bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACE2 Enhances Sensitivity to PD-L1 Blockade by Inhibiting Macrophage-Induced Immunosuppression and Angiogenesis
Authors: Xie Peiyi , Guo Lei , Yu Qiang , Zhao Yufei , Yu Mincheng , Wang Hui , Wu Mengyuan , Xu Wenxin , Xu Min , Zhu Xiao-Dong , Xu Yongfeng , Xiao Yong-Sheng , Huang Cheng , Zhou Jian , Fan Jia , Hung Mien-Chie , Sun Huichuan , Ye Qing-Hai , Zhang Bo , Li Hui 
Published: November 2024

Abstract
Anti–PD-L1–based combination immunotherapy has become the first-line treatment for unresectable hepatocellular carcinoma (HCC). However, the objective response rate is lower than 40%, highlighting the need to identify mechanisms of tolerance to immune checkpoint inhibitors and accurate biomarkers of response. In this study, we used next-generation sequencing to analyze HCC samples from 10 patients receiving anti–PD-L1 therapy. Activation of the renin–angiotensin system was elevated in nonresponders compared with responders, and angiotensin-converting enzyme 2 (ACE2) expression was significantly downregulated in nonresponders. ACE2 deficiency promoted HCC development and anti–PD-L1 resistance, whereas ACE2 overexpression inhibited HCC progression in immune-competent mice. Mass cytometry by time of flight revealed that ACE2-deficient murine orthotopic tumor tissues featured elevated M2-like tumor-associated macrophages, displayed a CCR5+PD-L1+ immunosuppressive phenotype, and exhibited high VEGFα expression. ACE2 downregulated tumor-intrinsic chemokine (C–C motif) ligand 5 expression by suppressing NF-κB signaling through the ACE2/angiotensin-(1–7)/Mas receptor axis. The lower chemokine (C–C motif) ligand 5 levels led to reduced activation of the JAK–STAT3 pathway and suppressed PD-L1 and VEGFα expression in macrophages, blocking macrophage infiltration and M2-like polarization. Pharmacologic targeting of CCR5 using maraviroc enhanced the tumor-suppressive effect of anti–PD-L1 therapy. Together, these findings suggest that activation of the ACE2 axis overcomes the immunosuppressive microenvironment of HCC and may serve as an immunotherapeutic target and predictive biomarker of response to PD-L1 blockade.
Significance: ACE2 regulates the immune landscape of hepatocellular carcinoma by abrogating M2-like macrophage polarization and sensitizes tumors to anti–PD-L1, suggesting that harnessing the ACE2 axis could be a promising strategy to improve immunotherapy efficacy.
ASCL1 Drives the Development of Neuroendocrine Prostate Cancer
Authors: McQuillen Caden N. , Brady Nicholas J. 
Published: November 2024

Therapeutic resistance to androgen receptor (AR)–targeting agents remains a significant clinical problem during the treatment of prostate cancer, with the incidence rate of resistant disease increasing as more men are treated with next-generation AR-targeted therapies. Lineage plasticity and progression to neuroendocrine prostate cancer (NEPC) are mechanisms by which prostate tumors lose dependence on androgen signaling and escape treatment. Although many known genetic alterations can predispose tumors to acquiring the NEPC phenotype, it remains unclear what, if any, drivers are essential to this progression. In this issue of Cancer Research, Rodarte and colleagues identified ASCL1 as one such essential regulator. Through the use of genetically engineered mouse models, the authors demonstrated that whereas ASCL1 was dispensable for tumor formation and growth, ASCL1 loss nearly completely abrogated the development of NEPC and instead redirected lineage trajectories toward a basal-like phenotype. This study provides an important new model for the study of NEPC, reveals the ability of ASCL1+ NEPC cells to also assume a NEUROD1+ state, and demonstrates the changes to tumor cell phenotypes following ASCL1 loss.
See related article by Rodarte et al., p. 3522
The Influence of DNA Repair Genes and Prenatal Tobacco Exposure on Risk of Childhood Acute Lymphoblastic Leukemia: A Gene–Environment Interaction Study
Authors: Wang Xinran , Zhong Charlie , Ma Xiaomei , Metayer Catherine , Mancuso Nicolas , Gauderman W. James , Wiemels Joseph L. 
Published: November 2024

