bluuebunny/crossref_metadata_2025_split huggingface dataset:
miRNA profiling in renal carcinoma suggest the existence of a group of pro-angionenic tumors in localized clear cell renal carcinoma
Authors: Trilla-Fuertes Lucía , Miranda Natalia , Castellano Daniel , López-Vacas Rocío , Farfán Tello Carlos A. , de Velasco Guillermo , Villacampa Felipe , López-Camacho Elena , Prado-Vázquez Guillermo , Zapater-Moros Andrea , Espinosa Enrique , Vara Juan Ángel Fresno , Pinto Álvaro , Gámez-Pozo Angelo 
Published: December 2019

AbstractRenal cell carcinoma comprises a variety of entities, the most common being the clear-cell, papillary and chromophobe subtypes. These subtypes are related to different clinical evolution; however, most therapies have been developed for clear-cell carcinoma and there is not a specific treatment based on different subtypes. In this study, one hundred and sixty-four paraffin samples from primary nephrectomies for localized tumors were analyzed. MiRNAs were isolated and measured by microRNA arrays. Significance Analysis of Microarrays and Consensus Cluster algorithm were used to characterize different renal subtypes. The analyses showed that chromophobe renal tumors are a homogeneous group characterized by an overexpression of miR 1229, miR 10a, miR 182, miR 1208, miR 222, miR 221, miR 891b, miR 629-5p and miR 221-5p. On the other hand, clear cell renal carcinomas presented two different groups inside this histological subtype, with differences in miRNAs that regulate focal adhesion, transcription, apoptosis and angiogenesis processes. Specifically, one of the defined groups had an overexpression of proangiogenic microRNAs miR185, miR126 and miR130a. In conclusion, differences in miRNA expression profiles between histological renal subtypes were established. In addition, clear cell renal carcinomas had different expression of proangiogenic miRNAs. With the emergence of antiangiogenic drugs, these differences could be used as therapeutic targets in the future or as a selection method for tailoring personalized treatments.
Patient-derived ovarian cancer organoids mimic clinical response and exhibit heterogeneous inter- and intrapatient drug responses
Authors: de Witte Chris J. , Valle-Inclan Jose Espejo , Hami Nizar , Lõhmussaar Kadi , Kopper Oded , Vreuls Celien P.H. , Jonges Trudy N. , van Diest Paul , Nguyen Luan , Clevers Hans , Kloosterman Wigard P. , Cuppen Edwin , Snippert Hugo J.G. , Zweemer Ronald P. , Witteveen Petronella O. , Stelloo Ellen 
Published: December 2019

AbstractPurposeThere remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Recently, patient-derived organoid (PDO) cultures of patients with OC have been established that faithfully represent the histopathological features and genomic landscape of the patient tumor. In this study, we evaluate the capacity of OC PDOs to predict clinical drug response and functional consequences of tumor heterogeneity.Experimental design36 genomically characterized PDOs from 23 patients with known clinical histories were exposed to chemotherapeutics and targeted drugs.ResultsOC PDOs maintained genomic features of the original tumor lesion and recapitulated patient response to neoadjuvant carboplatin and paclitaxel combination treatment, according to distinct clinical outcomes (histopathological, biochemical and radiological). PDOs displayed inter-as well as intrapatient drug response heterogeneity, which could in part be explained by genetic aberrations. All PDOs were resistant to PARP-inhibitors, in accordance with homologous recombination pathway fidelity and genome-wide mutation context. KRAS, BRAF and NRAS mutation status predicted response to BRAF-inhibitor vemurafenib and pan-HER-inhibitor afatinib, and explained differential response among four PDOs derived from distinct tumor locations of an individual patient. Importantly, PDO drug screening identified sensitivity to at least one drug for the majority of patients (88%).ConclusionsOC PDOs are a valuable preclinical model system that can provide insights in drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge on genetic and drug response heterogeneity.
Biological age in UK Biobank: biomarker composition and prediction of mortality, coronary heart disease and hospital admissions
Authors: Chan Mei Sum , Arnold Matthew , Offer Alison , Hammami Imen , Mafham Marion , Armitage Jane , Perera Rafael , Parish Sarah 
Published: December 2019

