bluuebunny/crossref_metadata_2025_split huggingface dataset:
Runs of homozygosity and testicular cancer risk
Authors: Loveday C. , Sud A. , Litchfield K. , Levy M. , Holroyd A. , Broderick P. , Kote‐Jarai Z. , Dunning A. M. , Muir K. , Peto J. , Eeles R. , Easton D. F. , Dudakia D. , Orr N. , Pashayan N. ,   UK Testicular Cancer Collaboration,   The PRACTICAL Consortium, Reid A. , Huddart R. A. , Houlston R. S. , Turnbull C. 
Published: July 2019

AbstractBackgroundTesticular germ cell tumour (TGCT) is highly heritable but > 50% of the genetic risk remains unexplained. Epidemiological observation of greater relative risk to brothers of men with TGCT compared to sons has long alluded to recessively acting TGCT genetic susceptibility factors, but to date none have been reported. Runs of homozygosity (RoH) are a signature indicating underlying recessively acting alleles and have been associated with increased risk of other cancer types.ObjectiveTo examine whether RoH are associated with TGCT risk.MethodsWe performed a genome‐wide RoH analysis using GWAS data from 3206 TGCT cases and 7422 controls uniformly genotyped using the OncoArray platform.ResultsGlobal measures of homozygosity were not significantly different between cases and controls, and the frequency of individual consensus RoH was not significantly different between cases and controls, after correction for multiple testing. RoH at three regions, 11p13‐11p14.3, 5q14.1‐5q22.3 and 13q14.11‐13q.14.13, were, however, nominally statistically significant at p < 0.01. Intriguingly, RoH200 at 11p13‐11p14.3 encompasses Wilms tumour 1 (WT1), a recognized cancer susceptibility gene with roles in sex determination and developmental transcriptional regulation, processes repeatedly implicated in TGCT aetiology.Discussion and conclusionOverall, our data do not support a major role in the risk of TGCT for recessively acting alleles acting through homozygosity, as measured by RoH in outbred populations of cases and controls.
A Gramscian Conjuncture in Latin America? Reflections on Violence, Hegemony, and Geographical Difference
Authors: Hesketh Chris 
Published: July 2019

AbstractThis article addresses whether the concepts of Antonio Gramsci still “travel” to Latin America. During the 20thcentury, Gramsci was one of the most important social theorists invoked to understand forms of social order in Latin America, as well as providing resources to reflect upon subaltern culture, resistance and the construction of alternatives. However, over the past two decades there have been several theoretical and practical challenges to the hegemony of Gramsci. These challenges are multifarious, but can be reduced to several important contentions that are explored in this article. These include the enduring role of violence, the alleged decline of ideology and finally the challenge of state‐centrism in the face of geographical difference. In the current regional conjuncture, marked by the return to power of right‐wing social forces, I therefore examine whether Gramscian concepts are still apposite for understanding the political economy of Latin America in the 21stcentury.
Blunted leptin sensitivity during hedonic overeating can be reinstated by activating galanin 2 receptors (Gal2R) in the lateral hypothalamus
Authors: Leidmaa Este , Gazea Mary , Patchev Alexandre V. , Pissioti Anna , Christian Gassen Nils , Kimura Mayumi , Liposits Zsolt , Kallo Imre , Almeida Osborne F. X. 
Published: July 2019

AbstractAimSince foods with high hedonic value are often consumed in excess of energetic needs, this study was designed to identify the mechanisms that may counter anorexigenic signalling in the presence of hedonic foods in lean animals.MethodsMice, in different states of satiety (fed/fasted, or fed/fasted and treated with ghrelin or leptin, respectively), were allowed to choose between high‐fat/high‐sucrose and standard foods. Intake of each food type and the activity of hypothalamic neuropetidergic neurons that regulate appetite were monitored. In some cases, food choice was monitored in leptin‐injected fasted mice that received microinjections of galanin receptor agonists into the lateral hypothalamus.ResultsAppetite‐stimulating orexin neurons in the lateral hypothalamus are rapidly activated when lean, satiated mice consume a highly palatable food (PF); such activation (upregulated c‐Fos expression) occurred even after administration of the anorexigenic hormone leptin and despite intact leptin signalling in the hypothalamus. The ability of leptin to restrain PF eating is restored when a galanin receptor 2 (Gal2R) agonist is injected into the lateral hypothalamus.ConclusionHedonically‐loaded foods interrupt the inhibitory actions of leptin on orexin neurons and interfere with the homeostatic control of feeding. Overeating of palatable foods can be curtailed in lean animals by activating Gal2R in the lateral hypothalamus.
Systematic review with meta‐analysis: risk of new onset IBD with the use of anti‐interleukin‐17 agents
Authors: Yamada Akihiro , Wang Jingzhou , Komaki Yuga , Komaki Fukiko , Micic Dejan , Sakuraba Atsushi 
Published: July 2019

