tbuckley/cabot-search huggingface dataset:
Mosaic Y Loss Is Moderately Associated with Solid Tumor Risk
Authors: Erikka Loftfield, Weiyin Zhou, Meredith Yeager, Stephen J. Chanock, Neal D. Freedman, Mitchell J. Machiela
Journal: Cancer Research (2018)

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes have lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Here, we investigated the relationship between mLOY and incident cancer in a large sample of 207,603 cancer-free men from the UK Biobank, in which 13,895 men developed an incident solid tumor during follow-up. We identified mLOY by scanning for deviations in genotyping array log R intensity ratios across the male-specific chromosome Y region. Overall, we detected low proportions of cells with mLOY in 3,358 (1.6%) men and high proportions of mLOY in 524 (0.3%) men. We found an association of mLOY with overall solid tumor incidence using both low and high mLOY thresholds [HRlow = 1.18; 95% confidence interval (CI)low, 1.07-1.30; Plow = 0.001; HRhigh = 1.36; 95% CIhigh, 1.09-1.71; Phigh = 0.007] and more specifically we observed an association with lung cancer (HRhigh = 2.25; 95% CIhigh, 1.36-3.71; Phigh = 0.002). Stronger associations were observed without adjustment for smoking, suggesting that smoking is an important confounder of tumor incidence. It is unlikely that mLOY is a major mediator of the effect of cigarette smoking on cancer risk, as mLOY was observed in only a small fraction of smokers who developed cancer. In summary, mLOY was modestly associated with incidence of solid tumors in the UK Biobank, although for some cancer subtypes these findings may reflect residual confounding by smoking. SIGNIFICANCE: Evidence from the UK Biobank indicates mosaic chromosome Y loss in leukocytes is moderately associated with increased incidence of select solid tumors.
Use of Big Data to Estimate Prevalence of Defective DNA Repair Variants in the US Population
Authors: Jennifer Pugh, Sikandar G. Khan, Deborah Tamura, Alisa M. Goldstein, Maria Teresa Landi, John J. DiGiovanna, Kenneth H. Kraemer
Journal: JAMA Dermatology (2018)

Wide use of genomic sequencing to diagnose disease has raised concern about the extent of genotype-phenotype correlations.To correlate disease-associated allele frequencies with expected and reported prevalence of clinical disease.Xeroderma pigmentosum (XP), a recessive, cancer-prone, neurocutaneous disorder, was used as a model for this study. From January 1, 2017, to May 4, 2018, the Human Gene Mutation Database and a cohort of patients at the National Institutes of Health were searched and screened to identify reported mutations associated with XP. The clinical phenotype of these patients was confirmed from reports in the literature and National Institutes of Health medical records. The genetically predicted prevalence of disease based on frequency of known pathogenic mutations was compared with the prevalence of patients clinically diagnosed with phenotypic XP. Exome sequencing of more than 200 000 alleles from the Genome Aggregation Database, the National Cancer Institute Division of Cancer Epidemiology and Genetics database of healthy controls, and an Inova Hospital Study database was used to investigate the frequencies of these mutations in the general population.Listing of all reported mutations associated with XP, their frequencies in 3 large exome sequence databases, determination of the number of patients in the United States with XP using modeling equations, and comparison of the observed and reported numbers of patients with XP with specific mutations.A total of 156 pathogenic missense and nonsense mutations associated with XP were identified in the National Institutes of Health cohort and the Human Gene Mutation Database. The Genome Aggregation Database provided frequency data for 65 of these mutations, with a total allele frequency of 1.13%. The XPF (ERCC4) mutation, p.P379S, had an allele frequency of 0.4%, and the XPC mutation, p.P334H, had an allele frequency of 0.3%. With the Hardy-Weinberg equation, it was determined that there should be more than 8000 patients who are homozygous for these mutations in the United States. In contrast, only 3 patients with XP were reported as having the XPF mutation, and 1 patient was reported as having the XPC mutation.The findings from this study suggest that clinicians should approach large genomic databases with caution when trying to correlate the clinical implications of genetic variants with the prevalence of disease risk. Unsuspected mutations in known genes with a predisposition for skin cancer may be responsible for some of the high frequency of skin cancers in the general population.
Harmonisation of laboratory tests for rheumatic diseases: still a long way to go
Authors: Lieve Van Hoovels, Xavier Bossuyt
Journal: Annals of the Rheumatic Diseases (2018)

Antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), rheumatoid factor (RF) and antibodies to citrullinated peptides (ACPA) are widely used laboratory markers to support the diagnosis of ANA-associated systemic rheumatic diseases, ANCA-associated vasculitis and rheumatoid arthritis. Despite the fact that these tests are broadly used, they all suffer from a lack of harmonisation.

