bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extracellular Hsp90α, which participates in vascular inflammation, is a novel serum predictor of atherosclerosis in type 2 diabetes
Authors: Ding Xinyi , Meng Chuzhen , Dong Hangming , Zhang Shili , Zhou Hui , Tan Wenchong , Huang Lei , He Aiping , Li Jieyou , Huang Jiali , Li Wei , Zou Fei , Zou MengChen 
Published: January 2022

IntroductionAtherosclerosis is the main pathological change in diabetic angiopathy, and vascular inflammation plays an important role in early atherosclerosis. Extracellular heat shock protein 90 (eHsp90) is secreted into the serum and is involved in various physiological and pathophysiological processes. However, the specific mechanism of eHsp90 in early atherosclerosis remains unclear. This study explored the relationship between Hsp90 and diabetic lower extremity arterial disease and investigated the expression of eHsp90 in vascular endothelial cells under environmental stimulation and the function and mechanism of eHsp90α involved in diabetic atherosclerosis.Research design and methodsOne hundred and three selected patients were divided into three groups: the diabetes mellitus group (n=27), the diabetic lower extremity arterial disease group (n=46), and the diabetic critical limb ischemia group (n=30). The relationships among serum Hsp90, oxidative stress indexes, and patient outcomes and the correlations among the indexes were analyzed. H&E staining and immunohistochemistry were used to observe the vasculature of amputated feet from patients with diabetic foot. An oxidative stress endothelial injury model was established under high glucose in vitro to explore the role of eHsp90 release in atherosclerosis progression.ResultsThe level of serum Hsp90 was upregulated with aggravation of diabetic vascular disease. Hsp90α was correlated with malondialdehyde to some extent and was an independent risk factor in the progression of diabetic vascular disease, with predictive ability. The expression area of Hsp90α was consistent with the area of inflammatory infiltration in the vessel lumen. Vascular endothelial cells were found to increase eHsp90α secretion under stress. Then inhibition of eHsp90α can reduce the degree of cellular inflammation and damage. Endothelial cell-conditioned medium and recombinant human Hsp90α increased monocyte migration via the low-denisity lipoprotein receptor-related protein 1 (LRP1) receptor to promote disease progression.ConclusionseHsp90α plays a critical role in the early inflammatory injury stage of atherosclerosis.Trial registration numberNCT04787770.
Application of liquid biopsy-based targeted capture sequencing analysis to improve the precision treatment of non-small cell lung cancer by tyrosine kinase inhibitors
Authors: Zhang Lei , Coffin John , Formenti Kim , Chu Quincy , Izevbaye Iyare 
Published: January 2022

BackgroundTargeted therapy of patients with non-small cell lung cancer (NSCLC) who harbour sensitising mutations by tyrosine kinase inhibitors (TKIs) has been found more effective than traditional chemotherapies. However, target genes status (eg, epidermal growth factor receptor (EGFR) TKIs sensitising and resistant mutations) need to be tested for choosing appropriate TKIs. This study is to investigate the performance of a liquid biopsy-based targeted capture sequencing assay on the molecular analysis of NSCLC.MethodsPlasma samples from patients with NSCLC who showed resistance to the first/second-generationEGFRTKIs treatment were collected. The AVENIO ctDNA Expanded Kit is a 77 pan-cancer genes detection assay that was used for detectingEGFRTKIs resistance-associated gene mutations. Through comparison of theEGFRgene testing results from the CobasEGFRMutation Test v2, and UltraSEEK Lung Panel, the effectiveness of the targeted capture sequencing assay was verified.ResultsA total of 24 plasma cell-free DNA (cfDNA) samples were tested by the targeted capture sequencing assay. 33.3% (8/24) cfDNA samples were positive forEGFRexon 20 p.T790M which leads toEGFRdependent TKIs resistance. 8.3% (2/24) and 4.2% (1/24) samples were positive for mesenchymal-epithelial transition gene amplification and B‐Raf proto‐oncogene, serine/threonine kinase exon 15 p.V600E mutations which lead toEGFRindependent TKIs resistance. The median value of the p.T790M variant allele fraction and variant copy numbers was 2% and 36.10 copies/mL plasma, respectively. The next-generation sequencing test showed higher than 90% concordance with either MassArray or qPCR-based methods for detecting eitherEGFRTKIs sensitising or resistance mutations.ConclusionThe targeted capture sequencing test can support comprehensive molecular analysis needed for TKIs treatment, which is promising to be clinically applied for the improved precision treatment of NSCLC.
Toll-like receptor 8 agonists improve NK-cell function primarily targeting CD56brightCD16−subset
Authors: Veneziani Irene , Alicata Claudia , Pelosi Andrea , Landolina Nadine , Ricci Biancamaria , D'Oria Valentina , Fagotti Anna , Scambia Giovanni , Moretta Lorenzo , Maggi Enrico 
Published: January 2022

