tbuckley/cabot-search huggingface dataset:
Toward a standard pathological and molecular characterization of recurrent glioma in adults: a Response Assessment in Neuro-Oncology effort
Authors: Ali S Haider, Martin van den Bent, Patrick Y Wen, Michael A Vogelbaum, Susan Chang, Peter D Canoll, Craig M Horbinski, Jason T Huse
Journal: Neuro-Oncology (2019)

Abstract Regardless of subtype, diffuse gliomas of adulthood are characterized by inexorable progression through treatment. Cancer recurrence in the context of therapy is by no means unique to gliomas. For many tumors residing outside the central nervous system (CNS), tissue-based analyses are routinely employed to document the molecular and cellular features of disease recurrence. Such interventions are inconsistently applied for gliomas, however, and lack rigorous standardization when they are. While many of the reasons underlying these discrepancies reflect pragmatic realities inherent to CNS disease, the suboptimal employment of histological and molecular assessment at recurrence nevertheless represents a missed opportunity to proactively guide patient management and increase knowledge. Herein, we address this quandary by pairing a succinct description of the histological, biological, and molecular characteristics of recurrent glioma with recommendations for how to better standardize and implement quality pathological assessment into patient management. We hope this review will prompt thoughtful revision of standard operating procedures to maximize the utility of glioma re-biopsy.
Genetics of Type 1 Diabetes Comes of Age
Authors: Maria J. Redondo, Patrick Concannon
Journal: Diabetes Care (2019)

Younger age at diagnosis often reflects a greater influence of genetic factors in disease. Type 1 diabetes, which develops most frequently in childhood but can also present in adult life, is a prime candidate to explore the relationships among risk loci, age at diagnosis, and genetic contribution to disease. Type 1 diabetes genetic risk scores (GRS) (calculated as the weighted sum of alleles statistically associated with type 1 diabetes present in a given individual) are inversely correlated with age at diagnosis. Studies have suggested age-related heterogeneity in the association of established risk alleles with type 1 diabetes, although no consistent pattern has developed. Further investigations into the genetic factors that influence age of clinical onset may refine our understanding of type 1 diabetes pathogenesis and provide opportunities for individualized preventive therapies.

It has long been recognized that genetics plays a role in determining age at type 1 diabetes diagnosis. For monozygotic twins, concordance for type 1 diabetes increases with younger age at diagnosis in the index twin (1). HLA genotypes that confer risk for type 1 diabetes are more prevalent among subjects with younger age at clinical onset (2). GRS combining information from type 1 diabetes–associated HLA and non-HLA loci predict progression from single to multiple autoantibody positivity in individuals under age 35 years but not in older participants (3). A genome-wide analysis by Inshaw et al. (4) showed that rs9273363 single-nucleotide polymorphism (SNP) (tagging the HLA DQB1*03:02 haplotype) and the 6q22.33 region, which contains the genes encoding protein tyrosine phosphatase receptor κ ( PTPRK ) and thymocyte-expressed molecule involved in selection ( THEMIS ), are associated with younger age at diagnosis, although not with type 1 diabetes overall. Additional chromosomal regions reported to influence age at type 1 diabetes diagnosis are interleukin-2 ( IL2 ) (4q27, rs2069763) and renalase ( RNLS ) (10q23.31, rs10509540) (5). On the …
Cataract operations should take no longer than 30 minutes to maximise capacity, says report
Authors: Gareth Iacobucci
Journal: BMJ (2019)

All NHS trusts should perform routine cataract surgery in 30 minutes or less to optimise capacity and treat more patients with deteriorating eyesight, a new report has advised.1

Providing more consistent surgery across the country would help the NHS keep pace with growing demand for ophthalmology services, says the latest report from the national Getting It Right First Time programme, which assesses unwarranted variations in clinical care.

