bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mortality in biopsy-proven alcohol-related liver disease: a population-based nationwide cohort study of 3453 patients
Authors: Hagström Hannes , Thiele Maja , Roelstraete Bjorn , Söderling Jonas , Ludvigsson Jonas F 
Published: March 2020

ObjectivePatients with alcohol-related liver disease (ALD) are at increased risk of death, but studies have rarely investigated the significance of histological severity or estimated relative risks compared with a general population. We examined mortality in a nationwide cohort of biopsy-proven ALD.DesignPopulation-based cohort study in Sweden comparing 3453 individuals with an International Classification of Disease (ICD) code for ALD and a liver biopsy from 1969 to 2017 with 16 535 matched general population individuals. Swedish national registers were used to ascertain overall and disease-specific mortality, starting follow-up at the latest of first ICD diagnosis or liver biopsy plus 3 months. Cox regression adjusted for relevant confounders was used to estimate HRs in ALD and histopathological subgroups.ResultsMedian age at diagnosis was 58 years, 65% were men and 52% had cirrhosis at baseline. Five-year cumulative mortality was 40.9% in patients with ALD compared with 5.8% in reference individuals. The risk for overall mortality was significantly increased (adjusted HR (aHR)=4.70, 95% CI 4.35 to 5.08). The risk of liver-related death was particularly high (43% of all deaths, aHR=167.6, 95% CI 101.7 to 276.3). Mortality was significantly increased also in patients with ALD without cirrhosis and was highest in the first year after baseline but persisted after ≥10 years of follow-up (aHR=2.74, 95% CI 2.37 to 3.16).ConclusionIndividuals with biopsy-proven ALD have a near fivefold increased risk of death compared with the general population. Individuals with ALD without cirrhosis were also at increased risk of death, reaffirming the need to increase vigilance in the management of these individuals.
Autophagy induction by thiostrepton improves the efficacy of immunogenic chemotherapy
Authors: Wang Yan , Xie Wei , Humeau Juliette , Chen Guo , Liu Peng , Pol Jonathan , Zhang Zhen , Kepp Oliver , Kroemer Guido 
Published: March 2020

BackgroundImmunogenic cell death (ICD) is a peculiar modality of cellular demise that elicits adaptive immune responses and triggers T cell-dependent immunity.MethodsFluorescent biosensors were employed for an unbiased drug screen approach aiming at the identification of ICD enhancers.ResultsHere, we discovered thiostrepton as an enhancer of ICD able to boost chemotherapy-induced ATP release, calreticulin exposure and high-mobility group box 1 exodus. Moreover, thiostrepton enhanced anticancer immune responses of oxaliplatin (OXA) in vivo in immunocompetent mice, yet failed to do so in immunodeficient animals. Consistently, thiostrepton combined with OXA altered the ratio of cytotoxic T lymphocytes to regulatory T cells, thus overcoming immunosuppression and reinstating anticancer immunosurveillance.ConclusionAltogether, these results indicate that thiostrepton can be advantageously combined with chemotherapy to enhance anticancer immunogenicity.
Optimising the sampling procedure for forensic investigation of bruises on pigs
Authors: Barington Kristiane , Skovgaard Kerstin , Henriksen Nicole Lind , Jensen Henrik Elvang 
Published: March 2020

BackgroundHuman‐inflicted bruises on pigs are a violation of the law and affected tissue is regularly sent for forensic investigation. The authors aimed to evaluate the variation in inflammation within and between human‐inflicted porcine bruises in order to determine the optimal sampling procedure.MethodsSkin and muscle tissues from the centre and ends of 21 bruises were evaluated histologically. Moreover, RNA was extracted from the subcutaneous fat tissue. The bruises were detected during meat inspection at the slaughter line, and all carcases were kept at 5°C for 12–24 hours before sampling.ResultsThe sampling site with the most infiltration of neutrophils and macrophages differed between bruises inflicted on the same pig and between bruises inflicted on more pigs within the same delivery. The extracted RNA had RIN (RNA integrity number) values from 3 to 6.5.ConclusionsTissue samples should always be taken from both skin and underlying muscle tissue. Samples should be collected from several sites along each bruise, and all bruises should be sampled in order to include the site of maximum tissue damage and inflammation. Moreover, RNA of sufficient quality for quantitative PCR and subsequent age estimation cannot be obtained from carcases kept for 12–24 hours at 5°C.
Axial gravity and anomalies of fermions
Authors: Bastianelli Fiorenzo , Broccoli Matteo 
Published: March 2020