Abstract

Background:
Acute lymphoblastic leukemia (ALL) is the most common type of cancer among children. Tobacco exposure during gestation has been investigated as a potential risk factor, but its role remains undefined. Given tobacco’s toxicologic profile as a DNA-damaging agent, we examined the impact of DNA repair gene variability as a source of vulnerability to tobacco exposure risk for ALL.

Methods:
Leveraging demographic and genotype data from two large California-based ALL epidemiology studies, we used logistic regression, MinimumP (minP) statistical method, and permutation tests to examine interactions between DNA repair genes and prenatal tobacco exposure.

Results:
We found statistically significant interactions between prenatal tobacco exposure and DNA repair genes RECQL (minP = 1.00 × 10−4, FDR-P value = 1.86 × 10−2) and TDG (minP = 1.00 × 10−4, FDR-P value = 1.86 × 10−2) with regard to childhood ALL risk. Notable interactions in the homologous recombination pathway were observed among Latino children, whereas non-Latino White children displayed significant interactions in the base excision repair and nucleotide excision repair pathways.

Conclusions:
Our study highlights the significance of DNA repair genes and pathways when evaluating environmental exposure to tobacco smoke, suggesting that genetic variability within these pathways could impact vulnerability in the development of childhood ALL.

Impact:
This study highlights the significant impact of genetic variation interacting with prenatal tobacco exposure on ALL risk. Further research is needed to understand these interactions and their implications for ALL etiology. Expanding studies to other gene–environment interactions will aid in developing targeted prevention, diagnosis, and treatment strategies for pediatric oncology.
Unearthing a Prostate Cancer cfDNA Signature that “Stems” from AR Alterations
Authors: Nawfal Rashad , El Hajj Chehade Razane , Berchuck Jacob E. 
Published: November 2024

Summary
Androgen receptor alterations portend a poor prognosis in patients with advanced prostate cancer. A recent study identified a stemness signature enriched in cell-free DNA from androgen receptor–altered patients, associated with worse outcomes. These findings highlight the potential of epigenomic liquid biopsy tools to discover novel clinically relevant tumor molecular subtypes.
See related article by Chauhan et al., p. 151
ASAP1 and ARF1 Regulate Myogenic Differentiation in Rhabdomyosarcoma by Modulating TAZ Activity
Authors: Hebron Katie E. , Perkins Olivia L. , Kim Angela , Jian Xiaoying , Girald-Berlingeri Sofia A. , Lei Haiyan , Shern Jack F. , Conner Elizabeth A. , Randazzo Paul A. , Yohe Marielle E. 
Published: November 2024

