tbuckley/cabot-search huggingface dataset:
Assessment of Prevention Research Measuring Leading Risk Factors and Causes of Mortality and Disability Supported by the US National Institutes of Health
Authors: Ashley J. Vargas, Sheri D. Schully, Jennifer Villani, Luis Ganoza Caballero, David M. Murray
Journal: JAMA Network Open (2019)

No studies to date have examined support by the National Institutes of Health (NIH) for primary and secondary prevention research in humans and related methods research that measures the leading risk factors or causes of death or disability as outcomes or exposures.To characterize NIH support for such research.This serial cross-sectional study randomly sampled NIH grants and cooperative agreements funded during fiscal years 2012 through 2017. For awards with multiple subprojects, each was treated as a separate project. Study characteristics, outcomes, and exposures were coded from October 2015 through February 2019. Analyses weighted to reflect the sampling scheme were completed in March through June 2019. Using 2017 data from the Centers for Disease Control and Prevention and 2016 data from the Global Burden of Disease project, the leading risk factors and causes of death and disability in the United States were identified.The main outcome was the percentage of the NIH prevention research portfolio measuring a leading risk factor or cause of death or disability as an outcome or exposure.A total of 11 082 research projects were coded. Only 25.9% (95% CI, 24.0%-27.8%) of prevention research projects measured a leading cause of death as an outcome or exposure, although these leading causes were associated with 74.0% of US mortality. Only 34.0% (95% CI, 32.2%-35.9%) measured a leading risk factor for death, although these risk factors were associated with 57.3% of mortality. Only 31.4% (95% CI, 29.6%-33.3%) measured a leading risk factor for disability-adjusted life-years lost, although these risk factors were associated with 42.1% of disability-adjusted life-years lost. Relatively few projects included a randomized clinical trial (24.6%; 95% CI, 22.5%-26.9%) or involved more than 1 leading cause (3.3%; 95% CI, 2.6%-4.1%) or risk factor (8.8%; 95% CI, 7.9%-9.8%).In this cross-sectional study, the leading risk factors and causes of death and disability were underrepresented in the NIH prevention research portfolio relative to their burden. Because so much is already known about these risk factors and causes, and because randomized interventions play such a vital role in the development of clinical and public health guidelines, it appears that greater attention should be given to develop and test interventions that address these risk factors and causes, addressing multiple risk factors or causes when possible.
COMP-14. MOLECULAR PROFILING AND CELLULAR DECONVOLUTION OF GLIOBLASTOMA BRAIN TUMORS USING CHROMATIN RUN-ON AND SEQUENCING
Authors: Tinyi Chu, Edward Rice, Hans Salamanca, Zhong Wang, Sharon Longo, Robert Corona, Mariano Viapiano, Lawrence Chin, Charles Danko
Journal: Neuro-Oncology (2019)

Abstract Glioblastoma is among the most heterogeneous malignancies, making difficult the identification of clinically-relevant interactions between tumor cells and their supportive tumor microenvironment. Moreover, whether the heterogeneity of tumor cells is reflected by changes in the composition of the tumor microenvironment remains poorly defined. To further understand the cellular heterogeneity of GBM, we used our previously validated chromatin run-on and sequencing (ChRO-seq) method to analyze 61 GBMs from a retrospective cohort of patients banked at the State University of New York (Upstate Medical Center) between 1987 and 2007 (characteristics: Male:Female ratio= 2:1; median age at diagnosis= 59 years; median KPS=80; median overall survival= 343 days). We developed a new Bayesian statistical model that uses transcription at cell-type specific enhancers to identify the cellular composition of the tumor microenvironment in each patient. We validated our tool using simulations and scATAC-seq data from the same specimens, showing large improvements in sensitivity and accuracy compared with CYBERSORT. Integrative analysis of cellular composition and matching clinical data revealed correlations between the presence of specific cell types in the tumor mass and clinical variables. Finally, our analysis allowed us to identify transcription factors (e.g., NF-kB, C/EBPB) that control gene expression changes, revealing which cell types are controlled by each transcription factor in the GBM microenvironment. Our study uncovers new insights into the cellular heterogeneity of GBM and its impact on clinical progression and survival.