Cataract surgery is the most common surgical procedure in the NHS, with around 400 000 operations carried out in 2018. With an ageing population, demand is predicted to increase by more than 50% over the next 20 …
Abstract 11408: Improved Heart Failure Self-Care in a Medicare Population Receiving Virtual Behavioral Therapy: A Health Plan-Provider Collaboration
Authors: Heidi M Greenberger, Consuela Dennis, Evie Andreopoulos, Naomi Pollock, Aimee Peters, Reena L Pande
Journal: Circulation (2019)

Introduction: Behavioral health challenges are associated with suboptimal self-care and adverse clinical outcomes in heart failure (HF). Cognitive behavioral therapy addressing these challenges imp...
The art of life and death: 14 year follow-up analyses of associations between arts engagement and mortality in the English Longitudinal Study of Ageing
Authors: Daisy Fancourt, Andrew Steptoe
Journal: BMJ (2019)

Abstract Objective To explore associations between different frequencies of arts engagement and mortality over a 14 year follow-up period. Design Prospective cohort study. Participants English Longitudinal Study of Ageing cohort of 6710 community dwelling adults aged 50 years and older (53.6% women, average age 65.9 years, standard deviation 9.4) who provided baseline data in 2004-05. Intervention Self reported receptive arts engagement (going to museums, art galleries, exhibitions, the theatre, concerts, or the opera). Measurement Mortality measured through data linkage to the National Health Service central register. Results People who engaged with receptive arts activities on an infrequent basis (once or twice a year) had a 14% lower risk of dying at any point during the follow-up (809/3042 deaths, hazard ratio 0.86, 95% confidence interval 0.77 to 0.96) compared with those who never engaged (837/1762 deaths). People who engaged with receptive arts activities on a frequent basis (every few months or more) had a 31% lower risk of dying (355/1906 deaths, 0.69, 0.59 to 0.80), independent of demographic, socioeconomic, health related, behavioural, and social factors. Results were robust to a range of sensitivity analyses with no evidence of moderation by sex, socioeconomic status, or social factors. This study was observational and so causality cannot be assumed. Conclusions Receptive arts engagement could have a protective association with longevity in older adults. This association might be partly explained by differences in cognition, mental health, and physical activity among those who do and do not engage in the arts, but remains even when the model is adjusted for these factors.
Machine Learning and the Cancer-Diagnosis Problem — No Gold Standard
Authors: Adewole S. Adamson, H. Gilbert Welch
Journal: New England Journal of Medicine (2019)

Interview with Dr. Adewole Adamson on the role of machine learning in cancer diagnosis. (07:26)Download Machine learning has the potential to be extremely useful in medicine, particularly in the interpretation of medical images. But it also has inherent limitations, especially when it comes to diagnosing early-stage cancer.
A Depletion of Stop Codons in lincRNA is Owing to Transfer of Selective Constraint from Coding Sequences
Authors: Liam Abrahams, Laurence D Hurst
Journal: Molecular Biology and Evolution (2019)

Although the constraints on a gene's sequence are often assumed to reflect the functioning of that gene, here we propose transfer selection, a constraint operating on one class of genes transferred to another, mediated by shared binding factors. We show that such transfer can explain an otherwise paradoxical depletion of stop codons in long intergenic noncoding RNAs (lincRNAs). Serine/arginine-rich proteins direct the splicing machinery by binding exonic splice enhancers (ESEs) in immature mRNA. As coding exons cannot contain stop codons in one reading frame, stop codons should be rare within ESEs. We confirm that the stop codon density (SCD) in ESE motifs is low, even accounting for nucleotide biases. Given that serine/arginine-rich proteins binding ESEs also facilitate lincRNA splicing, a low SCD could transfer to lincRNAs. As predicted, multiexon lincRNA exons are depleted in stop codons, a result not explained by open reading frame (ORF) contamination. Consistent with transfer selection, stop codon depletion in lincRNAs is most acute in exonic regions with the highest ESE density, disappears when ESEs are masked, is consistent with stop codon usage skews in ESEs, and is diminished in both single-exon lincRNAs and introns. Owing to low SCD, the maximum lengths of pseudo-ORFs frequently exceed null expectations. This has implications for ORF annotation and the evolution of de novo protein-coding genes from lincRNAs. We conclude that not all constraints operating on genes need be explained by the functioning of the gene but may instead be transferred owing to shared binding factors.
Abstract 10747: Gender Differences in the Incidence, Management and Outcomes of In-Hospital Cardiac Arrest Complicating Acute Coronary Syndromes: A 20-Year Experience From a Middle-Eastern Country (1991-2010)
Authors: Amar M Salam, Hajar AlBinali, Rajvir Singh, Awad Al-Qahtani, Nidal Asaad, Jassim Al Suwaidi
Journal: Circulation (2013)