BackgroundToll-like receptors (TLRs) are pattern-recognition sensors mainly expressed in innate immune cells that directly recognize conserved pathogen structures (pathogen-associated molecular patterns-PAMPs). Natural killer (NK) cells have been described to express different endosomal TLRs triggered by RNA and DNA sequences derived from both viruses and bacteria. This study was addressed to establish which endosomal TLR could directly mediate NK activation and function after proper stimuli. It was also important to establish the most suitable TLR agonist to be used as adjuvant in tumor vaccines or in combined cancer immunotherapies.MethodsWe assessed endosomal TLR expression in total NK cells by using RT-qPCR and western blotting technique. In some experiments, we purified CD56brightCD16−and CD56dimCD16+cells subsets by using NK Cell Isolation Kit Activation marker, cytokine production, CD107a expression and cytotoxicity assay were evaluated by flow cytometry. Cytokine release was quantified by ELISA. NK cells obtained from ovarian ascites underwent the same analyses.ResultsAlthough the four endosomal TLRs (TLR3, TLR7/8, and TLR9) were uniformly expressed on CD56brightCD16−and CD56dimCD16+cell subsets, the TLR7/8 (R848), TLR3 (polyinosinic-polycytidylic acid, Poly I:C) and TLR9 (ODN2395) ligands promoted NK-cell function only in the presence of suboptimal doses of cytokines, including interleukin (IL)-2, IL-12, IL-15, and IL-18, producedin vivoby other environmental cells. We showed that R848 rather than TLR3 and TLR9 agonists primarily activated CD56brightCD16−NK cells by increasing their proliferation, cytokine production and cytotoxic activity. Moreover, we demonstrated that R848, which usually triggers TLR7 and TLR8 on dendritic cells, macrophages and neutrophils cells, activated CD56brightCD16−NK-cell subset only via TLR8. Indeed, specific TLR8 but not TLR7 agonists increased cytokine production and cytotoxic activity of CD56brightCD16−NK cells. Importantly, these activities were also observed in peritoneal NK cells from patients with metastatic ovarian carcinoma, prevalently belonging to the CD56brightCD16−subset.ConclusionThese data highlight the potential value of TLR8 in NK cells as a new target for immunotherapy in patients with cancer.
CD4 T cell-intrinsic STING signaling controls the differentiation and effector functions of TH1 and TH9 cells
Authors: Benoit-Lizon Isis , Jacquin Elise , Rivera Vargas Thaiz , Richard Corentin , Roussey Aurélie , Dal Zuffo Ludivine , Martin Tiffany , Melis Andréa , Vinokurova Daria , Shahoei Sayyed Hamed , Baeza Garcia Alvaro , Pignol Cassandre , Giorgiutti Stéphane , Carapito Raphaël , Boidot Romain , Végran Frédérique , Flavell Richard A , Ryffel Bernhard , Nelson Eric R , Soulas-Sprauel Pauline , Lawrence Toby , Apetoh Lionel 
Published: January 2022

BackgroundWhile stimulator of interferon genes (STING) activation in innate immune cells of the tumor microenvironment can result in CD8 T cell-dependent antitumor immunity, whether STING signaling affects CD4 T-cell responses remains elusive.MethodsHere, we tested whether STING activation modulated the effector functions of CD4 T cells in vivo by analyzing tumor-infiltrating CD4 T cells and evaluating the contribution of the CD4 T cell-derived cytokines in the antitumor activity of the STING ligand 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) in two mouse tumor models. We performed ex vivo experiments to assess the impact of STING activation on CD4 T-cell differentiation and investigate the underlying molecular mechanisms. Finally, we tested whether STING activation enhances TH9 cell antitumor activity against mouse melanoma upon adoptive transfer.ResultsWe found that activation of STING signaling cell-intrinsically enhances the differentiation and antitumor functions of TH1 and TH9 cells by increasing their respective production of interferon gamma (IFN-γ) and interleukin-9. IRF3 and type I interferon receptors (IFNARs) are required for the STING-driven enhancement of TH1 cell differentiation. However, STING activation favors TH9 cell differentiation independently of the IFNARs/IRF3 pathway but through mammalian target of rapamycin (mTOR) signaling, underscoring that STING activation differentially affects the fate of distinct CD4 T-cell subsets. The therapeutic effect of STING activation relies on TH1 and TH9-derived cytokines, and STING activation enhances the antitumor activity of TH9 cells upon adoptive transfer.ConclusionOur results reveal the STING signaling pathway as a therapeutic target to boost CD4 T-cell effector functions and antitumor immunity.
DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber’s hereditary optic neuropathy and optic atrophy
Authors: Kieninger Sinja , Xiao Ting , Weisschuh Nicole , Kohl Susanne , Rüther Klaus , Kroisel Peter Michael , Brockmann Tobias , Knappe Steffi , Kellner Ulrich , Lagrèze Wolf , Mazzola Pascale , Haack Tobias B , Wissinger Bernd , Tonagel Felix 
Published: January 2022