AbstractBackgroundAge is the strongest risk factor for most chronic diseases, and yet individuals may age at different rates biologically. A biological age formed from biomarkers may be a stronger risk factor than chronological age and understanding what factors contribute to it could provide insight into new opportunities for disease prevention.Methods and findingsAmong 480,019 UK Biobank participants aged 40-70 recruited in 2006-2010 and followed up for 6-12 years via linked death registry and secondary care records, a subpopulation of 141,254 (29.4%) non-smoking adults in good health and with no medication use or disease history at baseline were identified. Independent components of 72 biomarkers measured at baseline were characterised by principal component analysis. The Klemera Doubal method (KDM), which derived a weighted sum of biomarker principal components based on the strengths of their linear associations with chronological age, was used to derive sex-specific biological ages in this healthy subpopulation. The proportions of the overall biological and chronological age effects on mortality, coronary heart disease and age-related non-fatal hospital admissions (based on a hospital frailty index) that were explained by biological age were assessed using log-likelihoods of proportional hazards models.Reduced lung function, reduced kidney function, slower reaction time, lower insulin-like-growth factor 1, lower hand grip strength and higher blood pressure were key contributors to biological age (explaining the highest percentages of its variance) in both men and women, while lower albumin, higher sex hormone-binding globulin and lower muscle mass in men, and higher liver enzymes, blood lipids and HbA1c in women were also important. Across both sexes, a 51-principal component biological age explained 66%, 80% and 63% of the age effects on mortality, coronary heart disease and hospital admissions, respectively. Restricting the biological age to the 12-13 key biomarkers corresponding to the 10 most importantly contributing principal components resulted in little change in these proportions for women, but a reduction to 53%, 63% and 50%, respectively, for men.ConclusionsThis study identified that markers of impaired function in a range of organs account for a substantial proportion of the apparent effect of age on disease and hospital admissions. It supports a broader, multi-system approach to research and prevention of diseases of ageing.
Post-Exertional Malaise in People with Chronic Cancer-Related Fatigue
Authors: Twomey Rosie , Yeung Samuel T. , Wrightson James G. , Millet Guillaume Y. , Culos-Reed S. Nicole 
Published: December 2019

AbstractContextCancer-related fatigue (CRF) is a distressing and persistent sense of tiredness or exhaustion that interferes with usual functioning. Chronic CRF continues for months after curative cancer treatment is complete. Post-exertional malaise (PEM) is a worsening of symptoms after physical or mental activity, with limited investigations in people with chronic CRF.ObjectivesThe purpose of this study was to identify and describe self-reported incidences of PEM in people with chronic CRF.MethodsParticipants (n=18) were eligible if they scored ≤34 on the Functional Assessment of Chronic Illness Therapy-Fatigue scale and had a cancer-related onset of fatigue. Participants completed a brief questionnaire to assess PEM over a 6-month time-frame (the DePaul Symptom Questionnaire – Post-Exertional Malaise; DSQ-PEM). In addition, a maximal exercise test was used to investigate self-reported symptom exacerbation (via an open-ended questionnaire) after strenuous physical exertion.ResultsOn the DSQ-PEM, three participants met previously defined scoring criteria, which included experiencing moderate to very severe symptoms at least half of the time, worsening of fatigue after minimal effort, plus a recovery duration of >24 h. Content analysis of responses to open-ended questionnaires identified five people who experienced a delayed recovery and symptoms of PEM after maximal exercise.ConclusionA subset of people with chronic CRF (up to 33% in this sample) may experience PEM. Exercise specialists and health care professionals working with people with chronic CRF must be aware that PEM may be an issue. Symptom exacerbation after exercise should be monitored, and exercise should be tailored and adapted to limit the potential for harm.Key messageThis study provides preliminary evidence that a subset of people with chronic cancer-related fatigue experience post-exertional malaise.
Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease
Authors: Vallabh Sonia M , Minikel Eric Vallabh , Williams Victoria J , Carlyle Becky C , McManus Alison J , Wennick Chase D , Bolling Anna , Trombetta Bianca A , Urick David , Nobuhara Chloe K , Gerber Jessica , Duddy Holly , Lachmann Ingolf , Stehmann Christiane , Collins Steven J , Blennow Kaj , Zetterberg Henrik , Arnold Steven E 
Published: December 2019