Pisetsky et al 1 recently reported on assay variation in the detection of ANAs in the sera of patients with established systemic lupus erythematosus. Differences in ANA reactivity were found between different indirect immunofluorescence (IIF) methods and between IIF and immunoassays. Infantino et al 2 further stressed (1) that such …
Systematic evaluation of the efficacy–effectiveness gap of systemic treatments in metastatic nonsmall cell lung cancer
Authors: Christine M. Cramer-van der Welle, Bas J.M. Peters, Franz M.N.H. Schramel, Olaf H. Klungel, Harry J.M. Groen, Ewoudt M.W. van de Garde
Journal: European Respiratory Journal (2018)

The divergence between clinical trial results and real-world outcomes is largely unknown for many cancer types. The present study aims overall to assess the efficacy–effectiveness gap (difference between outcomes in clinical trials and the real world) in systemic treatment for metastatic nonsmall cell lung cancer (NSCLC). All patients diagnosed with stage IV NSCLC between 2008 and 2014 within a network of seven Dutch large teaching hospitals (Santeon) were studied. For every patient, an efficacy–effectiveness (EE) factor was calculated by dividing individual patients' overall survival (OS) by the pooled median OS assessed from clinical trials with the respective treatment. From 2989 diagnosed patients, 1214 (41%) started with first-line treatment. For all studied regimens, real-world OS was shorter than OS reported in clinical trials. Overall, the EE factor was 0.77 (95% CI 0.70–0.85; p&lt;0.001). Real-world patients completed their treatment plan less often and proceeded less frequently to further lines of treatment. These parameters together with Eastern Cooperative Oncology Group performance status explained 35% of the variation in EE factor. Survival of patients with metastatic NSCLC treated with chemotherapy or targeted therapy in real-world practice is nearly one-quarter shorter than for patients included in trials. Patients' performance status, earlier discontinuation and fewer subsequent lines of treatment partly explained this difference.
Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing
Authors: Cryptic And The 100,000 Genomes Project Consortium, Philip Supply
Journal: New England Journal of Medicine (2018)

The World Health Organization recommends drug-susceptibility testing of Mycobacterium tuberculosis complex for all patients with tuberculosis to guide treatment decisions and improve outcomes. Whether DNA sequencing can be used to accurately predict profiles of susceptibility to first-line antituberculosis drugs has not been clear.We obtained whole-genome sequences and associated phenotypes of resistance or susceptibility to the first-line antituberculosis drugs isoniazid, rifampin, ethambutol, and pyrazinamide for isolates from 16 countries across six continents. For each isolate, mutations associated with drug resistance and drug susceptibility were identified across nine genes, and individual phenotypes were predicted unless mutations of unknown association were also present. To identify how whole-genome sequencing might direct first-line drug therapy, complete susceptibility profiles were predicted. These profiles were predicted to be susceptible to all four drugs (i.e., pansusceptible) if they were predicted to be susceptible to isoniazid and to the other drugs or if they contained mutations of unknown association in genes that affect susceptibility to the other drugs. We simulated the way in which the negative predictive value changed with the prevalence of drug resistance.A total of 10,209 isolates were analyzed. The largest proportion of phenotypes was predicted for rifampin (9660 [95.4%] of 10,130) and the smallest was predicted for ethambutol (8794 [89.8%] of 9794). Resistance to isoniazid, rifampin, ethambutol, and pyrazinamide was correctly predicted with 97.1%, 97.5%, 94.6%, and 91.3% sensitivity, respectively, and susceptibility to these drugs was correctly predicted with 99.0%, 98.8%, 93.6%, and 96.8% specificity. Of the 7516 isolates with complete phenotypic drug-susceptibility profiles, 5865 (78.0%) had complete genotypic predictions, among which 5250 profiles (89.5%) were correctly predicted. Among the 4037 phenotypic profiles that were predicted to be pansusceptible, 3952 (97.9%) were correctly predicted.Genotypic predictions of the susceptibility of M. tuberculosis to first-line drugs were found to be correlated with phenotypic susceptibility to these drugs. (Funded by the Bill and Melinda Gates Foundation and others.).
SAT0143 Psychosomatic aspects of fibromyalgia versus rheumatoid arthritis
Authors: CA Silva, MJ Quartilho, JA Da Silva, A Malcata, A Porto
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The psico-social dimensions of fibromialgia (FM) remain controversial, not only regarding its characterisation but also its possible causal or consequential relationship with the chronic pain status. The usual discrepancy between the self-report instruments of functional impairment and the observed disability favours a process of somatization. The contribution of pain and emotions to general health status are open to debate. <h3>Objectives</h3> We attempted to investigate emotional disturbances in patients with fibromialgia and rheumatoid arthritis (RA) and their relationship with self-reported general health. <h3>Methods</h3> 58 FM patients and 43 RA patients, fulfilling the ACR criteria, were included on a consecutive basis from our Rheumatology outpatient clinic. Social and demographic data were collected and found to be comparable among the groups, as well as disease duration. The Short-Form Health Survey (SF-36) and the Brief Symptom Inventory (BSI) were applied twice, with 6 months interval. Both instruments were evaluated regarding each of their different dimensions and summary score. Statistical analysis employed Student's t test. <h3>Results</h3> FM patients scored significantly higher in every single BSI dimension (somatization; obsession/compulsion; interpersonal relationship; depression; anxiety; hostility; fobic anxiety, paranoid ideation and psicoticism. FM patients also showed significantly lower levels of general health, as evaluated by SF-36, both in mental and physical components. These differences remained stable in re-evaluation. <h3>Conclusion</h3> FM patients have a higher score for associated psychopathologic symptoms. This parallels their higher dissatisfaction with general health, not only in its mental aspects, but also on physical function and performance. These results demonstrate a strong coexistence of pain and psichopatological traits in FM patients, which may have a strong influence on reported functional status. The possibility that such psychological disturbances are a consequence of the disease, and especially chronic pain, is questioned by the much lower prevalence of such disorders in RA patients of similar disease duration.
Brexit: NHS contingency plans will start “this side of Christmas” if EU withdrawal bill is voted down
Authors: Gareth Iacobucci
Journal: BMJ (2018)