SummaryBackgroundNew onset IBD has been reported with the use of anti‐IL‐17 agents, but it remains unclear to what extent this is attributed to treatment or to underlying disease.AimTo evaluate the risk of new onset IBD with the use of anti‐IL‐17 agentsMethodsElectronic databases were searched for randomised controlled trials (RCT) of anti‐IL‐17 agents (brodalumab, ixekizumab and secukinumab). Risk of new onset IBD was compared to placebo by Mantel‐Haenszel (MH) risk difference (RD). Sensitivity analyses including meta‐analysis using fixed‐effect model, MH and Peto odds ratio and MH risk ratio were performed due to incidence of rare adverse events. The risk of diarrhoea was also assessed due to the possibility of underdiagnosis of IBD.ResultsThirty‐eight RCTs including 16 690 patients treated with anti‐IL‐17 agents were included. Twelve cases of new onset IBD were reported with anti‐IL‐17 agents in five studies, whereas no cases were reported with placebo. There was no difference in the risk of developing new onset IBD with anti‐IL‐17 agents compared to placebo (MH RD 0.00062, 95% CI −0.00072‐0.0021, P = 0.35). Sensitivity analyses demonstrated no consistent risk with any method. There was no difference in the risk of diarrhoea (MH RD 0.0013, 95% CI −0.0014‐0.0041, P = 0.34).ConclusionsNew onset IBD with the use of anti‐IL‐17 agents was rare. Interpretation of the results needs caution due to the presence of many zero‐event studies.
Effects of physically effective fiber in diets based on rice straw and cassava pulp on chewing activity, ruminal fermentation, milk production, and digestibility in dairy cows
Authors: Kaeokliang Ornvimol , Kawashima Tomoyuki , Narmseelee Ramphrai , Butcha Patima , Sunato Supakit , Thinowong Anusorn , Jindatajak Yaungyote 
Published: July 2019

AbstractThe objective of this study was to evaluate the effects of physically effective neutral detergent fiber (peNDF) in rice straw and cassava pulp diets on the chewing activity, ruminal fermentation, milk production, and digestibility in low‐producing dairy cows. Eight lactating Holstein crossbred cows were randomly divided into two groups in a crossover design with two dietary treatments over two 21‐day periods. The difference in peNDF contents was achieved by balancing the ratio of rice straw, cassava pulp, and concentrate. The high cassava pulp diet had 15.5% peNDF and the low cassava pulp diet had 20.2% peNDF. The results showed that feeding the low cassava pulp diet increased the concentrations of milk protein, milk fat, solids‐not‐fat, and total solids in the milk. In contrast, the dry matter intake, milk yield, lactose content, chewing activity, nutrient digestibility, ruminal fermentation, and pH were not affected by treatments.
Comparison of effects of midostaurin, crenolanib, quizartinib, gilteritinib, sorafenib and BLU‐285 on oncogenic mutants of KIT, CBL and FLT3 in haematological malignancies
Authors: Weisberg Ellen , Meng Chengcheng , Case Abigail E. , Sattler Martin , Tiv Hong L. , Gokhale Prafulla C. , Buhrlage Sara J. , Liu Xiaoxi , Yang Jing , Wang Jinhua , Gray Nathanael , Stone Richard M. , Adamia Sophia , Dubreuil Patrice , Letard Sebastien , Griffin James D. 
Published: July 2019