AbstractWe consider a Dirac fermion in a metric-axial-tensor (MAT) background. By regulating it with Pauli–Villars fields we analyze and compute its full anomaly structure. Appropriate limits of the MAT background allows to recover the anomalies of Dirac and Weyl fermions in the usual curved spacetime, obtaining in particular the trace anomaly of a chiral fermion, which has been the object of recent analyses.
China’s Economy on a Rocky Trajectory
Authors: LI Yao , TONG Sarah Y 
Published: March 2020

China’s economic growth has declined steadily since 2010. In 2019, trade conflict between China and the United States added uncertainties and weakened business and consumer confidence, thereby leading to further deceleration. Although the Chinese government has adopted policies to facilitate structural changes and support growth, changes would take time to occur and there may also be contradictions among policies. Promotion of the non-state sector may be difficult with the government’s prominent role in resource allocation. The year 2020 may be even more challenging for China’s economy. In addition to declining profits and slower income growth, the ongoing coronavirus disease 2019 (COVID-19) outbreak is a huge negative shock bringing new uncertainties.
Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts
Authors: Gris-Oliver Albert , Palafox Marta , Monserrat Laia , Brasó-Maristany Fara , Òdena Andreu , Sánchez-Guixé Mònica , Ibrahim Yasir H. , Villacampa Guillermo , Grueso Judit , Parés Mireia , Guzmán Marta , Rodríguez Olga , Bruna Alejandra , Hirst Caroline S. , Barnicle Alan , de Bruin Elza C. , Reddy Avinash , Schiavon Gaia , Arribas Joaquín , Mills Gordon B. , Caldas Carlos , Dienstmann Rodrigo , Prat Aleix , Nuciforo Paolo , Razavi Pedram , Scaltriti Maurizio , Turner Nicholas C. , Saura Cristina , Davies Barry R. , Oliveira Mafalda , Serra Violeta 
Published: March 2020

Abstract

Purpose:
AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor–positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.

Experimental Design:
Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.

Results:
Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K.

Conclusions:
This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
Adenocarcinoma of the Uterine Cervix Shows Impaired Recruitment of cDC1 and CD8+ T Cells and Elevated β-Catenin Activation Compared with Squamous Cell Carcinoma
Authors: Rotman Jossie , Heeren A. Marijne , Gassama Awa A. , Lougheed Sinead M. , Pocorni Noëlle , Stam Anita G.M. , Bleeker Maaike C.G. , Zijlmans Henry J.M.A.A , Mom Constantijne H. , Kenter Gemma G. , Jordanova Ekaterina S. , de Gruijl Tanja D. 
Published: March 2020

AbstractPurpose:Adenocarcinoma of the uterine cervix is the second most common type of cervical cancer after squamous cell carcinoma (SCC). Although both subtypes are treated similarly, patients with adenocarcinoma have a worse prognosis. In this study, immunologic features of the tumor microenvironment in these two subsets were pursued with potential therapeutic implications.Experimental Design:The immune microenvironment of primary tumors and nonmetastatic tumor-draining lymph nodes (TDLN) was compared between patients with cervical adenocarcinoma (n = 16) and SCC (n = 20) by polychromatic flow cytometry and by transcriptional profiling of the primary tumors (n = 299) using publicly available data from The Cancer Genome Atlas (TCGA).Results:Flow cytometric analyses revealed intact T-cell differentiation in TDLNs, but hampered effector T-cell trafficking to the primary tumors in adenocarcinoma, as compared with SCC. TCGA analysis demonstrated higher expression of chemokines involved in effector T-cell homing (CXCL9/10/11) in SCC primary tumors as compared with adenocarcinoma primary tumors, which was highly correlated to a transcriptional signature for type I conventional dendritic cells (cDC1). This was consistent with elevated frequencies of CD141/BDCA3+cDC1 in primary tumor SCC samples relative to adenocarcinoma and correspondingly elevated levels of CXCL9 and CXCL10 in 24-hour ex vivo cultures. Hampered cDC1 recruitment in adenocarcinoma was in turn related to lower transcript levels of cDC1-recruiting chemokines and an elevated β-catenin activation score and was associated with poor overall survival.Conclusions:Our data have identified an opportunity for the investigation of potentially novel therapeutic interventions in adenocarcinoma of the cervix, that is, β-catenin inhibition and cDC1 mobilization.
Long Noncoding RNA MALAT1 Contributes to Sorafenib Resistance by Targeting miR-140-5p/Aurora-A Signaling in Hepatocellular Carcinoma
Authors: Fan Lei , Huang Xiang , Chen Jing , Zhang Kai , Gu Yan-hong , Sun Jing , Cui Shi-yun 
Published: March 2020