ABSTRACTBACKGROUNDFluid biomarkers are important in the development of therapeutics to delay or prevent prion disease, but have not been systematically evaluated in pre-symptomatic individuals at risk for genetic prion disease.METHODSWe recruited pre-symptomatic individuals with pathogenic mutations in the prion protein gene (PRNP; N=27) and matched controls (N=16), to donate cerebrospinal fluid (CSF) and blood at multiple timepoints to a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF, and the neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in both CSF and plasma. We compared these markers cross-sectionally between mutation carriers and controls, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months for a subset of participants.FINDINGSCSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% both over 2-4 months in N=29 participants and over 10-20 months in N=10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with others, though still within the normal range, and remained asymptomatic one year later. Overall, tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.INTERPRETATIONCSF PrP will be interpretable as a pharmacodynamic readout of the effects of a PrP-lowering therapeutic in pre-symptomatic individuals, and may serve as a surrogate biomarker in a “primary prevention” trial paradigm. In contrast, current markers of prion seeding activity and of neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls, arguing against the feasibility of a “secondary prevention” paradigm in which trials specifically recruit pre-symptomatic participants with prodromal evidence of pathology.
All-cause mortality and causes of death in the Swiss Hepatitis C Cohort Study
Authors: Roelens Maroussia , Bertisch Barbara , Moradpour Darius , Cerny Andreas , Semmo Nasser , Schmid Patrick , Müllhaupt Beat , Clerc Olivier , Semela David , Junker Christoph , Negro Francesco , Keiser Olivia ,   for the Swiss Hepatitis C Cohort Study
Published: December 2019

AbstractBackground & AimsWith the introduction of direct-acting antiviral agents (DAA), mortality rates and causes of death among persons with hepatitis C virus (HCV) infection are likely to change over time. However, the emergence of such trends may be delayed by the relatively slow progression of chronic hepatitis C. To date, detailed analyses of cause-specific mortality among HCV-infected persons over time remain limited.MethodsWe evaluated changes in causes of death among the Swiss Hepatitis C Cohort Study (SCCS) participants, from 2008 to 2016. We analysed risk factors for all-cause and cause-specific mortality, accounting for changes in treatment, fibrosis stage and use of injectable drugs over time. Mortality ascertainment was completed by linking lost-to-follow-up participants to the Swiss Federal Statistical Office (SFSO) death registry.ResultsWe included 4,700 SCCS participants, of whom 478 died between 2008 and 2016. Linkage to the SFSO death registry substantially improved the information on causes of death (from 42% of deaths with unknown cause to 10% after linkage). Leading causes of death were liver failure (crude death rate 4.4/1000 person-years), liver cancer (3.4/1000 p-yrs) and non-liver cancer (2.8/1000 p-yrs), with an increasing proportion of cancer-related deaths over time. Cause-specific analysis showed that persons with sustained virologic response (SVR) were less at risk for liver-related mortality than those never treated or treated unsuccessfully.ConclusionsAlthough the expected decrease in mortality is not yet observable, causes of death among HCV-infected persons evolved over time. With the progressive widening of guidelines for DAA use, liver-related mortality is expected to decline in the future. Continued monitoring of cause-specific mortality will remain important to assess the long-term effect of DAA and to design effective interventions.Lay summaryLeading causes of death among persons with hepatitis C virus (HCV) infection in the Swiss Hepatitis C Cohort study evolved over the past years, with an increasing proportion of cancer-related deaths. The positive impact of new potent anti-HCV drugs on mortality among HCV-infected persons is not yet observable, due to both the slow progression of chronic hepatitis C and the progressive relaxation of guidelines for the use of those new drugs.
Disease progression modeling in Alzheimer’s disease: insights from the shape of cognitive decline
Authors: Raket Lars Lau ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2019