Biomineralized Gd<sub>2</sub>O<sub>3</sub>@HSA Nanoparticles as a Versatile Platform for Dual‐Modal Imaging and Chemo‐Phototherapy‐Synergized Tumor Ablation
Authors: Tangna Hao, Qixian Chen, Yan Qi, Pengyuan Sun, Dawei Chen, Weiwei Jiang, Kexin Liu, Huijun Sun, Lei Li, Jianxun Ding, Zhen Li
Journal: Advanced Healthcare Materials (2019)

Abstract A great challenge still remains to explore the facile approaches to construct multifunctional nanoparticles for acquiring precise cancer theranostics. Herein, a biocompatible theranostic nanoplatform capable of simultaneous cancer imaging and therapy is attempted by loading of paclitaxel (PTX) and indocyanine green (ICG) molecules into the matrix of Gd 2 O 3 @human serum albumin (HSA) nanoparticles (PIGH NPs) via hydrophobic interaction. The subsequent in vitro investigations reveal that the PIGH NPs afford uniform particle size, sustained drug release profile, strong longitudinal relaxivity, potent photothermal effect, effective singlet oxygen generation, and ideal resistance to photobleaching. Moreover, the PIGH NPs achieve high cellular uptake, efficient cytoplasmic drug translocation based on singlet oxygen‐triggered endolysosomal disruption and prominent cytotoxicity effect against 4T1 cells under 808 nm near‐infrared (NIR) irradiation in contrast to PTX/ICG‐loaded HSA nanoparticles (PIH NPs) and free PTX/ICG. After intravenous injection, the PIGH NPs exhibit preferable tumor accumulation and achieve effective tumor ablation in 4T1 tumor bearing mouse model with excellent dual near‐infrared fluorescence/magnetic resonance (NIRF/MR) imaging guided synergistic chemo‐phototherapy. Hence, the PIGH NPs can be utilized as potential theranostic nanosystem for simultaneous cancer imaging and therapy.
Crime and Sin
Authors: W. W. Simpson
Journal: BMJ (1960)

Ultraviolet (UV) and blue-light components of optical radiation can affect the eye with a photochemical mechanism; both acute and/or long term effects can be induced. By large, the most diffuse source of optical radiation is Solar Radiation (SR) that includes both components. Among factors influencing SR exposure one of the most important is outdoor work: only in Europe outdoor-workers (OWs) are about 15 million. Another factor specifically relevant to the eye is reflection as, for anatomical reasons, the eye is less protected from reflected rays. As a consequence the presence of highly reflecting surfaces, like fresh snow or water, can increase eye exposure. In OWs various adverse chronic eye effects, involving different structures of the eye, can be found, as pterygium, cataract and macular degeneration. We reviewed scientific studies on eye effects of optical radiation in OWs. The results confirm an increased risk of the abovementioned adverse effects, but knowledge on various aspects is largely insufficient. Among relevant aspects deserving further studies are the evaluation of lifetime ocular exposure to ultraviolet radiation and blue-light considering both occupational and leisure activities, and possibly integrating subjective questionnaires data with objective data, as UV effective irradiance, available through meteo-climatic databases or field measurements. Individual aspects to be adequately investigated must include among other, also the possible presence of reflection, protective habits as the use of hats (type, frequency, etc.) and of sunglasses (frequency, shape, UV/blue light filters, etc). These aspects are extremely important especially for the development of more adequate preventive measures.