Abstract
Despite aggressive, multimodal therapies, the prognosis of patients with refractory or recurrent rhabdomyosarcoma (RMS) has not improved in four decades. Because RMS resembles skeletal muscle precursor cells, differentiation-inducing therapy has been proposed for patients with advanced disease. In RAS-mutant PAX fusion–negative RMS (FN-RMS) preclinical models, MEK1/2 inhibition (MEKi) induces differentiation, slows tumor growth, and extends survival. However, the response is short-lived. A better understanding of the molecular mechanisms regulating FN-RMS differentiation could improve differentiation therapy. In this study, we identified a role in FN-RMS differentiation for ASAP1, an ADP ribosylation factor (ARF) GTPase–activating protein (GAP) with both proinvasive and tumor-suppressor functions. We found that ASAP1 knockdown inhibited differentiation in FN-RMS cells. Interestingly, knockdown of the GTPases ARF1 or ARF5, targets of ASAP1 GAP activity, also blocked differentiation of FN-RMS. We discovered that loss of ARF pathway components blocked myogenic transcription factor expression. Therefore, we examined the effects on transcriptional regulators. MEKi led to the phosphorylation and inactivation of WW domain–containing transcriptional regulator 1 (WWTR1; TAZ), a homolog of the pro-proliferative transcriptional co-activator YAP1, regulated by the Hippo pathway. However, loss of ASAP1 or ARF1 blocked this inactivation, which inhibits MEKi-induced differentiation. Finally, MEKi-induced differentiation was rescued by dual knockdown of ASAP1 and WWTR1. This study shows that ASAP1 and ARF1 are necessary for myogenic differentiation, providing a deeper understanding of differentiation in FN-RMS and illuminating an opportunity to advance differentiation therapy.
Implications: ASAP1 and ARF1 regulate MEKi-induced differentiation of FN-RMS cells by modulating WWTR1 (TAZ) activity, supporting YAP1/TAZ inhibition as a FN-RMS differentiation therapy strategy.
Bleeding Associated With Antiarrhythmic Drugs in Patients With Atrial Fibrillation Using Direct Oral Anticoagulants: A Nationwide Population Cohort Study
Authors: Wu Victor Chien‐Chia , Wang Chun‐Li , Huang Yu‐Chang , Tu Hui‐Tzu , Huang Yu‐Tung , Kuo Chang‐Fu , Chen Shao‐Wei , Hung Kuo‐Chun , Wen Ming‐Shien , Chang Shang‐Hung 
Published: November 2024

Background
This study investigated drug–drug interactions in patients with atrial fibrillation taking both a direct oral anticoagulant (DOAC) and an antiarrhythmic drug.

Methods and Results

Using data from the National Health Insurance database (2012–2018), we identified 78 805 patients with atrial fibrillation on DOACs, with 24 142 taking amiodarone, 8631 taking propafenone, 2784 taking dronedarone, 297 taking flecainide, 177 taking sotalol, and 42 772 on DOACs alone. Patients with bradycardia, heart block, heart failure, mitral stenosis, prosthetic valves, or incomplete data were excluded. Propensity score matching compared those taking both DOACs and antiarrhythmic drugs with those on DOACs alone. There was an increased risk of major bleeding in patients concomitantly taking DOACs with amiodarone when compared with matched patients taking DOACs alone (hazard ratio [HR],1.13 [95% CI, 1.04–1.23];
P
=0.0044), particularly in patients taking dabigatran (HR, 1.19 [95% CI, 1.03–1.38];
P
=0.0175). No significant difference in bleeding risk was found for propafenone, dronedarone, flecainide, or sotalol. The small sample sizes in the flecainide and sotalol groups limit interpretation. Notably, intracranial bleeding risk was higher in patients on DOACs and amiodarone, regardless of age. Additionally, patients <80 years old taking dabigatran with amiodarone or propafenone had a higher risk of gastrointestinal bleeding.

Conclusions
Concomitant use of DOACs with amiodarone, but not dronedarone or propafenone, increases the risk of major bleeding, particularly intracranial bleeding. This study provides new evidence to guide clinicians to tailor concomitant anticoagulation and antiarrhythmic therapy for patients with atrial fibrillation.
Incidence and Outcomes After Out‐of‐Hospital Cardiac Arrest at Train Stations in Denmark
Authors: Sheikh Annam Pervez , Grabmayr Anne Juul , Kjølbye Julie Samsøe , Ersbøll Annette Kjær , Hansen Carolina Malta , Folke Fredrik 
Published: November 2024

Background
Following international guidelines, communities have deployed automated external defibrillators at train stations without substantive evidence.