Objectives: There is scarce data about gender differences in in-hospital cardiac arrest (IHCA) complicating acute coronary syndromes (ACS), particularly from the developing countries. In the curren...
Comprehensive detection of recurring genomic abnormalities: a targeted sequencing approach for multiple myeloma
Authors: Venkata Yellapantula, Malin Hultcrantz, Even H. Rustad, Ester Wasserman, Dory Londono, Robert Cimera, Amanda Ciardiello, Heather Landau, Theresia Akhlaghi, Sham Mailankody, Minal Patel, Juan Santiago Medina-Martinez, Juan Esteban Arango Ossa, Max Fine Levine, Niccolo Bolli, Francesco Maura, Ahmet Dogan, Elli Papaemmanuil, Yanming Zhang, Ola Landgren
Journal: Blood Cancer Journal (2019)

Abstract Recent genomic research efforts in multiple myeloma have revealed clinically relevant molecular subgroups beyond conventional cytogenetic classifications. Implementing these advances in clinical trial design and in routine patient care requires a new generation of molecular diagnostic tools. Here, we present a custom capture next-generation sequencing (NGS) panel designed to identify rearrangements involving the IGH locus, arm level, and focal copy number aberrations, as well as frequently mutated genes in multiple myeloma in a single assay. We sequenced 154 patients with plasma cell disorders and performed a head-to-head comparison with the results from conventional clinical assays, i.e., fluorescent in situ hybridization (FISH) and single-nucleotide polymorphism (SNP) microarray. Our custom capture NGS panel had high sensitivity (&gt;99%) and specificity (&gt;99%) for detection of IGH translocations and relevant chromosomal gains and losses in multiple myeloma. In addition, the assay was able to capture novel genomic markers associated with poor outcome such as bi-allelic events involving TP53 . In summary, we show that a multiple myeloma designed custom capture NGS panel can detect IGH translocations and CNAs with very high concordance in relation to FISH and SNP microarrays and importantly captures the most relevant and recurrent somatic mutations in multiple myeloma rendering this approach highly suitable for clinical application in the modern era.
Nanotechnology in cancer diagnosis: progress, challenges and opportunities
Authors: Ye Zhang, Maoyu Li, Xiaomei Gao, Yongheng Chen, Ting Liu
Journal: Journal of Hematology & Oncology (2019)

Abstract In the fight against cancer, early detection is a key factor for successful treatment. However, the detection of cancer in the early stage has been hindered by the intrinsic limits of conventional cancer diagnostic methods. Nanotechnology provides high sensitivity, specificity, and multiplexed measurement capacity and has therefore been investigated for the detection of extracellular cancer biomarkers and cancer cells, as well as for in vivo imaging. This review summarizes the latest developments in nanotechnology applications for cancer diagnosis. In addition, the challenges in the translation of nanotechnology-based diagnostic methods into clinical applications are discussed.
The Need for Combined Assessment of Multiple Outcomes in Noninferiority Trials in Oncology
Authors: Ismail Jatoi, Mitchell H. Gail
Journal: JAMA Oncology (2019)

Noninferiority trials in oncology assess novel therapies with the potential for slightly worse recurrence or death outcomes (ie, the margin of noninferiority) than standard therapies. This poses a dilemma because, in the absence of potential health outcome advantages, these trials may not provide the treatment equipoise required for an ethical study. Any new treatment with the potential for slightly worse recurrence or death outcomes should have countervailing health outcome advantages, but these are rarely taken into account in the design of noninferiority trials. This article presents the argument that not only the potentially worse health outcomes but also the potential benefits of the novel therapy should be considered when designing, analyzing, and reporting noninferiority trials. Some approaches to study design and analysis that consider both primary and secondary end points are discussed, and reporting the joint distributions of end points for the novel and standard treatments is recommended.
Randomized Phase III Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, With Docetaxel Versus Docetaxel in Advanced Non–Small-Cell Lung Cancer (GALAXY-2)
Authors: Rathi N. Pillai, Dean A. Fennell, Vladimir Kovcin, Tudor-Eliade Ciuleanu, Rodryg Ramlau, Dariusz Kowalski, Michael Schenker, Ilker Yalcin, Florentina Teofilovici, Vojo M. Vukovic, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2019)