The NHS will enact contingency plans to protect medical supply chains “this side of Christmas” if a no deal Brexit looks likely, the chief executive of NHS England has told MPs.

Simon Stevens said that instructions will be issued to hospitals and general practices posthaste if the government’s withdrawal bill is voted down on 11 December.

He was appearing before the health and social care committee on Tuesday 27 November, where …
Effects of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, and free omega-3 carboxylic acids on liver steatosis and hepatocyte damage biomarkers in Type 2 diabetes patients with non-alcoholic fatty liver disease
Authors: Jan Oscarsson, Per Lundkvist, Per-Anders E. Jansson, Lars Johansson, Mats Kvarnström, Linda Moris, Ulf Risérus, Lars Lind, Jan W. Eriksson
Journal: Hepatology (2016)

Effects of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, and free omega-3 carboxylic acids on liver steatosis and hepatocyte damage biomarkers in Type 2 diabetes patients with non-alcoholic fatty liver disease
Interplay of personal, pet, and environmental colonization in households affected by community-associated methicillin-resistant Staphylococcus aureus
Authors: Patrick G. Hogan, Ryan L. Mork, Mary G. Boyle, Carol E. Muenks, John J. Morelli, Ryley M. Thompson, Melanie L. Sullivan, Sarah J. Gehlert, Jessica R. Merlo, Matt G. McKenzie, Juliane Bubeck Wardenburg, Andrey Rzhetsky, Carey-Ann D. Burnham, Stephanie A. Fritz
Journal: Journal of Infection (2018)
Patient-reported barriers for accessing supportive care among patients with metastatic cancer treated at a public cancer center in Mexico.
Authors: Mirza Alcalde Castro, Yanin Chavarri Guerra, Wendy Alicia Ramos-Lopez, Alfredo Covarrubias-Gómez, Sofia Sanchez, Paulina Quiroz, Africa Navarro-Lara, Andrea Medina-Campos, Sergio Contreras-Garduño, María Luisa Moreno-García, Viridiana Pérez-Montessoro, Paul E. Goss, Enrique Soto Perez De Celis
Journal: Journal of Clinical Oncology (2018)