Methods and Results
We geocoded public out‐of‐hospital cardiac arrests (OHCAs) (2016–2020), automated external defibrillators, and train stations. The stations were divided into the following groups according to passenger flow: 1 (0–499), 2 (500–4999), 3 (5000–9999), and 4 (>10 000) passengers per day. Risk ratios (RRs) were calculated using Poisson regression of rates, and odds ratios (ORs) were analyzed through logistic regression. OHCAs at train stations accounted for 102 (2.3%) of 4467 public OHCAs. The incidence rate (IR) and RR for OHCAs were for group 1: IR, 0.02 OHCA per station per year, RR, 1.0 (reference); group 2: IR, 0.07, RR, 4.1 (95% CI, 2.3–7.3); group 3: IR, 0.25, RR, 12.7 (95% CI, 6.2–25.9); and group 4: IR, 0.34, RR, 16.3 (95% CI, 8.6–30.9).
Compared with other public OHCAs, OHCAs at train stations were just as likely to receive bystander cardiopulmonary resuscitation (OR, 1.13 [95% CI, 0.60–2.12]). However, they had higher odds of bystander defibrillation (OR, 1.66 [95% CI, 1.06–2.58]), were more likely to achieve return of spontaneous circulation (OR, 1.88 [95% CI, 1.24–2.85]), and survive 30 days (OR, 2.37 [95% CI, 1.57–3.59]).

Conclusions
The incidence of OHCAs at train stations was associated with passenger flow, with the busiest stations having a 16‐fold higher risk of OHCAs than the lowest. OHCAs at train stations had better outcomes compared with other public OHCAs.
Invasive Versus Conservative Strategy in Older Adults ≥75 Years of Age With Non–ST‐segment–Elevation Acute Coronary Syndrome: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials
Authors: Rout Amit , Moumneh Mohamad B. , Kalra Kriti , Singh Sahib , Garg Aakash , Kunadian Vijay , Biscaglia Simone , Alkhouli Mohamad A. , Rymer Jennifer A. , Batchelor Wayne B. , Nanna Michael G. , Damluji Abdulla A. 
Published: November 2024

Background
Older adults with non–ST‐segment–elevation acute coronary syndrome are less likely to undergo an invasive strategy compared with younger patients. Randomized controlled trials traditionally exclude older adults because of their high burden of geriatric conditions.

Methods and Results

We searched for randomized controlled trials comparing invasive versus medical management or a selective invasive (conservative) strategy for older patients (age≥75 years) with non–ST‐segment–elevation acute coronary syndrome. Fixed effects meta‐analysis was conducted to estimate the odds ratio (OR) with 95% CI for the composite of death or myocardial infarction (MI) and individual secondary end points of all‐cause death, cardiovascular death, MI, revascularization, stroke, and major bleeding. Nine studies with 2429 patients (invasive: 1228 versus control: 1201) with a mean follow‐up of 21 months were included. An invasive strategy was associated with a significantly decreased risk of a composite of death and MI (OR, 0.67 [95% CI, 0.54–0.83],
P
<0.001), MI (OR, 0.56 [95% CI, 0.45–0.70],
P
<0.001) and subsequent revascularization (OR, 0.27 [95% CI, 0.16–0.48],
P
<0.001). There was no difference in all‐cause death (OR, 0.84 [95% CI, 0.65–1.10],
P
=0.21), cardiovascular death (OR, 0.85 [95% CI, 0.63–1.15],
P
=0.30), stroke (OR, 0.74 [95% CI, 0.38–1.47],
P
=0.39), or major bleeding (OR, 1.24 [95% CI, 0.42–3.66],
P
=0.70).

Conclusions
In older patients ≥75 years old with non–ST‐segment–elevation acute coronary syndrome, an invasive strategy reduced the risk of a composite of death and MI, MI, and subsequent revascularization compared with a conservative strategy alone. Older adults with higher burden of geriatric conditions should be included in future trials to improve generalizability to this growing population.
Associations Between Atherosclerosis and Subsequent Cognitive Decline: A Prospective Cohort Study
Authors: Liang Jie , Pan Yang , Zhang Wenya , Gao Darui , Ma Jingya , Zhang Yanyu , Ji Mengmeng , Dai Yiwen , Liu Yuling , Wang Yongqian , Zhu Yidan , Lu Bin , Xie Wuxiang , Zheng Fanfan 
Published: November 2024

Background
This study aimed to examine whether baseline atherosclerosis was associated with subsequent short‐term domain‐specific cognitive decline.