RARE-21. CLINICAL CHARACTERISTICS OF GLIOSARCOMA AND OUTCOME FROM STANDARDIZED TREATMENT RELATIVE TO CONVENTIONAL GLIOBLASTOMA
Authors: Simone Frandsen, Helle Broholm, Vibeke A Larsen, Kirsten Grunnet, Søren Møller, Hans Skovgaard Poulsen, Signe Regner Michaelsen
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Gliosarcoma (GS) is a rare histopathologic variant of glioblastoma (GBM) characterized by a biphasic growth pattern consisting of both glial and sarcomatous components. Reports regarding its relative prognosis compared to conventional GBM are conflicting and although GS is treated as conventional GBM, supporting evidence is lacking. The aim of this study was to characterize demographic trends, clinical outcomes and prognostic variables of GS patients receiving standardized therapy and compare these to conventional GBM. METHODS 680 GBM patients, treated with maximal safe resection followed by Stupp’s regimen (radiotherapy with concomitant and adjuvant temozolomide) at a single institution, were retrospective reevaluated by reviewing histopathological records and tumor tissue for identification of GS patients. Clinicohistopathological characteristics obtained via assessment of medical records and imaging analysis were compared between the GS and GBM cohorts. Kaplan-Meier survival estimates were compared with log-rank testing, while cox-regression modeling tested for prognostic factors in GS patients. RESULTS The cohort revealed 26 primary gliosarcoma (PGS) patients (3.8 %) and 7 secondary gliosarcoma (SGS) patients (1.0 %). Compared to conventional GBM tumors, PGS tumors were significantly more often located in the temporal lobe (53.8 %, p = 0.006) and MGMT-unmethylated (73.9 %, p = 0.009). No significant differences were found between PGS and conventional GBM in progression-free-survival (6.8 and 7.6 months respectively, p = 0.105) and in overall survival (13.4 and 15.7 months respectively, p = 0.201). Also, survival from recurrence was not significant different between PGS, SGS and GBM (5.8, 8.6 and 7.4 months respectively, p = 0.694). MGMT status was the only factor prognostic for PGS survival (p = 0.022). CONCLUSION Despite tumor difference between GS and GBM, the patients present similar survival outcome from standardized treatment. This support continues practice of radiation and temozolomide for GS patients.
Application of CRISPR genetic screens to investigate neurological diseases
Authors: Raphaella W. L. So, Sai Wai Chung, Heather H. C. Lau, Jeremy J. Watts, Erin Gaudette, Zaid A. M. Al-Azzawi, Jossana Bishay, Lilian Tsai-Wei Lin, Julia Joung, Xinzhu Wang, Gerold Schmitt-Ulms
Journal: Molecular Neurodegeneration (2019)

Abstract The adoption of CRISPR-Cas9 technology for functional genetic screens has been a transformative advance. Due to its modular nature, this technology can be customized to address a myriad of questions. To date, pooled, genome-scale studies have uncovered genes responsible for survival, proliferation, drug resistance, viral susceptibility, and many other functions. The technology has even been applied to the functional interrogation of the non-coding genome. However, applications of this technology to neurological diseases remain scarce. This shortfall motivated the assembly of a review that will hopefully help researchers moving in this direction find their footing. The emphasis here will be on design considerations and concepts underlying this methodology. We will highlight groundbreaking studies in the CRISPR-Cas9 functional genetics field and discuss strengths and limitations of this technology for neurological disease applications. Finally, we will provide practical guidance on navigating the many choices that need to be made when implementing a CRISPR-Cas9 functional genetic screen for the study of neurological diseases.