SummaryMutations in two type‐3 receptor tyrosine kinases (RTKs), KIT and FLT3, are common in both acute myeloid leukaemia (AML) and systemic mastocytosis (SM) and lead to hyperactivation of key signalling pathways. A large number of tyrosine kinase inhibitors (TKIs) have been developed that target either FLT3 or KIT and significant clinical benefit has been demonstrated in multiple clinical trials. Given the structural similarity of FLT3 and KIT, it is not surprising that some of these TKIs inhibit both of these receptors. This is typified by midostaurin, which has been approved by the US Food and Drug Administration for mutant FLT3‐positive AML and for KIT D816V‐positive SM. Here, we compare the in vitro activities of the clinically available FLT3 and KIT inhibitors with those of midostaurin against a panel of cells expressing a variety of oncogenic FLT3 or KIT receptors, including wild‐type (wt) FLT3, FLT3‐internal tandem duplication (ITD), FLT3 D835Y, the resistance mutant FLT3‐ITD+ F691L, KIT D816V, and KIT N822K. We also examined the effects of these inhibitors in vitro and in vivo on cells expressing mutations in c‐CBL found in AML that result in hypersensitization of RTKs, such as FLT3 and KIT. The results show a wide spectrum of activity of these various mutations to these clinically available TKIs.
Blood eosinophil count correlates with severity of respiratory failure in life‐threatening asthma and predicts risk of subsequent exacerbations
Authors: Yii Anthony C.A. , Tay Tunn‐Ren , Puah Ser Hon , Lim Hui‐Fang , Li Andrew , Lau Priscilla , Tan Raeann , Neo Lay‐Ping , Chung Kian Fan , Koh Mariko S. 
Published: July 2019

AbstractBackgroundAn elevated blood eosinophil count when asthma is stable predicts exacerbations and therapeutic response to corticosteroids or biologics targeting eosinophils. Few studies have examined the prognostic value of blood eosinophils measured at exacerbation.AimTo elucidate the relationship between a spot blood eosinophil count–measured at the onset of a life‐threatening asthma exacerbation–with indices of exacerbation severity and risk of subsequent exacerbations.MethodsReal‐world, retrospective review of all life‐threatening asthma cases admitted at 4 public hospitals in Singapore between 2011‐2015. We assessed the trends and correlations between blood eosinophil count on admission with arterial blood gas values, duration of mechanical ventilation, and risk of death, hypoxic ischemic encephalopathy or respiratory arrest. Risk of future exacerbations among survivors was modelled using Cox regression and survival curves.ResultsThere were 376 index life‐threatening exacerbations with median blood eosinophil count (5‐95th percentiles) of 0.270 × 109/L (0‐1.410 × 109/L). Arterial pH decreased and PCO2 increased with increasing eosinophil count. Duration of mechanical ventilation and risk of death, hypoxic ischaemic encephalopathy or respiratory arrest did not vary with eosinophils. Among 329 survivors who were followed‐up over a median of 52 months, blood eosinophils ≥1.200 × 109/L was associated with an increased hazard of emergency visits and/or admissions for asthma (hazard ratio 1.8, 95% confidence interval 1.1‐2.9, P = .02).ConclusionIn this study of life‐threatening asthma, we found that a spot blood eosinophil count correlates with severity of respiratory failure and predicts risk of subsequent exacerbations.
Heterozygous CTNNB1 and TBX4 variants in a patient with abnormal lung growth, pulmonary hypertension, microcephaly, and spasticity
Authors: Karolak Justyna A. , Szafranski Przemyslaw , Kilner David , Patel Chirag , Scurry Bonnie , Kinning Esther , Chandler Kate , Jhangiani Shalini N. , Coban Akdemir Zeynep H. , Lupski James R. , Popek Edwina , Stankiewicz Paweł 
Published: July 2019

AbstractThe canonical wingless (Wnt) and fibroblast growth factor (FGF) signaling pathways involving CTNNB1 and TBX4, respectively, are crucial for the regulation of human development. Perturbations of these pathways and disruptions from biological homeostasis have been associated with abnormal morphogenesis of multiple organs, including the lung. The aim of this study was to identify the underlying genetic cause of abnormal lung growth, pulmonary hypertension (PAH), severe microcephaly, and muscle spasticity in a full‐term newborn, who died at 4 months of age due to progressively worsening PAH and respiratory failure. Family trio exome sequencing showed a de novo heterozygous nonsense c.1603C>T (p.Arg535*) variant in CTNNB1 and a paternally inherited heterozygous missense c.1198G>A (p.Glu400Lys) variant in TBX4, both predicted to be likely deleterious. We expand the phenotypic spectrum associated with CTNNB1 and TBX4 variants and indicate that they could act synergistically to produce a distinct more severe phenotype. Our findings further support a recently proposed complex compound inheritance model in lethal lung developmental diseases and the contention that dual molecular diagnoses can parsimoniously explain blended phenotypes.
Prednisone‐free maintenance immunosuppression in obese kidney transplant recipients
Authors: Matas Arthur J. , Vock David M. 
Published: July 2019

