bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebrovascular events after transcatheter mitral valve interventions: a systematic review and meta-analysis
Authors: Châteauneuf Gabriel , Nazif Tamim M , Beaupré Frédéric , Kodali Susheel , Rodés-Cabau Josep , Paradis Jean-Michel 
Published: April 2020

ObjectiveCurrent guidelines support the use of transcatheter mitral valve interventions to treat some selected high-risk patients with significant mitral valvulopathy. As with any other interventional cardiac procedure, concerns have been raised about cerebrovascular event. The aim of this systematic review and meta-analysis was to determine the incidence of cerebrovascular events following (1) transcatheter mitral valve edge-to-edge repair with mitral valve clip and (2) transcatheter mitral valve replacement (TMVR).MethodsWe conducted a systematic review of studies reporting the cerebrovascular adverse events after transcatheter mitral valve edge-to-edge repair and TMVR procedures. The primary endpoint was the incidence of cerebrovascular events as defined by the Mitral Valve Academic Research Consortium. An event that occurred within 30 days or during index hospitalisation was defined as periprocedural; otherwise it was defined as non-periprocedural. This study was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Aggregated study-level data were pooled using a random effect model. The quality of each study was appraised with the Hawker checklist, a method of systematically reviewing research from different paradigms.ResultsSixty studies totalling 28 155 patients undergoing edge-to-edge repair with mitral valve clip were included in the analysis. Periprocedural stroke and non-periprocedural stroke rates were 0.9% (95% CI 0.6 to 1.1) and 2.4% (95% CI 1.6 to 3.2), respectively. For TMVR procedures, 26 studies including 1910 patients were analysed. The estimated periprocedural stroke incidence was 1% (95% CI 0.5 to 1.8) compared with 7% (95% CI 0.8 to 18.5) for non-periprocedural stroke.ConclusionsTranscatheter mitral valve interventions are associated with low rates of cerebrovascular events. The exact mechanisms of these complications are still poorly understood given the relative paucity of good quality data.Trial registration numberCRD42019117257.
Development and validation of the immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma
Authors: Liu Sai-Lan , Bian Li-Juan , Liu Ze-Xian , Chen Qiu-Yan , Sun Xue-Song , Sun Rui , Luo Dong-Hua , Li Xiao-Yun , Xiao Bei-Bei , Yan Jin-Jie , Lu Zi-Jian , Yan Shu-Mei , Yuan Li , Tang Lin-Quan , Li Jian-Ming , Mai Hai-Qiang 
Published: April 2020

BackgroundThe tumor immune microenvironment has clinicopathological significance in predicting prognosis and therapeutic efficacy. We aimed to develop an immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma (NPC).MethodsUsing multiplexed quantitative fluorescence, we detected 17 immune biomarkers in a primary screening cohort of 54 NPC tissues presenting with/without distant metastasis following radical therapy. The LASSO (least absolute shrinkage and selection operator) logistic regression model used statistically significant survival markers in the training cohort (n=194) to build an immune signature. The prognostic and predictive accuracy of it was validated in an external independent group of 304 patients.ResultsEight statistically significant markers were identified in the screening cohort. The immune signature consisting of four immune markers (PD-L1+ CD163+, CXCR5, CD117) in intratumor was adopted to classify patients into high and low risk in the training cohort and it showed a high level of reproducibility between different batches of samples (r=0.988 for intratumor; p<0.0001). High-risk patients had shorter distant metastasis-free survival (HR 5.608, 95% CI 2.619 to 12.006; p<0.0001) and progression-free survival (HR 2.798, 95% CI 1.498 to 5.266; p=0·001). The C-indexes which reflected the predictive capacity in training and validation cohort were 0.703 and 0.636, respectively. Low-risk patients benefited from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) (HR 0.355, 95% CI 0.147 to 0.857; p=0·021), while high-risk patients did not (HR 1.329, 95% CI 0.543 to 3.253; p=0·533). To predict the individual risk of distant metastasis, nomograms with the integration of both immune signature and clinicopathological risk factors were developed.ConclusionsThe immune signature provided a reliable estimate of distant metastasis risk in patients with NPC and might be applied to identify the cohort which benefit from IC+CCRT.
Decrease in tumor content assessed in biopsies is associated with improved treatment outcome response to pembrolizumab in patients with rare tumors
Authors: Tapia Coya , Aung Phyu P. , Roy-Chowdhuri Sinchita , Xu Mingxuan , Ouyang Fengying , Alshawa Anas , Hajjar Joud , Singh Gopal , Yang Vincent , Castillo Lilibeth , Le Hung , Murthy Ravi , Stephen Bettzy , Hess Kenneth R , Wistuba Ignacio , Naing Aung 
Published: April 2020