Abstract
Long noncoding RNAs (lncRNA) have been found to play critical roles in tumorigenesis and the development of various cancers, including hepatocellular carcinoma (HCC). Metastasis associated with lung adenocarcinoma transcript-1 (MALAT1) has been identified as an oncogene and prognostic biomarker in HCC. Here, we demonstrated that MALAT1 expression was obviously high in sorafenib-resistant HCC cells. Furthermore, knockdown of MALAT1 increased sorafenib sensitivity in nonresponsive HCC cells, whereas forced expression of MALAT1 conferred sorafenib resistance to responsive HCC cells in vitro. In addition, loss/gain-of-function assays revealed that MALAT1 promoted cell proliferation, migration, and epithelial–mesenchymal transition in HCC cells. Mechanistically, MALAT1 regulated Aurora-A expression by sponging miR-140-5p, thus promoting sorafenib resistance in HCC cells. Moreover, MALAT1 inhibition enhanced the antitumor efficacy of sorafenib in vivo. Clinically, we found that MALAT1 expression was negatively correlated with miR-140-5p expression but positively correlated with Aurora-A expression in patients with HCC and that upregulated MALAT1 was closely correlated with poor survival outcomes in patients with HCC. These findings indicated that MALAT1 may be a novel target for prognosis prediction and therapeutic strategies in patients with HCC treated with sorafenib.
Novel Dual BET and PLK1 Inhibitor WNY0824 Exerts Potent Antitumor Effects in CRPC by Inhibiting Transcription Factor Function and Inducing Mitotic Abnormality
Authors: Xu Ying , Wang Qianqian , Xiao Kunjie , Liu Zhihao , Zhao Lifeng , Song Xuejiao , Hu Xi , Feng Zhanzhan , Gao Tiantao , Zuo Weiqiong , Zeng Jun , Wang Ningyu , Yu Luoting 
Published: March 2020

Abstract
Castration-resistant prostate cancer (CRPC) is a lethal disease with few treatment alternatives once patients become resistant to second-generation antiandrogens. In CRPC, BET proteins are key regulators of AR- and MYC-mediated transcription, while the PLK1 inhibitor potentially downregulates AR and MYC besides influencing the cell cycle. Therefore, synchronous inhibition of BET and PLK1 would be a promising approach for CRPC therapy. This study developed a dual BET and PLK1 inhibitor WNY0824 with nanomolar and equipotent inhibition of BRD4 and PLK1. In vitro, WNY0824 exhibited excellent antiproliferation activity on AR-positive CRPC cells and induced apoptosis. These activities are attributable to its disruption of the AR-transcriptional program and the inhibition of the ETS pathway. Furthermore, WNY0824 downregulated MYC and induced mitotic abnormality. In vivo, oral WNY0824 administration suppressed tumor growth in the CRPC xenograft model of enzalutamide resistance. These findings suggest that WNY0824 is a selective dual BET and PLK1 inhibitor with potent anti-CRPC oncogenic activity and provides insights into the development of other novel dual BET- and PLK1-inhibiting drugs.
Vitamin D Receptor Activation and Photodynamic Priming Enables Durable Low-dose Chemotherapy
Authors: Anbil Sriram , Pigula Michael , Huang Huang-Chiao , Mallidi Srivalleesha , Broekgaarden Mans , Baglo Yan , De Silva Pushpamali , Simeone Diane M. , Mino-Kenudson Mari , Maytin Edward V. , Rizvi Imran , Hasan Tayyaba 
Published: March 2020