Methods and Results

This research was based on the BRAVE (Beijing Research on Aging and Vessel) study, a population‐based prospective cohort study of adults aged 40 to 80 years, free of dementia. At baseline (wave 1, 2019), cognitive assessments and atherosclerosis measures, including carotid intima‐media thickness, carotid plaques, coronary artery calcification, and brachial–ankle pulse wave velocity were conducted. Cognitive function was reassessed in wave 2 (2022–2023) using linear mixed models for analysis. A total of 932 participants (63.7% women; mean age, 60.0±6.9 years) were included. Compared with the lowest tertile of carotid intima‐media thickness, carotid plaques, and brachial–ankle pulse wave velocity, or a coronary artery calcification score=0, the highest tertile of carotid intima‐media thickness (β=−0.065 SD/y [95% CI, −0.112 to −0.017];
P
=0.008), carotid plaques (β=−0.070 SD/y [95% CI, −0.130 to −0.011];
P
=0.021), and brachial–ankle pulse wave velocity (β=−0.057 SD/y [95% CI, −0.105 to −0.010];
P
=0.018), and a coronary artery calcification score≥400 (β=−0.081 SD/y [95% CI, −0.153 to −0.008];
P
=0.029) were significantly associated with a faster decline in semantic fluency after multivariable adjustment. Moreover, greater carotid intima‐media thickness, coronary artery calcification, and brachial–ankle pulse wave velocity were significantly associated with a faster decline in global cognition.

Conclusions
More significant atherosclerosis was associated with faster semantic fluency and global cognition declines.
Super‐Enhancer–Driven Syndecan‐4 Regulates Intercellular Communication in Hypoxic Pulmonary Hypertension
Authors: Wang Xiaoying , Zhu Xiangrui , Huang Wei , Wang Zhaosi , Mei Jian , Ou Langlin , Chen Yunwei , Ma Cui , Zhang Lixin 
Published: November 2024

Background
Unveiling pro‐proliferation genes involved in crosstalk between pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs) are important to improving the therapeutic outcome of pulmonary hypertension (PH). Although growing studies have shown that super‐enhancers (SEs) play a pivotal role in pathological and physiological processes, the SE‐associated genes in PH and their impact on PASMC proliferation remain largely unexplored.

Methods and Results
We used serotype 5 adenovirus‐associated virus to interfere with syndecan‐4 and constructed an SU5416 combined with hypoxia–PH model. Chromatin immunoprecipitation sequencing analysis, chromatin immunoprecipitation quantitative polymerase chain reaction, and bioinformatics were used to confirm early growth response 1 was involved in regulating syndecan‐4‐associated SE in PASMCs. The effects of syndecan‐4 and its underlying mechanisms were subsequently elucidated using Western blot, coimmunoprecipitation, and cell coculture assays. Herein, we identified a novel SE‐associated gene, syndecan‐4, in hypoxia‐exposed PASMCs. Syndecan‐4 was transcriptionally driven by early growth response 1 via an SE and was significantly overexpressed in hypoxic PASMCs and plasma from patients with PH. Mechanism studies revealed that syndecan‐4 induces PASMC proliferation by interacting and regulating protein kinase C α ubiquitination. In addition, syndecan‐4 was enriched in exosomes secreted from hypoxic PASMCs, which subsequently transported and led to pulmonary artery endothelial cell dysfunction. Syndecan‐4 inhibition in hypoxia by serotype 5 adenovirus‐associated virus treatment attenuated the pulmonary artery remodeling and development of PH in vivo.