BackgroundLeber’s hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inheritance linked to certain disease-causing variants in the mitochondrial genome. Recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30.Methods and resultsIn this study, we screened the DNAJC30 gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA). We identified likely pathogenic variants in 35/1202 patients, corresponding to a detection rate of 2.9%. The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect. Furthermore, we identified two novel pathogenic variants in DNAJC30: the nonsense variant c.610G>T;p.(Glu204*) and the in-frame deletion c.230_232del;p.(His77del). Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA.ConclusionThis study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients.
National evaluation of trauma teaching for students (NETTS)
Authors: Large Jamie , Kumar Prakrit R , Konda Nagarjun N , Hashmi Yousuf , Lee Justine J 
Published: January 2022

Abstract
Despite the shift towards consultant-led care, many patients with trauma are still seen by junior doctors. Previous research has demonstrated that junior doctors feel unprepared to work in acute care but there is a paucity of recent research in trauma specifically. Thus, a national study is required to investigate the current state of undergraduate trauma teaching and identify specific areas for improvement. Between August and September 2020, a 35-item structured questionnaire was distributed among doctors who graduated from UK medical schools within the last 4 years. The questionnaire retrospectively assessed their experience of trauma teaching at medical school and their confidence to diagnose and manage patients with trauma. 398 responses were recorded from graduates of 39 UK medical schools. With 79.6% reporting only 0–5 hours of bedside trauma teaching and 51.8% reporting less than 20 hours in Accident and Emergency, graduates reported that trauma teaching was deficient compared with other specialties (78.1%). The majority of graduates were not confident in the initial assessment (72.9%) of a patient with trauma and almost all felt that a short course in trauma would be useful (93.7%). 77.4% of students felt that online learning would be beneficial and 92.9% felt that simulation would be useful. There is lack of standardised undergraduate trauma teaching nationally; a formal undergraduate teaching to ensure that new graduates are competent in the management of trauma would be supported by students. It is likely that a blended learning approach, incorporating e-learning with traditional teaching and clinical experience would be well received.
Tumor Genomic Testing for &gt;4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib)
Authors: Hussain Maha , Corcoran Claire , Sibilla Caroline , Fizazi Karim , Saad Fred , Shore Neal , Sandhu Shahneen , Mateo Joaquin , Olmos David , Mehra Niven , Kolinsky Michael P. , Roubaud Guilhem , Özgüroǧlu Mustafa , Matsubara Nobuaki , Gedye Craig , Choi Young Deuk , Padua Charles , Kohlmann Alexander , Huisden Robert , Elvin Julia A. , Kang Jinyu , Adelman Carrie A. , Allen Allison , Poehlein Christian , de Bono Johann 
Published: January 2022

Abstract

Purpose:
Successful implementation of genomic testing in clinical practice is critical for identification of men with metastatic castration-resistant prostate cancer (mCRPC) eligible for olaparib and future molecularly targeted therapies.

Patients and Methods:
An investigational clinical trial assay, based on the FoundationOneCDx tissue test, was used to prospectively identify patients with qualifying homologous recombination repair gene alterations in the phase III PROfound study. Evaluation of next-generation sequencing (NGS) tissue test outcome against preanalytic parameters was performed to identify key factors influencing NGS result generation.

Results:
A total of 4,858 tissue samples from 4,047 patients were tested and reported centrally. NGS results were obtained in 58% (2,792/4,858) of samples (69% of patients). Of samples submitted, 83% were primary tumor samples (96% were archival and 4% newly obtained). Almost 17% were metastatic tumor samples (60% were archival and 33% newly obtained). NGS results were generated more frequently from newly obtained compared with archival samples (63.9% vs. 56.9%) and metastatic compared with primary samples (63.9% vs. 56.2%). Although generation of an NGS result declined with increasing sample age, approximately 50% of samples ages &gt;10 years generated results. While higher tumor content and DNA yield resulted in greater success in obtaining NGS results, other factors, including selection and preservation of samples, may also have had an impact.