BackgroundDecreased tumor content (TC) in resection specimens after neoadjuvant therapy is used to predict prognosis. We investigated whether TC assessed in biopsy specimens or the shift in TC from baseline to on-treatment can be used accordingly to predict response in patients with rare tumors who were treated with pembrolizumab.MethodsA total of 57 tumors (represented by 173 baseline and 179 on-treatment biopsies) from 57 patients with rare tumors participating in an ongoing phase II clinical trial of pembrolizumab were evaluated. TC was estimated on H&E-stained slides and tumors were dichotomized into low and high TC according to a cut-off of 10%. Necrosis, proliferative fibrosis (PF) and normal tissue were assessed in on-treatment biopsies. TC at baseline and on-treatment, as well as the shift in TC from baseline to on-treatment, was correlated with clinical response defined according to Response Evaluation Criteria in Solid Tumors.ResultsA decrease in TC was seen in 14% (n=8); no change in TC was seen in 75% (n=43); and an increase in TC from baseline to on-treatment was seen in 11% (n=6). Objective response was significantly associated with decrease in TC from baseline to on-treatment (38%, 3/8) compared with no change/increase in TC (6%, 3/49) (p=0.031). Patients with a decrease in TC had a significantly increased time to progression (TTP) (75% probability) compared with patients with an increase (20% probability) or no change in TC (19% probability) (p=0.0042). Low TC was seen in 23% (13/57) of the tumors at baseline and in 26% (15/57) on-treatment. High TC was seen in 77% (44/57) of tumors at baseline and in 74% (42/57) on-treatment. No significant associations with response were seen for necrosis, PF or normal tissue in on-treatment biopsies.ConclusionPatients with a decrease in TC from baseline to on-treatment had a significant improvement in objective response and a longer TTP. Our data suggest that the shift in TC might be used to predict response to pembrolizumab in rare tumors. However, further investigations in larger cohorts are needed to determine the clinical value of TC, the shift in TC and the cut-off of 10% assessed in biopsies.Trial registration numberNCT02721732
Inhibition of TGF-β-receptor signaling augments the antitumor function of ROR1-specific CAR T-cells against triple-negative breast cancer
Authors: Stüber Tanja , Monjezi Razieh , Wallstabe Lars , Kühnemundt Johanna , Nietzer Sarah Louise , Dandekar Gudrun , Wöckel Achim , Einsele Hermann , Wischhusen Jörg , Hudecek Michael 
Published: April 2020