Ganetespib, a highly potent heat shock protein 90 inhibitor, blocks multiple oncogenic pathways, resulting in antitumor activity. We evaluated the combination of ganetespib and docetaxel for second-line therapy of patients with advanced adenocarcinoma of the lung.In this international phase III trial, patients with stage IIIB or IV adenocarcinoma diagnosed > 6 months before study entry and 1 prior systemic therapy were randomly assigned (1:1) to ganetespib 150 mg/m2 on days 1 and 15 with docetaxel 75 mg/m2 on day 1 of a 21-day cycle or to docetaxel alone. The primary end point was overall survival (OS).Of 677 enrolled patients, 335 were randomly assigned to ganetespib and docetaxel and 337 were assigned to docetaxel. The trial was stopped early as a result of futility at a planned interim analysis. The median OS time was 10.9 months (95% CI, 9.0 to 12.3 months) in the ganetespib and docetaxel arm compared with 10.5 months (95% CI, 8.6 to 12.2 months) in docetaxel arm (hazard ratio [HR], 1.11; 95% CI, 0.899 to 1.372; P = .329). Median progression-free survival was 4.2 months in the ganetespib and docetaxel arm and 4.3 months in the docetaxel arm (HR, 1.16; 95% CI, 0.96 to 1.403; P = .119). The addition of ganetespib did not improve outcomes compared with docetaxel alone for any secondary end point, including survival in the elevated lactate dehydrogenase or EGFR and ALK wild-type populations. The most common grade 3 or 4 adverse event in both arms was neutropenia (30.9% with ganetespib and docetaxel v 25% with docetaxel).The addition of ganetespib to docetaxel did not result in improved survival for salvage therapy of patients with advanced-stage lung adenocarcinoma.
Driving Under the Influence of Marijuana and Illicit Drugs Among Persons Aged ≥16 Years — United States, 2018
Authors: Alejandro Azofeifa, Bárbara D. Rexach-Guzmán, Abby N. Hagemeyer, Rose A. Rudd, Erin K. Sauber-Schatz
Journal: MMWR Morbidity and Mortality Weekly Report (2019)

In the United States, driving while impaired is illegal. Nonetheless, an estimated 10,511 alcohol-impaired driving deaths occurred in 2018.* The contribution of marijuana and other illicit drugs to these and other impaired driving deaths remains unknown. Data from the Substance Abuse and Mental Health Services Administration's National Survey on Drug Use and Health (NSDUH) indicated that in the United States during 2014, 12.4% of all persons aged 16-25 years reported driving under the influence of alcohol, and 3.2% reported driving under the influence of marijuana (1). The impairing effects of alcohol are well established, but less is known about the effects of illicit substances or other psychoactive drugs (e.g., marijuana, cocaine, methamphetamines, and opioids, including heroin). This report provides the most recent national estimates of self-reported driving under the influence of marijuana and illicit drugs among persons aged ≥16 years, using 2018 public-use data from NSDUH. Prevalences of driving under the influence of marijuana and illicit drugs other than marijuana were assessed for persons aged ≥16 years by age group, sex, and race/ethnicity. During 2018, 12 million (4.7%) U.S. residents reported driving under the influence of marijuana in the past 12 months; 2.3 million (0.9%) reported driving under the influence of illicit drugs other than marijuana. Driving under the influence was more prevalent among males and among persons aged 16-34 years. Effective measures that deter driving under the influence of drugs are limited (2). Development, evaluation, and further implementation of strategies to prevent alcohol-impaired,† drug-impaired, and polysubstance-impaired driving, coupled with standardized testing of impaired drivers and drivers involved in fatal crashes, could advance understanding of drug- and polysubstance-impaired driving and support prevention efforts.
Immune checkpoint inhibitors (ICI) in combination with chemotherapy as first-line (1L) treatment for non-small cell lung cancer (NSCLC): A pair-wise meta-analysis (MA)
Authors: F.J. Afonso-Afonso, M. Amenedo Gancedo, M.C. Areses Manrique, B. Campos Balea, J. Casal Rubio, N. Fernández-Núñez, J.L. Firvida Perez, J. García González, M. Lázaro Quintela, L. León-Mateos, J. Ruíz-Bañobre, D. Pérez Parente, L. Crama, P. Ruiz Gracia, L. Santomé Couto
Journal: Annals of Oncology (2019)
Spinal subpial delivery of AAV9 enables widespread gene silencing and blocks motoneuron degeneration in ALS
Authors: Mariana Bravo-Hernandez, Takahiro Tadokoro, Michael R. Navarro, Oleksandr Platoshyn, Yoshiomi Kobayashi, Silvia Marsala, Atsushi Miyanohara, Stefan Juhas, Jana Juhasova, Helena Skalnikova, Zoltan Tomori, Ivo Vanicky, Hana Studenovska, Vladimir Proks, PeiXi Chen, Noe Govea-Perez, Dara Ditsworth, Joseph D. Ciacci, Shang Gao, Wenlian Zhu, Eric T. Ahrens, Shawn P. Driscoll, Thomas D. Glenn, Melissa McAlonis-Downes, Sandrine Da Cruz, Samuel L. Pfaff, Brian K. Kaspar, Don W. Cleveland, Martin Marsala
Journal: Nature Medicine (2019)
Non-enhanced magnetic resonance imaging as a surveillance tool for hepatocellular carcinoma: Comparison with ultrasound
Authors: Hyo Jung Park, Hye Young Jang, So Yeon Kim, So Jung Lee, Hyung Jin Won, Jae Ho Byun, Sang Hyun Choi, Seung Soo Lee, Jihyun An, Young-Suk Lim
Journal: Journal of Hepatology (2019)
Structure-based design of charge-conversional drug self-delivery systems for better targeted cancer therapy
Authors: Haijun Xiao, Yiping Guo, Hongmei Liu, Yushi Liu, Yumin Wang, Changqing Li, Jaroslav Císař, David Škoda, Ivo Kuřitka, Li Guo, Vladimír Sedlařík
Journal: Biomaterials (2019)
Herbal drug discovery for the treatment of nonalcoholic fatty liver disease
Authors: Tingting Yan, Nana Yan, Ping Wang, Yangliu Xia, Haiping Hao, Guangji Wang, Frank J. Gonzalez
Journal: Acta Pharmaceutica Sinica B (2019)