124 Background: Although referral to supportive care (SC) services improves quality of life in patients with cancer, several barriers can hamper access to SC, particularly in developing countries with limited resources. We studied patient-reported barriers for accessing SC in a cancer center in Mexico City, and factors associated with those barriers. Methods: Patients with metastatic cancer enrolled in a randomized clinical trial of patient navigation to improve access to SC in a public cancer center in Mexico City (NCT03293849) were included. At baseline, sociodemographic and clinical characteristics were collected, and patients answered a survey in which they reported barriers to obtain cancer treatment and SC. We analyzed the frequency of reported barriers using descriptive statistics, and explored if sociodemographic factors were associated with a higher likelihood of reporting any barrier. Results: 134 patients were included between 08/17 and 04/18. Median age was 60 years (range 23-93; 51.5% male); 89.5% lived in urban areas; 42.5% had less than high school education; 12% had formal employment; and 27.3% had no insurance coverage. 61% had gastrointestinal, 16 % genitourinary, and 23 % other tumors. Home-to-hospital time was &lt; 2 hours (h) in 60%, 2-6 h in 27%, and ≥6 h in 13%. 47.7% of the patients reported a household income of less than 630 USD/month. The mean number of reported barriers was 1.96 (Standard Deviation 1.77). 78% identified at least one barrier to care, and 35% reported ≥3 barriers (range 1-8). The most commonly reported barriers were: financial burden (47%), beliefs about treatment (28%), lack of transportation (22%), fear (19%), home-to-hospital distance (16%), patient-provider communication (13%), employment (9%), and caregiving for other people (3%). Patients living in rural areas more often reported home-to-hospital distance as a barrier than those living in urban areas (69 vs 11%, p &lt; .01). Conclusions: Most patients with metastatic cancer seen at a cancer center in Mexico identified at least one barrier to cancer care, with some reporting up to 8. Many of the reported barriers are potentially modifiable through patient navigation or SC interventions.
Evaluation of Hospital-Based Hematuria Diagnosis and Subsequent Cancer Risk Among Adults in Denmark
Authors: Mette Nørgaard, Katalin Veres, Anne Gulbech Ording, Jens Christian Djurhuus, Jørgen Bjerggaard Jensen, Henrik Toft Sørensen
Journal: JAMA Network Open (2018)

Data on the long-term risk of urologic and nonurologic cancer after hematuria diagnosis are sparse. Such data can improve understanding of hematuria and cancer and can provide insight into the clinical course of patients with hematuria.To assess the risk of urologic or nonurologic cancer after a hospital-based diagnosis of hematuria.This cohort study used population-based, nationwide health care databases covering all hospitals in Denmark. The data set included records of all adults (n = 134 173) with an inpatient, outpatient, or emergency department diagnosis of hematuria. The study was conducted from January 1, 1995, to December 31, 2013. Follow-up ended on December 31, 2013. Data analysis was performed from January 16, 2017, to September 18, 2018.Cumulative risk of cancer was computed, and observed cancer incidence was compared with incidence expected in the general population, using standardized incidence ratios.Of the 134 173 patients included, 52 367 (39.0%) were women, 81 806 (61.0%) were men, and the median (interquartile range) age was 59 (44-72) years. Within 3 months after hematuria diagnosis, 2647 patients (1.9%) received an invasive bladder cancer diagnosis, 1077 (0.8%) a noninvasive bladder cancer diagnosis, 569 (0.4%) a kidney cancer diagnosis, and 908 (1.1%) a prostate cancer diagnosis. The 3-month cumulative incidence (or absolute risk) of any cancer diagnosis was 4.81% (95% CI, 4.70%-4.93%), the 1-year risk was 6.65% (95% CI, 6.51%-6.78%), and the 5-year risk was 12.34% (95% CI, 12.15%-12.53%). The cumulative incidence of bladder cancer only increased from 1.20% (95% CI, 1.11%-1.30%) after 1 year to 1.36% (95% CI, 1.26%-1.46%) after 5 years of follow-up in women and from 2.93% (95% CI, 2.82%-3.05%) to 3.31% (95% CI, 3.19%-3.44%) in men. For noninvasive bladder cancer, the standardized incidence ratio in the 1 year to less than 5 years of follow-up was 5.39 (95% CI, 4.58-6.30) in patients without initial cystoscopy and was 0.16 (95% CI, 0.04-0.42) in patients with cystoscopy within 3 months after hospital-based diagnosis of hematuria. For kidney cancer, the standardized incidence ratio in the 1 year to less than 5 years of follow-up was 2.63 (95% CI, 2.15-3.18) in patients without cystoscopy and 1.20 (95% CI, 0.87-1.61) in patients with cystoscopy within 3 months after hospital-based diagnosis of hematuria. After 1 year, the risk of gynecologic and colorectal cancers was as expected or even lower, whereas the risk of hematologic malignant neoplasms remained slightly elevated.Increased risk of bladder and kidney cancers even more than 1 year after hospital-based hematuria diagnosis, as well as the slightly elevated risk of invasive bladder cancer after 5 years, may indicate that it is a marker of greater cancer risk; these findings could inform follow-up recommendations for hematuria.
Comparative effectiveness of exercise and drug interventions on mortality outcomes: metaepidemiological study
Authors: H. Naci, J. P. A. Ioannidis
Journal: BMJ (2013)