Feasibility of Peripheral Blood Stem Cell Collection from Heterozygoussickle Cell Trait Donors
Authors: Juergen Foell, Morad Morez, Anja Troeger, Katharina Kleinschmidt, Beatrix Pfirstinger, Andreas Brosig, Ralph Burkhardt, Selim Corbacioglu, Norbert Ahrens
Journal: Blood (2019)
Use of a Electronic Sickle Cell Dashboard to Improve Annual Transcranial Doppler Ultrasound (TCD) Completion Rates
Authors: Joanna L. Gendreau, Kelli Fischbeck, Brooke Cook, Steve McCalley, Lori Wagner, Vinay Vaidya, Meenakshi Goyal-Khemka, Esteban Gomez, Christine M. Knoll, Sanjay J. Shah
Journal: Blood (2019)
Magnesium prevents vascular calcification in Klotho deficiency
Authors: Anique D. ter Braake, Anna E. Smit, Caro Bos, Antonius E. van Herwaarden, Wynand Alkema, Huib W. van Essen, Nathalie Bravenboer, Marc G. Vervloet, Joost G.J. Hoenderop, Jeroen H.F. de Baaij
Journal: Kidney International (2019)
Serum Cell-Free DNA Concentration Is Predictive of Survival Outcomes and Its Genetic Mutation Analysis May Be Viable in Obtaining Pathological Information
Authors: Yuko Shirouchi, Yuko Mishima, Yuji Mishima, Masahiro Yokoyama, Noriko Nishimura, Yoshiharu Kusano, Hideki Uryu, Takashi Okabe, Norihito Inoue, Takanori Fukuta, Kiyohiko Hatake, Yasuhito Terui
Journal: Blood (2019)
TMIC-16. THE EXPRESSION OF CX43 AND GAP43 AS CELL-TO-CELL LINKING FACTORS WITHIN THE GROUP OF DIFFUSE AND ANAPLASTIC GLIOMAS
Authors: Aleksandrs Krigers, Patrizia Moser, Helga Fritsch, Claudius Thomé, Christian F Freyschlag
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION The diversity of expansion and resistance within the group of diffuse and anaplastic gliomas might be possible due to variations in the cell-to-cell communication, determined by the Cx43- junctional activity and microtubules-defined networking with GAP43 as the main structural component. The aim of our trial was to assess the expression of these crucial proteins in samples of patients. METHODS Tissue of adult patients with WHO°II and III gliomas, who underwent surgery 2014 to 2018, were selected from institutional biobank. The expression was analyzed using immunohistochemistry and routine findings gained from patient charts. RESULTS 43 (57%) males and 33 (43%) females with a median age of 47 years (IqR: 35–61) were analyzed. In 15 (20%) patients a diffuse glioma (WHO°II) and in 46 (60%) an anaplastic glioma (WHO°III) was diagnosed. Further 15 patients (20%) were diagnosed with a diffuse glioma showing focal anaplasia. The IDH1 wildtype tumors demonstrated higher Cx43 expression in patients with longer intervals between imaging-based diagnosis and biopsy (p=0.032), whereas this association was absent in IDH1 mutated gliomas (p=0.549). The IDH1 wildtype tumors showed a higher expression of Cx43 (p=0.003) and a trend towards higher expression of GAP43 (p=0.075). Advanced Cx43 expression correlated with lower Ki67 nuclear expression in both IDH1 wildtype (p=0.003) and mutated gliomas (p=0.019). DISCUSSION The IDH1 wildtype gliomas showed advanced expression of Cx43 and GAP43 as well as longitudinal increase of Cx43. In the same time, tumors with lower mitosis rate produced more communication proteins, probably due to longer interphase. It can be interpreted as the intercellular networking provides acquired pathogenicity in the tumors with lower, e.g. “favorable”, proliferation rate. Moreover, IDH1 wildtype gliomas showed here advanced results, matching their aggressive behavior and poor outcome. Thus, diffuse and anaplastic gliomas are not homogenic and need to be evaluated considering their genetic profile.
