrocytoma grade II), we found that the combination of carboplatin with either everolimus or trametinib decreased cellular proliferation in a dose-dependent manner (P<0.05). Both cell lines and drug combinations gave a combination index of <1, indicating synergy. Everolimus sensitized Res259 to carboplatin treatment, despite Res259 being resistant to everolimus treatment alone. Interestingly, the carboplatin and everolimus combination did not increase levels of apoptosis in cells, as measured by cleaved caspase 3 (CC3) staining and probing for cleaved PARP by western blot. We extended our findings to a human neural stem cell glioma model which has MAP kinase activation and confirmed that carboplatin and everolimus combined to suppress proliferation, as measured by BrdU incorporation, greater than either single agent (P<0.001 by ANOVA). Treatments again did not increase apoptosis as measured by CC3 immunofluroescence. Using BT40 patient derived xenografts, a low grade glioma-derived model that harbors a BRAF V600E mutation, preliminary data shows that the combining everolimus with carboplatin had superior growth suppression compared to either drug alone. In conclusion, the combination of carboplatin with everolimus demonstrates combinatorial efficacy in our in vivo and in vitro systems.
Bone Marrow Wilms Tumor Gene 1 Expression before Allogeneic Hematopoietic Cell Transplantation Correlates with Relapse in Acute Myeloid Leukemia Patients
Authors: Semra Aydin, Chiara Frairia, Ernesta Audisio, Ludovica Riera, Sabrina Aliberti, Bernardino Allione, Alessandro Busca, Stefano D'Ardia, Chiara Dellacasa, Anna Demurtas, Andrea Evangelista, Paola Francia di celle, Martina Gaveglio, Barbara Nicolino, Alessandra Stacchini, Filippo Marmont, Umberto Vitolo
Journal: Blood (2014)
Exercise induced recurrence of concussion symptoms after symptom free status
Authors: Michael J O’Brien, Michael J Pepin, David Howell, William P Meehan
Journal: British Journal of Sports Medicine (2017)

Objective Determine the proportion of athletes who have a recurrence of concussion symptoms with exercise after being symptom free at rest. Design Prospective cohort studyProspective cohort study Setting Sport Concussion clinic Participants Patients diagnosed with a concussion and returned to the clinic after resuming exercise. Intervention Assessment of risk factors Outcome measures Our main outcome variable was recurrence of symptoms with exercise after being symptom free at rest while recovering from a sport-related concussion. Co-factors included age, gender, loss of consciousness with injury, prior concussions (diagnosed and undiagnosed), post-concussion symptom scale (PCSS) score, time until clinical presentation, and duration of symptoms. Main Results Of the 217 patients included, 25 (12%) experienced a return of symptoms. Losing consciousness at the time of injury (aOR=0.079, 95%CI=0.003–0.563) and a longer time period between injury and clinic presentation (aOR=0.936, 95%CI=0.877–0.984) were associated with a decreased risk of symptoms recurring with exercise, while those athletes that had sustained previous undiagnosed concussions (aOR=5.036, 95%CI=1.634–16.83), and had suffered a longer duration of symptoms at rest (aOR=1.006, 95%CI=1.002–1.010) were at increased risk of symptoms recurrence with exercise. Conclusions Relatively few athletes who are symptom free at rest after a concussion will have a recurrence of symptoms when they start exercising. The risk of symptoms recurring with exercise may be higher among those athletes who have sustained previous undiagnosed concussion and had a longer period of symptoms at re. Competing interests None. Dr. Meehan receives royalties from ABC-Clio publishing for the book, Kids, Sports, and Concussion: A guide for coaches and parents, from Springer International for the book, Head and Neck Injuries in Young Athletes, and from Wolters Kluwer for working as an author for UpToDate. He is under contract with ABC-Clio publishing for a future book entitled, Concussions. His research is funded, in part, by the Football Players Health Study at Harvard, which is funded by the National Football League Players Association and by philanthropic support from the National Hockey League Alumni Association through the Corey C. Griffin Pro-Am Tournament. Dr. O’Brien receives royalties from Wolters Kluwer for working as an author for UpToDate and from Springer International publishing for the book, Head and Neck Injuries in Young Athletes. Dr. Howell and Mr. Pepin have nothing to disclose.
Towards an expert consensus to delineate a clinical syndrome of chronic breathlessness
Authors: Miriam J. Johnson, Janelle Yorke, John Hansen-Flaschen, Robert Lansing, Magnus Ekström, Thomas Similowski, David C. Currow
Journal: European Respiratory Journal (2017)