AbstractObese transplant recipients (BMI ≥ 30 kg/m2) have decreased posttransplant patient and graft survival compared with their nonobese counterparts. At the same time, many prednisone‐related side effects (eg, new‐onset diabetes) are similar to those associated with obesity. Using SRTR data, we studied outcomes associated with prednisone‐free maintenance immunosuppression (rapid discontinuation of prednisone—RDP). Between January 1, 2000, and December 31, 2014, 44 635 first transplant recipients with BMI ≥ 30 kg/m2 had a first kidney transplant (28 176 DD; 16 459, LD); 12,994 (29%) were discharged from the hospital on a prednisone‐free protocol. We compared outcomes to those discharged on a protocol incorporating maintenance prednisone (intention‐to‐treat analysis). RDP‐treated obese first DD recipients had significantly better patient survival (HR, 0.88; CI, 0.81‐0.96) and graft survival (HR, 0.93; CI, 0.88‐0.99) compared with their counterparts on maintenance immunosuppression. Although not statistically significant, the same trends were seen for LD recipients. For both DD and LD recipients, there was no difference between groups for death‐censored graft survival, suggesting that the benefit of RDP was due to improved patient survival. Our findings suggest that kidney transplant recipients with BMI ≥ 30 kg/m2 benefit from a protocol that incorporates RDP.
Differentiation between duodenal neoplasms and non‐neoplasms using magnifying narrow‐band imaging – Do we still need biopsies for duodenal lesions?
Authors: Yamasaki Yasushi , Takeuchi Yoji , Kanesaka Takashi , Kanzaki Hiromitsu , Kato Minoru , Ohmori Masayasu , Tonai Yusuke , Hamada Kenta , Matsuura Noriko , Iwatsubo Taro , Akasaka Tomofumi , Hanaoka Noboru , Higashino Koji , Uedo Noriya , Ishihara Ryu , Okada Hiroyuki , Iishi Hiroyasu 
Published: July 2019

ObjectivesEndoscopic biopsies for nonampullary duodenal epithelial neoplasms (NADENs) can induce submucosal fibrosis, making endoscopic resection difficult. However, no biopsy‐free method exists to distinguish between NADENs and non‐neoplasms. We developed a diagnostic algorithm for duodenal neoplasms based on magnifying endoscopy findings and evaluated the model's diagnostic ability.MethodsMagnified endoscopic images and duodenal lesion histology were collected consecutively between January 2015 and April 2016. Diagnosticians classified the surface patterns as pit, groove or absent. In cases of nonvisible surface patterns, the vascular pattern was evaluated to determine regularity or irregularity. The correlation between our algorithm (pit‐type or absent with irregular vascular pattern) and the lesion histology were evaluated. Four evaluators, who were blinded to the histology, also classified the endoscopic findings and evaluated the diagnostic performance and interobserver agreement.ResultsEndoscopic images of 114 lesions were evaluated (70 NADENs and 44 non‐neoplasms, 31 in the superior and 83 in the descending and horizontal duodenum). Of the NADEN surface patterns, 88% (62/70) were pit‐type, while 79% (35/44) of the non‐neoplasm surface patterns were groove‐type. Our diagnostic algorithm for differentiating NADENs from non‐neoplasms was high (sensitivity 96%, specificity 95%) in the descending and horizontal duodenum. The evaluators’ diagnostic performances were also high, and interobserver agreement for the algorithm was good between each diagnostician and evaluator (κ = 0.60–0.76).ConclusionDiagnostic performance of our algorithm sufficiently enabled eliminating endoscopic biopsies for diagnosing the descending and horizontal duodenum.
Adaptive functional reorganization in amyotrophic lateral sclerosis: coexisting degenerative and compensatory changes
Authors: Abidi M. , de Marco G. , Couillandre A. , Feron M. , Mseddi E. , Termoz N. , Querin G. , Pradat P. ‐F. , Bede P. 
Published: July 2019