BackgroundImmunotherapy with chimeric antigen receptor (CAR)-engineered T-cells is effective in some hematologic tumors. In solid tumors, however, sustained antitumor responses after CAR T-cell therapy remain to be demonstrated both in the pre-clinical and clinical setting. A perceived barrier to the efficacy of CAR T-cell therapy in solid tumors is the hostile tumor microenvironment where immunosuppressive soluble factors like transforming growth factor (TGF)-β are thought to inhibit the cellular immune response. Here, we analyzed whether CAR T-cells specific for the receptor tyrosine kinase-like orphan receptor 1 (ROR1) antigen, that is frequently expressed in triple-negative breast cancer (TNBC), are susceptible to inhibition by TGF-β and evaluated TGF-β-receptor signaling blockade as a way of neutralizing the inhibitory effect of this cytokine.MethodsCD8+and CD4+ROR1-CAR T-cells were prepared from healthy donors and their antitumor function analyzed using the TNBC cell line MDA-MB-231 in vitro and in a microphysiologic 3D tumor model. Analyses were performed in co-culture assays of ROR1-CAR T-cells and MDA-MB-231 cells with addition of exogenous TGF-β.ResultsThe data show that exposure to TGF-β engages TGF-β-receptor signaling in CD8+and CD4+ROR1-CAR T-cells as evidenced by phosphorylation of small mothers against decapentaplegic homolog 2. In the presence of TGF-β, the cytolytic activity, cytokine production and proliferation of ROR1-CAR T-cells in co-culture with MDA-MB-231 TNBC cells were markedly impaired, and the viability of ROR1-CAR T-cells reduced. Blockade of TGF-β-receptor signaling with the specific kinase inhibitor SD-208 was able to protect CD8+and CD4+ROR1-CAR T-cells from the inhibitory effect of TGF-β, and sustained their antitumor function in vitro and in the microphysiologic 3D tumor model. Combination treatment with SD-208 also led to increased viability and lower expression of PD-1 on ROR1-CAR T-cells at the end of the antitumor response.ConclusionWe demonstrate the TGF-β suppresses the antitumor function of ROR1-CAR T-cells against TNBC in preclinical models. Our study supports the continued preclinical development and the clinical evaluation of combination treatments that shield CAR T-cells from TGF-β, as exemplified by the TGF-β-receptor kinase inhibitor SD-208 in this study.
Homozygous variants in SYCP2L cause premature ovarian insufficiency
Authors: He Wen-Bin , Tan Chen , Zhang Ya-Xin , Meng Lan-Lan , Gong Fei , Lu Guang-Xiu , Lin Ge , Du Juan , Tan Yue-Qiu 
Published: April 2020

BackgroundThe genetic causes of the majority of cases of female infertility caused by premature ovarian insufficiency (POI) are unknown.ObjectiveTo identify the genetic causes of POI in 110 patients.MethodsWhole-exome sequencing was performed on 110 patients with POI, and putative disease-causative variants were validated by Sanger sequencing. Bioinformatic and in vitro functional analyses were performed for functional characterisation of the identified candidate disease-causative variants.ResultsWe identified two homozygous variants (NM_001040274: c.150_151del (p.Ser52Profs*7), c.999A>G (p.Ile333Met)) in SYCP2L in two patients, which had co-segregated with POI in these families. Bioinformatic analysis predicted that the two variants are deleterious, and in vitro functional analysis showed that mutant SYCP2L proteins exhibited mislocalisation and loss of function.ConclusionsSYCP2L is a novel gene found to be responsible for human POI. Our findings provide a potential molecular marker for POI and improve the understanding of the genetic basis of female infertility.
Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lprmice
Authors: Fortner Karen A , Blanco Luz P , Buskiewicz Iwona , Huang Nick , Gibson Pamela C , Cook Deborah L , Pedersen Hege L , Yuen Peter S T , Murphy Michael P , Perl Andras , Kaplan Mariana J , Budd Ralph C 
Published: April 2020

ObjectivesRecent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants.MethodsLupus-prone MRL-lprmice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function.ResultsMitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody .ConclusionsThese findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.
Prevalence of lymphogranuloma venereum among anorectalChlamydia trachomatis-positive MSM using pre-exposure prophylaxis for HIV
Authors: Peuchant Olivia , Touati Arabella , Laurier-Nadalié Cécile , Hénin Nadege , Cazanave Charles , Bébéar Cécile , de Barbeyrac Bertille 
Published: April 2020

ObjectivesWe evaluated the prevalence of lymphogranuloma venereum (LGV) in anorectalChlamydia trachomatis-positive French men who have sex with men (MSM) using pre-exposure prophylaxis (PrEP) for HIV. Here, we describe the clinical, biological and behavioural characteristics of these patients.MethodsLaboratories throughout French metropolitan areas performing routine testing forC. trachomatissent positive anorectal specimens to the National Reference Centre for bacterial STIs for LGV real-time PCR targeting thepmpH gene. Identification of theC. trachomatisgenovar was performed byompA gene sequencing. For each patient, clinical, biological and sexual behaviour data were collected after obtaining written informed consent.ResultsIn 2017, 486 anorectalC. trachomatis-positive specimens from MSM PrEP users were analysed. A strain of genovar L was detected in 91 cases (18.7%). Patients with LGV were significantly more symptomatic, had more sexual partners and more concurrent syphilis compared with their non-LGV counterparts.OmpA gene sequencing, successful in two-thirds of anorectalC. trachomatis-positive specimens, showed that the LGV cases were mainly of variant L2b (n=33), followed by genovar L2 (n=27) and genetic L2bompA variants (n=16). In 11 cases, the results indicated the occurrence of genetic exchange between L and non-L genovars.ConclusionsLGV was diagnosed in 18.7% of anorectalC. trachomatis-positive specimens from French MSM using PrEP. LGV testing should be carried out for MSM diagnosed with chlamydia and with a large number of sexual partners, high-risk practices and anorectal symptoms. These patients should be presumptively treated as having LGV. This is the first surveillance study of LGV among MSM PrEP users and monitoring should continue.
Niobium quarter-wave resonator with the optimized shape for quantum information systems
Authors: Kutsaev S. V. , Taletski K. , Agustsson R. , Carriere P. , Cleland A. N. , Conway Z. A. , Dumur É. , Moro A. , Smirnov A. Yu. 
Published: April 2020