Conclusions:
The PROfound study shows that tissue testing to identify homologous recombination repair alterations is feasible and that high-quality tumor tissue samples are key to obtaining NGS results and identifying patients with mCRPC who may benefit from olaparib treatment.
Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma
Authors: Mundy-Bosse Bethany L. , Weigel Christoph , Wu Yue-Zhong , Abdelbaky Salma , Youssef Youssef , Casas Susana Beceiro , Polley Nicholas , Ernst Gabrielle , Young Karen A. , McConnell Kathleen K. , Nalin Ansel P. , Wu Kevin G. , Broughton Megan , Lordo Matthew R. , Altynova Ekaterina , Hegewisch-Solloa Everardo , Enriquez-Vera Daniel Y. , Dueñas Daniela , Barrionuevo Carlos , Yu Shan-Chi , Saleem Atif , Suarez Carlos J. , Briercheck Edward L. , Molina-Kirsch Hernan , Loughran Thomas P. , Weichenhan Dieter , Plass Christoph , Reneau John C. , Mace Emily M. , Gamboa Fabiola Valvert , Weinstock David M. , Natkunam Yasodha , Caligiuri Michael A. , Mishra Anjali , Porcu Pierluigi , Baiocchi Robert A. , Brammer Jonathan E. , Freud Aharon G. , Oakes Christopher C. 
Published: January 2022

Abstract

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL.

Significance:
Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival.
This article is highlighted in the In This Issue feature, p. 85
EM-Earth: The Ensemble Meteorological Dataset for Planet Earth
Authors: Tang Guoqiang , Clark Martyn P. , Papalexiou Simon Michael 
Published: January 2022

Abstract
Gridded meteorological estimates are essential for many applications. Most existing meteorological datasets are deterministic and have limitations in representing the inherent uncertainties from both the data and methodology used to create gridded products. We develop the Ensemble Meteorological Dataset for Planet Earth (EM-Earth) for precipitation, mean daily temperature, daily temperature range, and dewpoint temperature at 0.1° spatial resolution over global land areas from 1950 to 2019. EM-Earth provides hourly/daily deterministic estimates, and daily probabilistic estimates (25 ensemble members), to meet the diverse requirements of hydrometeorological applications. To produce EM-Earth, we first developed a station-based Serially Complete Earth (SC-Earth) dataset, which removes the temporal discontinuities in raw station observations. Then, we optimally merged SC-Earth station data and ERA5 estimates to generate EM-Earth deterministic estimates and their uncertainties. The EM-Earth ensemble members are produced by sampling from parametric probability distributions using spatiotemporally correlated random fields. The EM-Earth dataset is evaluated by leave-one-out validation, using independent evaluation stations, and comparing it with many widely used datasets. The results show that EM-Earth is better in Europe, North America, and Oceania than in Africa, Asia, and South America, mainly due to differences in the available stations and differences in climate conditions. Probabilistic spatial meteorological datasets are particularly valuable in regions with large meteorological uncertainties, where almost all existing deterministic datasets face great challenges in obtaining accurate estimates.
Theory of Parcel Vorticity Evolution in Supercell-Like Flows
Authors: Davies-Jones Robert 
Published: January 2022

Abstract
In a prior paper, insights into tornadogenesis in supercell storms were gained by discovering analytical formulas for vorticity variations along streamlines in idealized, steady, frictionless, isentropic inflows of dry air imported from a horizontally uniform environment. This work is simplified and extended to the evolution of parcel vorticity in unsteady, nonisentropic flows by integrating the vorticity equation using nonorthogonal Lagrangian coordinates. The covariant basis vectors
,
, and
are material line elements attached to each parcel. Initially they form an orthonormal set with
in the direction of and
left normal to the storm-relative wind at each level in the environment, and
upward. The surface containing all parcels with the same initial height constitutes a material surface, within which initially streamwise and transverse material lines are reoriented and stretched or shrunk. The basis vectors propagate a parcel’s barotropic vorticity through time by factoring in the “frozen-field” effect. With a horizontally uniform environment, the barotropic vorticity of a parcel depends on its initial streamwise vorticity times its current
plus its initial crosswise vorticity times its current
. For baroclinic and frictional vorticity, each contravariant component is the integral from initial to current time of the corresponding contravariant component of the generation vector. The “river-bend” effect acting on all parts (baroclinic, frictional, and barotropic) of transverse vorticity produces streamwise vorticity (parallel to 3D wind). In left-turning steady flow, it arises from
rotating toward
. For steady, frictionless, dry isentropic flow, previous vorticity formulas are recovered.

Significance Statement
Air parcels rising in a tornado spin rapidly about their direction of motion. Theory herein describes the processes that can produce this streamwise spin in supercells. Cyclonic updraft rotation originates from strong low-level environmental storm-relative winds that turn clockwise with height. Parcels flowing into the updraft have initially large streamwise spins that are amplified by streamwise stretching. Rain curtains falling through the cyclonic updraft cause other parcels to descend and turn leftward. Buoyancy and frictional torques give them horizontal spin. Even if these spins are transverse to the flow initially, they are turned streamwise by secondary flow that develops in left-hand bends. As the parcels reach the ground and converge into the tornado, streamwise stretching greatly magnifies their streamwise spins.