AbstractBackgroundThe characterizing symptom of Alzheimer disease (AD) is cognitive deterioration. While much recent work has focused on defining AD as a biological construct, most patients are still diagnosed, staged, and treated based on their cognitive symptoms. But the cognitive capability of a patient at any time throughout this deterioration will not directly reflect the disease state, but rather the effect of the cognitive decline on the patient’s predisease cognitive capability. Patients with high predisease cognitive capabilities tend to score better on cognitive tests relative to patients with low predisease cognitive capabilities at the same disease stage. Thus, a single assessment with a cognitive test is not adequate for determining the stage of an AD patient.Methods and FindingsI developed a joint statistical model that explicitly modeled disease stage, baseline cognition, and the patients’ individual changes in cognitive ability as latent variables. The developed model takes the form of a nonlinear mixed-effects model. Maximum-likelihood estimation in this model induces a data-driven criterion for separating disease progression and baseline cognition. Applied to data from the Alzheimer’s Disease Neuroimaging Initiative, the model estimated a timeline of cognitive decline in AD that spans approximately 15 years from the earliest subjective cognitive deficits to severe AD dementia. It was demonstrated how direct modeling of latent factors that modify the observed data patterns provide a scaffold for understanding disease progression, biomarkers and treatment effects along the continuous time progression of disease.ConclusionsThe suggested framework enables direct interpretations of factors that modify cognitive decline. The results give new insights to the value of biomarkers for staging patients and suggest alternative explanations for previous findings related to accelerated cognitive decline among highly educated patients and patients on symptomatic treatments.
Clinical validity of expanded carrier screening: evaluating the gene-disease relationship in more than 200 conditions
Authors: Balzotti Marie , Meng Linyan , Muzzey Dale , Taber Katherine Johansen , Beauchamp Kyle ,   Myriad Genetics Curation Team,   Baylor Genetics Curation Team, Mar-Heyming Rebecca , Buckley Bethany , Moyer Krista 
Published: December 2019

AbstractObjectiveClinical guidelines consider expanded carrier screening (ECS) to be an acceptable method of carrier screening. However, broader guideline support and payer adoption require evidence for associations between the genes on ECS panels and the conditions for which they aim to identify carriers. We applied a standardized framework for evaluation of gene-disease association to assess the clinical validity of conditions screened by ECS panels.MethodsThe ClinGen gene curation framework was used to assess genetic and experimental evidence of associations between 208 genes and conditions screened on two commercial ECS panels. Twenty-one conditions were previously classified by ClinGen, and the remaining 187 were evaluated by curation teams at two laboratories. To ensure consistent application of the framework across the laboratories, concordance was evaluated on a subset of conditions.ResultsAll 208 evaluated conditions met the evidence threshold for supporting a gene-disease association. Furthermore, 203 of 208 (98%) achieved the strongest (“Definitive”) level of gene-disease association. All conditions evaluated by both commercial laboratories were similarly classified.ConclusionAssessment using the ClinGen standardized framework revealed strong evidence of gene-disease association for conditions on two ECS panels. This result establishes the disease-level clinical validity of the panels considered herein.
OASIS-3: Longitudinal Neuroimaging, Clinical, and Cognitive Dataset for Normal Aging and Alzheimer Disease
Authors: LaMontagne Pamela J. , Benzinger Tammie LS. , Morris John C. , Keefe Sarah , Hornbeck Russ , Xiong Chengjie , Grant Elizabeth , Hassenstab Jason , Moulder Krista , Vlassenko Andrei G. , Raichle Marcus E. , Cruchaga Carlos , Marcus Daniel 
Published: December 2019

ABSTRACTOASIS-3 is a compilation of MRI and PET imaging and related clinical data for 1098 participants who were collected across several ongoing studies in the Washington University Knight Alzheimer Disease Research Center over the course of 15 years. Participants include 605 cognitively normal adults and 493 individuals at various stages of cognitive decline ranging in age from 42 to 95 years. The OASIS-3 dataset contains over 2000 MR sessions, including multiple structural and functional sequences. PET metabolic and amyloid imaging includes over 1500 raw imaging scans and the accompanying post-processed files from the PET Unified Pipeline (PUP) are also available in OASIS-3. OASIS-3 also contains post-processed imaging data such as volumetric segmentations and PET analyses. Imaging data is accompanied by dementia and APOE status and longitudinal clinical and cognitive outcomes. OASIS-3 is available as an open access data set to the scientific community to answer questions related to healthy aging and dementia.
Blimp-1 in adipose resident Tregs controls adipocyte beiging and obesity
Authors: Beppu Lisa Y. , Qu Xiaoyao , Marrero Giovanni J. , Fooks Allen N. , Frias Adolfo B. , Helfrich Katherine E. , Sipula Ian , Xie Bingxian , Watkins Simon C. , Poholek Amanda C. , Jurczak Michael J. , D’Cruz Louise M. 
Published: December 2019