AbstractQuantum computers (QC), if realized, could disrupt many computationally intense fields of science. The building block element of a QC is a quantum bit (qubit). Qubits enable the use of quantum superposition and multi-state entanglement in QC calculations, allowing a QC to simultaneously perform millions of computations at once. However, quantum states stored in a qubit degrade with decreased quality factors and interactions with the environment. One technical solution to improve qubit lifetimes and network interactions is a circuit comprised of a Josephson junction-based qubit located inside of a high Q-factor superconducting 3D cavity.It is known that niobium resonators can reach $Q_{0}>10^{11}$Q0>1011. However, existing cavity geometries are optimized for particle acceleration rather than hosting qubits. RadiaBeam Technologies, in collaboration with Argonne National Laboratory and The University of Chicago, has developed a niobium superconducting radio frequency quarter-wave resonant cavity (QWR) for quantum computation. A 6 GHz QWR was optimized to include tapering of the inner and outer conductors, a toroidal shape for the resonator shorting plane, and an inner conductor tip to reduce parasitic capacitance. In this paper, we present the results of the resonator design optimization, fabrication, processing, and testing.
Tumor Cell–Derived Angiopoietin-2 Promotes Metastasis in Melanoma
Authors: Abdul Pari Ashik Ahmed , Singhal Mahak , Hübers Corinne , Mogler Carolin , Schieb Benjamin , Gampp Anja , Gengenbacher Nicolas , Reynolds Louise E. , Terhardt Dorothee , Géraud Cyrill , Utikal Jochen , Thomas Markus , Goerdt Sergij , Hodivala-Dilke Kairbaan M. , Augustin Hellmut G. , Felcht Moritz 
Published: April 2020

Abstract

The angiopoietin (Angpt)–TIE signaling pathway controls vascular maturation and maintains the quiescent phenotype of resting vasculature. The contextual agonistic and antagonistic Tie2 ligand ANGPT2 is believed to be exclusively produced by endothelial cells, disrupting constitutive ANGPT1–TIE2 signaling to destabilize the microvasculature during pathologic disorders like inflammation and cancer. However, scattered reports have also portrayed tumor cells as a source of ANGPT2. Employing ISH-based detection of ANGPT2, we found strong tumor cell expression of ANGPT2 in a subset of patients with melanoma. Comparative analysis of biopsies revealed a higher fraction of ANGPT2-expressing tumor cells in metastatic versus primary sites. Tumor cell–expressed Angpt2 was dispensable for primary tumor growth, yet in-depth analysis of primary tumors revealed enhanced intratumoral necrosis upon silencing of tumor cell Angpt2 expression in the absence of significant immune and vascular alterations. Global transcriptional profiling of Angpt2-deficient tumor cells identified perturbations in redox homeostasis and an increased response to cellular oxidative stress. Ultrastructural analyses illustrated a significant increase of dysfunctional mitochondria in Angpt2-silenced tumor cells, thereby resulting in enhanced reactive oxygen species (ROS) production and downstream MAPK stress signaling. Functionally, enhanced ROS in Angpt2-silenced tumor cells reduced colonization potential in vitro and in vivo. Taken together, these findings uncover the hitherto unappreciated role of tumor cell–expressed ANGPT2 as an autocrine-positive regulator of metastatic colonization and validate ANGPT2 as a therapeutic target for a well-defined subset of patients with melanoma.