Abstract
Patients with cancer often confront the decision of whether to continue high-dose chemotherapy at the expense of cumulative toxicities. Reducing the dose of chemotherapy regimens while preserving efficacy is sorely needed to preserve the performance status of these vulnerable patients, yet has not been prioritized. Here, we introduce a dual pronged approach to modulate the microenvironment of desmoplastic pancreatic tumors and enable significant dose deescalation of the FDA-approved chemotherapeutic nanoliposomal irinotecan (nal-IRI) without compromising tumor control. We demonstrate that light-based photodynamic priming (PDP) coupled with vitamin D3 receptor (VDR) activation within fibroblasts increases intratumoral nal-IRI accumulation and suppresses protumorigenic CXCL12/CXCR7 crosstalk. Combined photodynamic and biochemical modulation of the tumor microenvironment enables a 75% dose reduction of nal-IRI while maintaining treatment efficacy, resulting in improved tolerability. Modifying the disease landscape to increase the susceptibility of cancer, via preferentially modulating fibroblasts, represents a promising and relatively underexplored strategy to enable dose deescalation. The approach presented here, using a combination of three clinically available therapies with nonoverlapping toxicities, can be rapidly translated with minimal modification to treatment workflow, and challenges the notion that significant improvements in chemotherapy efficacy can only be achieved at the expense of increased toxicity.
Bleeding Risk, Dual Antiplatelet Therapy Cessation, and Adverse Events After Percutaneous Coronary Intervention
Authors: Sorrentino Sabato , Sartori Samantha , Baber Usman , Claessen Bimmer E. , Giustino Gennaro , Chandrasekhar Jaya , Chandiramani Rishi , Cohen David J. , Henry Timothy D. , Guedeney Paul , Ariti Cono , Dangas George , Gibson C. Michael , Krucoff Mitchell W. , Moliterno David J. , Colombo Antonio , Vogel Birgit , Chieffo Alaide , Kini Annapoorna S. , Witzenbichler Bernhard , Weisz Giora , Steg Philippe Gabriel , Pocock Stuart , Urban Philip , Mehran Roxana 
Published: March 2020

Background:
Whether the underlying risk of bleeding influences the associations between patterns of dual antiplatelet therapy (DAPT) cessation and adverse events after percutaneous coronary intervention is unknown.

Methods:
Patients enrolled in the prospective, international, multicenter PARIS registry (Patterns of Non-Adherence to Anti-Platelet Regimens in Stented Patients) were categorized according to their risk of bleeding using the PARIS bleeding risk score. We evaluated the incidence, patterns, and association between modes of DAPT cessation and outcomes across bleeding risk groups. Modes of DAPT cessations were defined as physician-guided DAPT discontinuation, brief interruption (<14 days) or disruption for bleeding, or noncompliance. The primary end point of interest was major adverse cardiac events, defined as the composite of cardiac death, myocardial infarction, or definite-probable stent thrombosis.

Results:

From a total of 5018 patients, 513 (10.2%) were classified as high, 2058 (41.0%) as intermediate, and 2447 (48.8%) as low risk for bleeding. High bleeding risk (HBR) patients were older and had greater prevalence of comorbidities. Compared with non-HBR, HBR patients had higher rates of both ischemic and bleeding events. The cumulative incidence of DAPT cessation was higher in HBR patients, mostly driven by physician-guided discontinuation and disruption. Of note, DAPT disruption occurred in 17.7%, 10.4%, and 7.8% at 1 year and 22.0%, 15.1%, and 12.0% at 2 years (
P
<0.0001) in high, intermediate, and low bleeding risk groups, respectively. Physician-guided DAPT discontinuation was not associated with increased risk of major adverse cardiac events in both HBR and non-HBR patients, while DAPT disruption was associated with an increased risk of major adverse cardiac events across all bleeding risk groups. There was no interaction between bleeding risk status and clinical outcomes for any cessation mode.