To determine the comparative effectiveness of exercise versus drug interventions on mortality outcomes.Metaepidemiological study.Meta-analyses of randomised controlled trials with mortality outcomes comparing the effectiveness of exercise and drug interventions with each other or with control (placebo or usual care).Medline and Cochrane Database of Systematic Reviews, May 2013.Mortality.We combined study level death outcomes from exercise and drug trials using random effects network meta-analysis.We included 16 (four exercise and 12 drug) meta-analyses. Incorporating an additional three recent exercise trials, our review collectively included 305 randomised controlled trials with 339,274 participants. Across all four conditions with evidence on the effectiveness of exercise on mortality outcomes (secondary prevention of coronary heart disease, rehabilitation of stroke, treatment of heart failure, prevention of diabetes), 14,716 participants were randomised to physical activity interventions in 57 trials. No statistically detectable differences were evident between exercise and drug interventions in the secondary prevention of coronary heart disease and prediabetes. Physical activity interventions were more effective than drug treatment among patients with stroke (odds ratios, exercise v anticoagulants 0.09, 95% credible intervals 0.01 to 0.70 and exercise v antiplatelets 0.10, 0.01 to 0.62). Diuretics were more effective than exercise in heart failure (exercise v diuretics 4.11, 1.17 to 24.76). Inconsistency between direct and indirect comparisons was not significant.Although limited in quantity, existing randomised trial evidence on exercise interventions suggests that exercise and many drug interventions are often potentially similar in terms of their mortality benefits in the secondary prevention of coronary heart disease, rehabilitation after stroke, treatment of heart failure, and prevention of diabetes.
The functional role of eIF-4E in primary central nervous system lymphoma
Authors: Daisuke Muta, Keishi Makino, Hideo Nakamura, Jun-ichi Kuratsu
Journal: Cancer Research (2008)

3418  Primary central nerve system malignant lymphoma (PCNSL) is defined as a diffuse lymphoma presenting in the brain or spinal cord without systemic lymphoma. The incidence of PCNSL has increased among both immunocompetent and immunodeficient patients, although there are no lymph nodes or lymphatics within the nervous system, the pathogenesis and histogenetic origin of PCNSL is poorly understood. The mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF-4E), plays an important role in mRNA translation and the activity is implicated in cell growth and proliferation. Increased eIF-4E expression has been associated with tumor formation and progression in human malignancies including leukemias, lymphomas and cancers of breast, colon, bladder, lung, prostate, head and neck. We observed the overexpression of eIF-4E and phosphorylated eIF4E, activated form, in the immunohistochemical analysis of the specimens from the PCNSL patients.  In order to examine the participation of eIF4E in PCNSL for molecular biology, we used a cell line derived from human brain malignant lymphoma (HKBML). Western blotting analysis showed that eIF4E was activated in HKBML, but wasn9t inhibited by the inhibitors of MAPK (PD98059) and p38MAPK (SB203580). However, the inhibitor of Mnk-1 (CGP57380) could inhibit the activation of eIF4E. Furthermore, CGP57380 inhibited the cell proliferation of HKBML cells in MTT assay and induced a G1 arrest in cell cycle by flow cytometry.  These data suggested that the activity of eIF-4E in the cell line derived from human brain malignant lymphoma is dependent on Mnk-1. The activated eIF4E may play an important role in cell proliferation in PCNSL.
Rituximab-Bendamustine in First Line Treatment of Patients with Follicular Lymphoma. Results of Prospective Multicenter Study
Authors: Nesterova Ekaterina, Sergey K. Kravchenko, Alla M. Kovrigina, Lubov V. Plastinina, Yana K. Mangasarova, Liliya Gorenkova, Vladimir Vorobyev, Dmitriy Mariin, Elena A. Baryakh, Yuriy Polyakov, Pervin Zeynalova, Elena Volodicheva, Nataliya Glonina, Valeriy G. Savchenko
Journal: Blood (2017)