Background and purposeConsiderable functional reorganization takes place in amyotrophic lateral sclerosis (ALS) in face of relentless structural degeneration. This study evaluates functional adaptation in ALS patients with lower motor neuron predominant (LMNp) and upper motor neuron predominant (UMNp) dysfunction.MethodsSeventeen LMNp ALS patients, 14 UMNp ALS patients and 14 controls participated in a functional magnetic resonance imaging study. Study‐group‐specific activation patterns were evaluated during preparation for a motor task. Connectivity analyses were carried out using the supplementary motor area (SMA), cerebellum and striatum as seed regions and correlations were explored with clinical measures.ResultsIncreased cerebellar, decreased dorsolateral prefrontal cortex and decreased SMA activation were detected in UMNp patients compared to controls. Increased cerebellar activation was also detected in UMNp patients compared to LMNp patients. UMNp patients exhibit increased effective connectivity between the cerebellum and caudate, and decreased connectivity between the SMA and caudate and between the SMA and cerebellum when performing self‐initiated movement. In UMNp patients, a positive correlation was detected between clinical variables and striato‐cerebellar connectivity.ConclusionsOur findings indicate that, despite the dysfunction of SMA–striatal and SMA–cerebellar networks, cerebello‐striatal connectivity increases in ALS indicative of compensatory processes. The coexistence of circuits with decreased and increased connectivity suggests concomitant neurodegenerative and adaptive changes in ALS.
In situ antioxidant activity of a dermo‐cosmetic product: A randomized controlled clinical study
Authors: Ribet Virginie , Nobile Vincenzo , Rossi Ana Beatris 
Published: July 2019

AbstractUltraviolet light enhances the generation of reactive oxygen species that are responsible for skin photoageing. The aim of this randomized, vehicle‐ and active‐controlled double‐blind, intra‐individual monocentric study was to evaluate in situ the antioxidant activity of a dermo‐cosmetic product in photoaged skin. Twenty healthy volunteers had defined skin areas randomized to receive a topical product containing 3 antioxidants (pre‐tocopheryl®, retinaldehyde and glycylglycine ole‐amide), its vehicle and a positive antioxidant control cream. The products were applied daily for 30‐day period. The skin areas were exposed to a controlled dose of UVA rays, and the skin oxidative status was evaluated 4 and 24 hours post‐UVA exposure at D0 (basal value) and after 15 and 30 days of product application. Skin layers were collected by stripping, and antioxidant capacity was measured using the ferric reducing ability of a plasma assay. Lipid peroxidation (LPO) was assessed using the malonyldialdehyde test. The tested product significantly improved the skin antioxidant capacity after 15 and 30 days and significantly decreased the basal level of the skin LPO. The skin LPO level significantly decreased 4 and 24 hours after UVA exposure at 15 and 30 days. These findings were comparable to positive control treated sites and were significantly different from the vehicle and untreated sites. This minimally invasive methodology enabled a quantitative evaluation of potent antioxidant activity in situ in the stratum corneum reflecting real‐life skin conditions and confirming the benefits of the topical application of a product containing 3 antioxidants in the prevention of UVA‐induced oxidative damage.
Seborrheic dermatitis—Looking beyond Malassezia
Authors: Wikramanayake Tongyu C. , Borda Luis J. , Miteva Mariya , Paus Ralf 
Published: July 2019

AbstractSeborrhoeic Dermatitis (SD) is a very common chronic and/or relapsing inflammatory skin disorder whose pathophysiology remains poorly understood. Yeast of the genus Malassezia has long been regarded as a main predisposing factor, even though causal relationship has not been firmly established. Additional predisposing factors have been described, including sebaceous activity, host immunity (especially HIV infection), epidermal barrier integrity, skin microbiota, endocrine and neurologic factors, and environmental influences. Genetic studies in humans and mouse models—with particularly interesting insights from examining the Mpzl3 knockout mice and their SD‐like skin phenotype, and patients carrying a ZNF750 mutation—highlight defects in host immunity, epidermal barrier and sebaceous activity. After synthesizing key evidence from the literature, we propose that intrinsic host factors, such as changes in the amount or composition of sebum and/or defective epidermal barrier, rather than Malassezia, may form the basis of SD pathobiology. We argue that these intrinsic changes provide favourable conditions for the commensal Malassezia to over‐colonize and elicit host inflammatory response. Aberrant host immune activity or failure to clear skin microbes may bypass the initial epidermal or sebaceous abnormalities. We delineate specific future clinical investigations, complemented by studies in suitable SD animal models, that dissect the roles of different epidermal compartments and immune components as well as their crosstalk and interactions with the skin microbiota during the process of SD. This research perspective beyond the conventional Malassezia‐centric view of SD pathogenesis is expected to enable the development of better therapeutic interventions for the management of recurrent SD.