Breathlessness that persists despite treatment for the underlying conditions is debilitating. Identifying this discrete entity as a clinical syndrome should raise awareness amongst patients, clinicians, service providers, researchers and research funders. Using the Delphi method, questions and statements were generated via expert group consultations and one-to-one interviews (n=17). These were subsequently circulated in three survey rounds (n=34, n=25, n=31) to an extended international group from various settings (clinical and laboratory; hospital, hospice and community) and working within the basic sciences and clinical specialties. The a priori target agreement for each question was 70%. Findings were discussed at a multinational workshop. The agreed term, chronic breathlessness syndrome, was defined as breathlessness that persists despite optimal treatment of the underlying pathophysiology and that results in disability. A stated duration was not needed for “chronic”. Key terms for French and German translation were also discussed and the need for further consensus recognised, especially with regard to cultural and linguistic interpretation. We propose criteria for chronic breathlessness syndrome. Recognition is an important first step to address the therapeutic nihilism that has pervaded this neglected symptom and could empower patients and caregivers, improve clinical care, focus research, and encourage wider uptake of available and emerging evidence-based interventions.
Effects of metformin and sulfonylureas on overall and colorectal cancer-specific mortality.
Authors: Susan Spillane, Kathleen Bennett, Linda Sharp, Thomas Ian Barron
Journal: Journal of Clinical Oncology (2012)

2599 Background: Preclinical studies have suggested a role for metformin in the treatment of colorectal cancer (CRC). Associations between metformin versus sulfonylurea exposure and mortality (all-cause and colorectal cancer specific) are assessed in this population-based study of patients with a diagnosis of stage I-IV CRC. Methods: National Cancer Registry Ireland records were linked to prescription claims data and used to identify a cohort of patients with incident TNM stage I-IV CRC diagnosed 2001-2006. From this cohort, 2 patient groups were identified and compared for outcomes - those who received a prescription for metformin +/- a sulfonylurea (MET) or a prescription for sulfonylurea alone (SUL) in the 90 days pre CRC diagnosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models adjusted for age, sex, stage, grade, site, comorbidities, year of diagnosis, and insulin, aspirin or statin exposure. Analyses were repeated stratifying by stage and site. Results: 5,617 patients with stage I-IV CRC were identified, of whom 369 received a prescription for metformin or a sulfonylurea in the 90 days pre diagnosis (median follow-up 1.6 years; MET: n=257; SUL: n=112). In adjusted analyses metformin exposure was associated with a 28% lower risk of all-cause mortality relative to sulfonylurea exposure (HR 0.72, 95% CI 0.53-0.98) and a non-significant 24% reduction in CRC-specific mortality (HR 0.76, 95% CI 0.52-1.13). In analyses stratified by site, in colon cancer, metformin exposure was associated with a significant one-third reduction in all-cause mortality (HR 0.66, 95% CI 0.46-0.95) and a non-significant reduction in site-specific mortality (HR 0.64, 95% CI 0.40-1.02). No mortality benefit was observed for rectal cancer. The association between metformin exposure and reduced mortality was strongest for stage I/II disease (all-cause mortality: HR 0.56, 95% CI 0.32-0.98; CRC-specific mortality: HR 0.48, 95% CI 0.21-1.11). Conclusions: Pre-diagnosis metformin exposure in CRC patients was associated with a significant reduction in mortality relative to sulfonylurea exposure. This benefit was greatest in patients with colon cancer and early stage disease.
Enhanced endothelin-1/Rho-kinase signalling and coronary microvascular dysfunction in hypertensive myocardial hypertrophy
Authors: Shu-Huai Tsai, Guangrong Lu, Xin Xu, Yi Ren, Travis W. Hein, Lih Kuo
Journal: Cardiovascular Research (2017)