Few medications are available for meeting the increasing disease burden of nonalcoholic fatty liver disease (NAFLD) and its progressive stage, nonalcoholic steatohepatitis (NASH). Traditional herbal medicines (THM) have been used for centuries to treat indigenous people with various symptoms but without clarified modern-defined disease types and mechanisms. In modern times, NAFLD was defined as a common chronic disease leading to more studies to understand NAFLD/NASH pathology and progression. THM have garnered increased attention for providing therapeutic candidates for treating NAFLD. In this review, a new model called "multiple organs-multiple hits" is proposed to explain mechanisms of NASH progression. Against this proposed model, the effects and mechanisms of the frequently-studied THM-yielded single anti-NAFLD drug candidates and multiple herb medicines are reviewed, among which silymarin and berberine are already under U.S. FDA-sanctioned phase 4 clinical studies. Furthermore, experimental designs for anti-NAFLD drug discovery from THM in treating NAFLD are discussed. The opportunities and challenges of reverse pharmacology and reverse pharmacokinetic concepts-guided strategies for THM modernization and its global recognition to treat NAFLD are highlighted. Increasing mechanistic evidence is being generated to support the beneficial role of THM in treating NAFLD and anti-NAFLD drug discovery.
Systematic underestimation of the epigenetic clock and age acceleration in older subjects
Authors: Louis Y. El Khoury, Tyler Gorrie-Stone, Melissa Smart, Amanda Hughes, Yanchun Bao, Alexandria Andrayas, Joe Burrage, Eilis Hannon, Meena Kumari, Jonathan Mill, Leonard C. Schalkwyk
Journal: Genome biology (2019)

Abstract Background The Horvath epigenetic clock is widely used. It predicts age quite well from 353 CpG sites in the DNA methylation profile in unknown samples and has been used to calculate “age acceleration” in various tissues and environments. Results The model systematically underestimates age in tissues from older people. This is seen in all examined tissues but most strongly in the cerebellum and is consistently observed in multiple datasets. Age acceleration is thus age-dependent, and this can lead to spurious associations. The current literature includes examples of association tests with age acceleration calculated in a wide variety of ways. Conclusions The concept of an epigenetic clock is compelling, but caution should be taken in interpreting associations with age acceleration. Association tests of age acceleration should include age as a covariate.