ABSTRACTCrosstalk between the immune system and adipocytes is critical for maintaining tissue homeostasis and regulating chronic systemic inflammation during diet-induced obesity (DIO). How visceral adipose tissue resident regulatory T cells (aTregs) signal to adipocytes in the visceral adipose tissue (VAT) is not understood. Here we show that Treg-specific ablation of the transcriptional regulator Blimp-1 resulted in increased insulin sensitivity, decreased body weight and increased Ucp-1 in adipocytes in high fat diet (HFD)-fed mice. Mechanistically, we demonstrate that Blimp-1 drives IL-10 production in Tregs, thus suppressing beiging and energy expenditure in adipocytes. Moreover, IL-10 mRNA expression positively correlated with increasing body weight in humans. These findings reveal a surprising relationship between aTregs and adipocytes in promoting insulin resistance during excessive caloric intake, placing Blimp-1-regulated IL-10 expression by aTregs at a critical juncture in the development of obesity and its associated comorbidities in mice and humans.SUMMARYHere we show that ablation of Blimp-1 in adipose tissue resident Tregs (aTregs) leads to decreased IL-10 production, resulting in increased Ucp-1 expression and beiging by adipocytes and protection from diet-induced obesity and insulin resistance.
Dual blockade of IL‐4 and IL‐13 with dupilumab, an IL‐4Rα antibody, is required to broadly inhibit type 2 inflammation
Authors: Le Floc’h Audrey , Allinne Jeanne , Nagashima Kirsten , Scott George , Birchard Dylan , Asrat Seblewongel , Bai Yu , Lim Wei Keat , Martin Joel , Huang Tammy , Potocky Terra B. , Kim Jee H. , Rafique Ashique , Papadopoulos Nicholas J. , Stahl Neil , Yancopoulos George D. , Murphy Andrew J. , Sleeman Matthew A. , Orengo Jamie M. 
Published: December 2019

AbstractBackgroundDupilumab, a fully human monoclonal antibody that binds IL‐4Rα and inhibits signaling of both IL‐4 and IL‐13, has shown efficacy across multiple diseases with underlying type 2 signatures and is approved for treatment of asthma, atopic dermatitis, and chronic sinusitis with nasal polyposis. We sought to provide a comprehensive analysis of the redundant and distinct roles of IL‐4 and IL‐13 in type 2 inflammation and report dupilumab mechanisms of action.MethodsUsing primary cell assays and a mouse model of house dust mite–induced asthma, we compared IL‐4 vs IL‐13 vs IL‐4Rα blockers.ResultsIntranasal administration of either IL‐4 or IL‐13 confers an asthma‐like phenotype in mice by inducing immune cell lung infiltration, including eosinophils, increasing cytokine/chemokine expression and mucus production, thus demonstrating redundant functions of these cytokines. We further teased out their respective contributions using human in vitro culture systems. Then, in a mouse asthma model by comparing in head‐to‐head studies, either IL‐4 or IL‐13 inhibition to dual IL‐4/IL‐13 inhibition, we demonstrate that blockade of both IL‐4 and IL‐13 is required to broadly block type 2 inflammation, which translates to protection from allergen‐induced lung function impairment. Notably, only dual IL‐4/IL‐13 blockade prevented eosinophil infiltration into lung tissue without affecting circulating eosinophils, demonstrating that tissue, but not circulating eosinophils, contributes to disease pathology.ConclusionsOverall, these data support IL‐4 and IL‐13 as key drivers of type 2 inflammation and help provide insight into the therapeutic mechanism of dupilumab, a dual IL‐4/IL‐13 blocker, in multiple type 2 diseases.