Significance:
This study reveals that tumor cells can be a source of ANGPT2 in the tumor microenvironment and that tumor cell-derived ANGPT2 augments metastatic colonization by protecting tumor cells from oxidative stress.
Racial/Ethnic Disparities in Prostate Cancer Incidence, Distant Stage Diagnosis, and Mortality by U.S. Census Region and Age Group, 2012–2015
Authors: Iyengar Siddharth , Hall Ingrid J. , Sabatino Susan A. 
Published: April 2020

Abstract

Background:
We sought to characterize recent prostate cancer incidence, distant stage diagnosis, and mortality rates by region, race/ethnicity, and age group.

Methods:
In SEER*Stat, we examined age-specific and age-adjusted prostate cancer incidence, distant stage diagnosis, and mortality rates by race/ethnicity, census region, and age group. Incidence and mortality analyses included men diagnosed with (n = 723,269) and dying of (n = 112,116) prostate cancer between 2012 and 2015.

Results:
Non-Hispanic black (NHB) and non-Hispanic Asian/Pacific Islander (NHAPI) men had the highest and lowest rates, respectively, for each indicator across regions and age groups. Hispanic men had lower incidence and mortality rates than non-Hispanic white (NHW) men in all regions except the Northeast where they had higher incidence [RR, 1.16; 95% confidence interval (CI), 1.14–1.19] and similar mortality. Hispanics had higher distant stage rates in the Northeast (RR, 1.18; 95% CI, 1.08–1.28) and South (RR, 1.22; 95% CI, 1.15–1.30), but similar rates in other regions. Non-Hispanic American Indian/Alaskan Native (NHAIAN) men had higher distant stage rates than NHWs in the West (RR, 1.38; 95% CI, 1.15–1.65). NHBs and Hispanics had higher distant stage rates than NHWs among those aged 55 to 69 years (RR, 2.91; 95% CI, 2.81–3.02 and 1.24; 95% CI, 1.18–1.31, respectively), despite lower overall incidence for Hispanics in this age group.

Conclusions:
For Hispanic and NHAIAN men, prostate cancer indicators varied by region, while NHB and NHAPI men consistently had the highest and lowest rates, respectively, across regions.

Impact:
Regional and age group differences in prostate cancer indicators between populations may improve understanding of prostate cancer risk and help inform screening decisions.
Objectively-Measured Light-Intensity Physical Activity and Risk of Cancer Mortality: A Meta-analysis of Prospective Cohort Studies
Authors: Qiu Shanhu , Cai Xue , Wu Tongzhi , Sun Zilin , Guo Haijian , Kirsten Johannes , Wendt Janine , Steinacker Jürgen Michael , Schumann Uwe 
Published: April 2020

AbstractBackground:The impact of light-intensity physical activity (LPA) in preventing cancer mortality has been questioned. To address this concern, the present meta-analysis aimed to quantify the association between objectively-measured LPA and risk of cancer mortality.Methods:We conducted a systematic literature search in PubMed and Scopus to January 2020. Prospective cohort studies reporting the association between objectively-measured LPA using activity monitors (e.g., accelerometers) and risk of cancer mortality in the general population were included. The summary hazard ratios (HR) per 30 min/day of LPA and 95% confidence intervals (CI) were obtained using a random-effects model. Dose–response analysis was used to plot their relationship.Results:Five prospective cohort studies were included, in which the definition of LPA based on accelerometer readings was mainly set within 100 to 2,100 counts/min. The summary HR for cancer mortality per 30 min/day of LPA was 0.86 (95% CI, 0.79–0.95; I2 &lt; 1%), and the association between LPA and risk reduction in cancer mortality was linearly shaped (Pnonlinearity = 0.72). LPA exhibited a comparable magnitude of risk reduction in cancer mortality of moderate-to-vigorous physical activity regardless of equal time-length (0.87 per 30 min/day vs. 0.94 per 30 min/day, Pinteraction = 0.46) or equal amount (0.74 vs. 0.94 per 150 metabolic equivalents-min/day, Pinteraction = 0.11). Furthermore, replacing sedentary time by LPA of 30 min/day decreased the risk of cancer mortality by 9%.Conclusions:Objectively-measured LPA conferred benefits in decreasing the risk of cancer mortality.Impact:LPA should be considered in physical activity guidelines to decrease the risk of cancer mortality.