Genomic Profiling of a Phase III Clinical Trial of Interferon Versus Hydroxyurea in MPN Patients Reveals Mutation-Specific and Treatment-Specific Patterns of Response
Authors: Trine Alma Knudsen, Vibe Skov, Lillian Werner, William Duke, Christopher J. Gibson, Anwesha Nag, Aaron R. Thorner, Bruce Wollison, Dennis Lund Hansen, Thomas Stauffer Larsen, Christina Ellervik, Daniel El Fassi, Karin de Stricker, Lukas Frans Ocias, Mette Brabrand, Ole Weis Bjerrum, Ulrik Malthe Overgaard, Mikael Frederiksen, Thomas Kielsgaard Kristensen, Torben A Kruse, Mads Thomassen, Torben Mourits-Andersen, Marianne Tang Severinsen, Jesper Stentoft, Joern Starklint, Peter Møller, Donna S Neuberg, Lasse Kjær, Hans Hasselbalch, R. Coleman Lindsley, Ann Mullally
Journal: Blood (2019)
STAT3-miR-17/20 signalling axis plays a critical role in attenuating myocardial infarction following rapamycin treatment in diabetic mice
Authors: Arun Samidurai, Sean K Roh, Meeta Prakash, David Durrant, Fadi N Salloum, Rakesh C Kukreja, Anindita Das
Journal: Cardiovascular Research (2019)

Abstract Aims Deregulation of mTOR (mammalian target of rapamycin) signalling occurs in diabetes, which exacerbates injury following myocardial infarction (MI). We therefore investigated the infarct-limiting effect of chronic treatment with rapamycin (RAPA, mTOR inhibitor) in diabetic mice following myocardial ischaemia/reperfusion (I/R) injury and delineated the potential protective mechanism. Methods and results Adult male diabetic (db/db) or wild-type (WT) (C57) mice were treated with RAPA (0.25 mg/kg/day, intraperitoneal) or vehicle (5% DMSO) for 28 days. The hearts from treated mice were subjected to global I/R in Langendorff mode. Cardiomyocytes, isolated from treated mice, were subjected to simulated ischaemia/reoxygenation (SI/RO) to assess necrosis and apoptosis. Myocardial infarct size was increased in diabetic heart following I/R as compared to WT. Likewise, enhanced necrosis and apoptosis were observed in isolated cardiomyocytes of diabetic mice following SI/RO. Treatment with RAPA reduced infarct size as well as cardiomyocyte necrosis and apoptosis of diabetes and WT mice. RAPA increased STAT3 phosphorylation and miRNA-17/20a expression in diabetic hearts. In addition, RAPA restored AKT phosphorylation (target of mTORC2) but suppressed S6 phosphorylation (target of mTORC1) following I/R injury. RAPA-induced cardioprotection against I/R injury as well as the induction of miR-17/20a and AKT phosphorylation were abolished in cardiac-specific STAT3-deficient diabetic mice, without alteration of S6 phosphorylation. The infarct-limiting effect of RAPA was obliterated in cardiac-specific miRNA-17-92-deficient diabetic mice. The post-I/R restoration of phosphorylation of STAT3 and AKT with RAPA were also abolished in miRNA-17-92-deficient diabetic mice. Additionally, RAPA suppressed the pro-apoptotic prolyl hydroxylase (Egln3/PHD3), a target of miRNA-17/20a in diabetic hearts, which was abrogated in miRNA-17-92-deficient diabetic mice. Conclusion Induction of STAT3-miRNA-17-92 signalling axis plays a critical role in attenuating MI in RAPA-treated diabetic mice. Our study indicates that chronic treatment with RAPA might be a promising pharmacological intervention for attenuating MI and improving prognosis in diabetic patients.
Synthetic Partially Reduced Human Neutrophil Peptide (HNP)-1 Inhibits Platelet Adhesion and Aggregation on Von Willebrand Factor-Collagen Surfaces Under Arterial Shear Stress through a Disulfide Bond Reduction Mechanism
Authors: Jenny K. McDaniel, Khalil Bdeir, Douglas B. Cines, X. Long Zheng
Journal: Blood (2016)
Novel Mechanisms of Cancer Emerge When Accounting for Sex as a Biological Variable
Authors: Melissa A. Wilson, Kenneth H. Buetow
Journal: Cancer Research (2019)

There is a large gap between the aspiration of considering sex as biological variable and the execution of such studies, particularly in genomic studies of human cancer. This represents a lost opportunity to identify sex-specific molecular etiologies that may underpin the dramatic sex differences in cancer incidence and outcome. There are conceptual and practical challenges associated with considering sex as a biological variable, including the definition of sex itself and the need for novel study designs. A better understanding of cancer mechanisms, resulting in improved outcomes, will reward the effort invested in incorporating sex as a biological variable.