Hypertensive cardiac hypertrophy is associated with reduced coronary flow reserve, but its impact on coronary flow regulation and vasomotor function remains incompletely understood and requires further investigation.
Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: José Baselga, Seock-Ah Im, Hiroji Iwata, Javier Cortés, Michele De Laurentiis, Zefei Jiang, Carlos L Arteaga, Walter Jonat, Mark Clemons, Yoshinori Ito, Ahmad Awada, Stephen Chia, Agnieszka Jagiełło-Gruszfeld, Barbara Pistilli, Ling-Ming Tseng, Sara Hurvitz, Norikazu Masuda, Masato Takahashi, Peter Vuylsteke, Soulef Hachemi, Bharani Dharan, Emmanuelle Di Tomaso, Patrick Urban, Cristian Massacesi, Mario Campone
Journal: The Lancet Oncology (2017)
Pediatric Cancer Predisposition Imaging: Focus on Whole-Body MRI
Authors: Mary-Louise C. Greer, Stephan D. Voss, Lisa J. States
Journal: Clinical Cancer Research (2017)

The American Association for Cancer Research convened a meeting of international pediatric oncologists, geneticists, genetic counselors, and radiologists expert in childhood cancer predisposition syndromes (CPS) in October 2016 to propose consensus surveillance guidelines. Imaging plays a central role in surveillance for most, though not all, syndromes discussed. While encompassing the full gamut of modalities, there is increasing emphasis on use of nonionizing radiation imaging options such as magnetic resonance imaging (MRI) in children and adolescents, especially in the pediatric CPS population. In view of rapid evolution and widespread adoption of whole-body MRI (WBMRI), the purpose of our review is to address WBMRI in detail. We discuss its place in the surveillance of a range of pediatric CPS, the technical and logistical aspects of acquiring and interpreting these studies, and the inherent limitations of WBMRI. We also address issues associated with sedation and use of gadolinium-based contrast agents in MRI in children. Clin Cancer Res; 23(11); e6-e13. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.
Longitudinal changes in health-related quality of life during concussion recovery among youth athletes
Authors: Kelly Russell, Erin Selci, Samuel Fineblit, Michael Ellis
Journal: British Journal of Sports Medicine (2017)

Objective Determine longitudinal changes in health-related quality of life (HRQoL) in youth during recovery from a sport-related concussion. Design Prospective case-series. Participants 68 youth (13–18 years; 62% male) with an acute sport-related concussion were enrolled with 5 lost to follow-up. Intervention (or assessment of risk factors) Subsequently developing Post-Concussion Syndrome (PCS: symptomatic after 30 days), initial symptom severity (Post Concussion Symptom Scale), concussion history, sex, age, and academic accommodations during recovery. Outcome measures PedsQL Cognitive Functioning Scale and PedsQL 4.0 measured physical, social, and emotional domains of HRQoL. They were administered before each appointment until medical clearance. Multivariable mixed modelling accounted for repeated measures within an athlete and expressed as point increase per week. Main results Initial mean HRQoL was highest for social (non-PCS: 92.7 out of 100; PCS: 86.3), followed by emotional (non-PCS: 86.45; PCS: 69.7), physical (non-PCS: 80.95; PCS: 49.2), and cognitive domains (non-PCS: 69.1; PCS: 50.3). There was effect modification by developing PCS. Changes in HRQoL subscores were: cognitive functioning non-PCS (+9.8 points [95% CI: 6.9, 12.7]) and PCS (+4.2 points [95% CI: 2.8, 5.6]); social HRQoL non-PCS (+2.3 points [1.0, 4.0]) and PCS (+0.5 points [0.1, 1.0); emotional HRQoL non-PCS (+5.0 points [95% CI: 2.9, 7.0]) and PCS points (+2.2 [1.6, 2.9]); and physical non-PCS (+6.3 points [95% CI: [3.5, 9.2]) and PCS (+3.3 points (95% CI: 2.5, 4.2). Conclusions HRQoL significantly improved longitudinally with greater improvement among non-PCS athletes. HRQoL impairment was most apparent in the cognitive and physical domains. Competing interests None.