Conclusions
Taken together, our results demonstrate that an SE‐driven syndecan‐4 modulates crosstalk of PASMCs and pulmonary artery endothelial cells and promotes vascular remodeling via the protein kinase C α and exosome pathway, thus providing potential targets for the early diagnosis and treatment of hypoxic PH.
Prognostic Value of Hospital Frailty Risk Score and Clinical Outcomes in Critical Limb‐Threatening Ischemia and End‐Stage Kidney Disease
Authors: Majmundar Monil , Chan Wan‐Chi , Bhat Vivek , Patel Kunal N. , Hance Kirk A. , Hajj Georges , Thors Axel , Gupta Kamal 
Published: November 2024

Background
End‐stage kidney disease (ESKD) is commonly associated with critical limb‐threatening ischemia (CLTI) and frailty. Yet there are no specific tools to predict outcomes of CLTI in ESKD, particularly those that incorporate frailty. We aimed to assess the utility of the medical record–based Hospital Frailty Risk (HFR) score in predicting outcomes of CLTI in ESKD.

Methods and Results

We identified patients with ESKD diagnosed with CLTI from the US Renal Data System from 2015 to 2018. These patients were categorized into 3 frailty risk groups on the basis of their HFR scores: low (<5), intermediate (5–10), high‐risk (>10), and on the basis of whether they underwent revascularization (endovascular revascularization [ER]/surgical revascularization [SR]) or not (no revascularization). Primary outcomes of interest included in‐hospital composite of death or major amputation and in‐hospital death. We included 49 454 eligible patients, with ER/SR cohort including 19.8% (n=9777). A total of 88.4% (ER/SR) and 90.0% (no revascularization) were frail on the HFR scale. We found a nonlinear association between HFR score and in‐hospital adverse outcomes. In both cohorts, intermediate and high‐risk HFR scores were associated with greater risk of in‐hospital death (high‐risk, ER/SR: odds ratio, 2.7 [95% CI, 1.6–4.8];
P
<0.0001; no revascularization: odds ratio, 7.8 [95% CI, 5.3–11.6];
P
<0.01) and composite of in‐hospital major amputation or death (high‐risk, ER/SR: odds ratio, 2.4 [95% CI, 1.9–3.1];
P
<0.0001; no revascularization: odds ratio, 1.7 [95% CI, 1.5–1.9];
P
<0.0001).

Conclusions
The HFR score can predict risk of in‐hospital death and composite of death or major amputation in patients with ESKD and CLTI. Further data are needed to determine the utility of the HFR score in this population.
Morbidity Burden in Patients With Ebstein Anomaly: The Natural History
Authors: Eckerström Filip , Hjortdal Vibeke Elisabeth , Eriksson Peter , Dellborg Mikael , Mandalenakis Zacharias 
Published: November 2024

Background
The lifetime morbidity burden of patients with Ebstein anomaly (EA) has not been well described.

Methods and Results
Through an extensive 2‐country register‐based collaboration, patients diagnosed with EA who were born between 1930 and 2017 were identified in Danish and Swedish nationwide medical registries. Each patient was matched by age and sex with 10 control subjects from the general population. Cox proportional‐hazards regression, Fine–Gray competing risk regression, and Kaplan–Meier failure function were used to estimate the morbidity burden. The study included 794 patients diagnosed with EA and 7940 controls, with a median follow‐up period of 33 years. Among patients with EA, approximately half (n=442) had isolated EA, and 28% (n=218) had concomitant atrial septal defect. Patients with complex anatomy demonstrated the highest cardiovascular morbidity burden, followed by those with concomitant atrial septal defect and isolated EA. The lifetime cumulative incidence of supraventricular arrhythmia and ventricular preexcitation in patients with EA, with or without atrial septal defect, was approximately 70% and 19%, respectively. Supraventricular arrhythmia substantially increased the risk of ischemic stroke (hazard ratio [HR] 22.6 [95% CI, 11.1–45.9]). Presence of atrial septal defect significantly affected arrhythmia and heart failure burden compared with isolated EA. In the total cohort of patients with EA, supraventricular arrhythmia onset led to an immediate high incidence of heart failure, with a 10‐year cumulative incidence of 18%.

Conclusions
The natural history of EA, whether isolated or not, involves a substantial burden of cardiovascular morbidity and thus a highly vulnerable long‐term prognosis.