Single-Cell Deconvolution Identifies T-Cell Correlates of Response to PD-1 Blockade Treatment in AML
Authors: Xingyue An, Jay R Adolacion, Mansour Alfayez, Jairo Matthews, Wilmer Flores, Steven M. Kornblau, Arash Saeedi, Sreyashi Basu, Naval G. Daver, Navin Varadarajan
Journal: Blood (2019)
A Randomized, Open-Label, Multicenter, Phase 2 Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared with Ruxolitinib in Patients with Phlebotomy-Dependent Polycythemia Vera
Authors: Jason Gotlib, Nashat Gabrail, Casey L. O'Connell, Regina Garcia-Delgado, Timothy Sbardellati, Wayne M. Rothbaum, Jesse McGreivy, Claire N Harrison, Jean-Jacques Kiladjian
Journal: Blood (2019)
INNV-21. IN NEWLY-DIAGNOSED GLIOBLASTOMA, FRAILTY/SARCOPENIA PREDICTS 30D MORBIDITY &amp; 30D, 90D, AND OVERALL MORTALITY AS ACCURATELY AS CURRENT STANDARDS
Authors: Hesham Zakaria, Ankush Chandra, Mohamed Macki, Adam Robin, Tobias Walbert, Victor Chang, Steven Kalkanis, Ian Lee
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Identification of novel prognostic biomarkers for glioblastoma (GBM) could stratify patients between aggressive or palliative treatments. Frailty, as measured by sarcopenia (lack of muscle mass), has been proven to predict survival in cancers. We evaluate whether the frailty/sarcopenia phenotype (FSP) predicts morbidity and mortality in GBM, and compare it to other survival markers. METHODS In 257 patients undergoing initial diagnostic surgery for GBM, FSP was defined by temporalis muscle thickness from preoperative MRI; patients were grouped into tertiles (thirds) based on size, which corresponded to the severity of FSP. Morbidity and mortality hazard ratios were calculated from surgery using multivariate analysis, accounting for age, gender, past medical history, tumor focality / laterality / eloquence / volume, extent of resection, MGMT / IDH status, and initiation of postoperative chemo/radiation. Morbidity was defined as any of these events within 30d: DVT, PE, SSI, UTI, MI, urinary retention, ileus, readmission. RESULTS FSP at diagnostic surgery predicted any morbidity (OR2.98, P= 0.005) at 30d. FSP at diagnostic surgery was the only risk factor associated with 30d mortality (OR10.0, P= 0.030), and was also strongly associated with 90d mortality (OR25.0, P= 0.003). FSP at diagnostic surgery was associated with decreased overall survival (OR0.41, P&lt; 0.001) at a level comparable to other mortality predictors, including temozolomide/EBRT (OR0.27), gross total resection (OR0.54), favorable MGMT (OR0.44) or IDH (OR0.44) mutations. Kaplan-Meier curves display overall survival based on severity of FSP. CONCLUSION FSP is a preoperative, simple, accurate, and non-invasive methodology to predict 30d morbidity &amp; 30-day, 90-day, and overall mortality from diagnosis in GBM. FSP is independent of age (not an age surrogate), demographic, oncologic, genetic, surgical, and therapeutic factors. Mortality prediction is comparable to temozolamid/EBRT, total resection, MGMT, and IDH. It is a low cost, intuitive, and potentially universal methodology to guide treatment decision making.
The Real-Life Data on the Outcome of Hepatitis B Infection in Patients with B-Cell Lymphoproliferative Neoplasms Treated with Ibrutinib
Authors: Abdulkadir Ercaliskan, Ahmet Emre Eskazan, Nurgul Ozgur Yurttas, Selin Kucukyurt, Ayse Salihoglu, Dilek Keskin, Deniz Ozmen, Tugrul Elverdi, Muhlis Cem Ar, Teoman Soysal
Journal: Blood (2019)
Acute Promyelocytic Leukemia (APL) in Very Elderly Patients: Real-Life behind Protocols
Authors: Serena Rosati, Massimo Breccia, Carmelo Gurnari, Ida Carmosino, Emilia Scalzulli, Enrico Montefusco, Salvatore Perrone, Ombretta Annibali, Vincenza Martini, Giulio Trapè, Malgorzata Monika Trawinska, Clara Minotti, Giuseppe Cimino, Agostino Tafuri, Giuseppe Avvisati, Maria Teresa Voso, Robin Foà, Roberto Latagliata
Journal: Blood (2019)