Conclusions:
Patients at HBR remain at higher risk of adverse events. Disruption of DAPT is associated with an increased risk of major adverse cardiac events irrespective of the underlying bleeding risk. Physician-guided discontinuation of DAPT appears to be safe, irrespective of HBR.
Independent Prognostic Value of MRproANP (Midregional Proatrial Natriuretic Peptide) Levels in Patients With Stroke Is Unaltered Over Time
Authors: Arnold Markus , Nakas Christos , Luft Andreas , Christ-Crain Mirjam , Leichtle Alexander , Katan Mira 
Published: March 2020

Background and Purpose—
MRproANP (midregional proatrial natriuretic peptide) is known to be independently associated with cardioembolic stroke cause and to improve risk stratification for 90-day mortality when measured within 24 to 72 hours after symptom onset in patients with acute ischemic stroke. However, the optimal time point for assessment remains unclear. This study aimed to evaluate prognostic utility of MRproANP at different time points during the first 5 days of hospitalization in patients with acute ischemic stroke.

Methods—
Samples of MRproANP were collected on admission (<72 hours after onset) and at multiple time points during the first 5 days of hospitalization in 348 consecutively enrolled patients with acute ischemic stroke. The prognostic value for 90-day mortality, 90-day functional outcome, and the association with cardioembolic stroke cause was assessed regarding the time of measurement, and change over time was modeled using generalized estimating equations.

Results—

MRproANP levels modestly decease over the initial 5 days but remain highly predictive for cardioembolic stroke cause (odds ratio, 9.75 [95% CI, 3.2–29]; 10.62 [95% CI, 3.4–33.3]; 10.8 [95% CI, 3.1–37.1]; 19.4 [95% CI, 5.49–68.7] on admission, day 1, 3 and 5) and 90-day mortality (odds ratio, 59.4 [95% CI, 7.4–480.7]; 78.3 [95% CI, 7.9–772.6]; 14.5 [95% CI, 1.4–145]; 19.81 [95% CI, 2.7–143.4] on admission, day 1, 3, and 5). Change over time does not significantly modify the prognostic value of MRproANP (
P
=0.65 and
P
=0.56 for the interaction term in the multivariate model).

Conclusions—
Independent prognostic value of MRproANP remains unaltered in the acute phase of stroke at least up to 5 days; repeated measurements do not improve the prognostic value.
Christ’s Body Is One
Authors: Wood James R. 
Published: March 2020

Abstract
This essay argues that the ecclesiology of John W. Nevin furnishes American Presbyterians, both evangelical and mainline, with significant resources for the pursuit of Reformed catholicity. Nevin believed that the church must exhibit contemporary unity and historical continuity as a result of its mystical union with the incarnate Christ. He opposed the forces prevalent in American Protestantism that undermined visible, catholic unity. In Nevin’s assessment, the foundational factor in these ecclesiological errors was a defective, truncated Christology. Nevin sought to renew Reformed theology through retrieving an orthodox ecclesiology rooted in a robust understanding of the incarnation. The concluding section will argue that both streams of American Presbyterianism fall short in terms of catholicity and would benefit by attending to Nevin’s ecclesial vision.
Religious Education and the Anglo-World
Authors: Jackson Stephen 
Published: March 2020

Abstract
Focusing on Australia, Canada, and New Zealand, “Religious Education and the Anglo-World” historiographically examines the relationship between empire and religious education. In each case the analysis centres on the foundational moments of publicly funded education in the mid- to late-nineteenth centuries when policy makers created largely Protestant systems of religious education, and frequently denied Roman Catholics funding for private education. Secondly, the period from 1880 to 1960 during which campaigns to strengthen religious education emerged in each context. Finally, the era of decolonisation from the 1960s through the 1980s when publicly funded religious education was challenged by the loss of Britishness as a central ideal, and Roman Catholics found unprecedented success in achieving state aid in many cases. By bringing these disparate national literatures into conversation with one another, the essay calls for a greater transnational approach to the study of religious education in the Anglo-World.