bluuebunny/crossref_metadata_2025_split huggingface dataset:
Uncovering Risks Associated with Smoking Types and Intensities in Esophageal Cancer within High-Prevalence Regions in Africa: A Comprehensive Meta-analysis
Authors: Kamsu Gabriel T. , Ndebia Eugene J. 
Published: April 2024

Abstract
Tobacco is usually cited among the well-known risk factors of esophageal cancer; nevertheless, the extent of the contribution of the type of smoking and its intensity to the disease has not been comprehensively elucidated in Africa. We searched MEDLINE/PubMed, Excerpta Medica Database, Web of Science, Scopus, Cochrane Library, and African Journals Online studies published before September 2023. The quality of the studies was assessed using the Newcastle–Ottawa scale, and the funnel plot was used for assessing potential publication bias. Meta-analyses were conducted to estimate summary effects using random-effects models. This study included 22,319 participants from 27 studies. The results strongly indicate a significant association between tobacco use and a higher risk of esophageal cancer. The risk of esophageal cancer is notably higher among pipe smokers [OR = 4.68; 95% confidence interval (CI), 3.38–6.48], followed by hand-rolled cigarette smokers (OR = 3.79; 95% CI, 2.68–5.35), in comparison with those who smoked commercially manufactured cigarettes (OR = 2.46; 95% CI, 1.69–3.60). Our findings also showed that the risk of esophageal cancer is highest in people smoking &gt;183 packs per year (OR = 5.47; 95% CI, 3.93–7.62), followed by those smoking 93 to 183 packs per year (OR = 3.90; 95% CI, 3.13–4.86), in comparison with those smoking ≤92 packs per year (OR = 2.90; 95% CI, 2.19–3.84). Our findings strongly show that among the different types of tobacco use in Africa, pipe and hand-roller smokers face a higher risk of esophageal cancer.
Assessing Management of Abnormal Cervical Cancer Screening Results and Concordance with Guideline Recommendations in Three US Healthcare Settings
Authors: Cheng David , Rieu-Werden Meghan L. , Lykken Jacquelyn M. , Werner Claudia L. , Feldman Sarah , Silver Michelle I. , Atlas Steven J. , Tiro Jasmin A. , Haas Jennifer S. , Kamineni Aruna 
Published: April 2024

Abstract

Background:
Follow-up of abnormal results is essential to cervical cancer screening, but data on adherence to follow-up are limited. We describe patterns of follow-up after screening abnormalities and identify predictors of guideline-concordant follow-up.

Methods:
We identified the index screening abnormality (positive human papillomavirus test or atypical squamous cells of undetermined significance or more severe cytology) among women of ages 25 to 65 years at three US healthcare systems during 2010 to 2019. We estimated the cumulative incidence of surveillance testing, colposcopy, or treatment after the index abnormality and initial colposcopy. Logistic regressions were fit to identify predictors of guideline-concordant follow-up according to contemporaneous guidelines.

Results:
Among 43,007 patients with an index abnormality, the cumulative incidence of any follow-up was 49.6% by 4 years for those with atypical squamous cells of undetermined significance/human papillomavirus–negative and higher for abnormalities warranting immediate colposcopy. The 1-year cumulative incidence of any follow-up after colposcopy was 70% for patients with normal results or cervical intraepithelial neoplasia I and 90% for patients with cervical intraepithelial neoplasia II+. Rates of concordant follow-up after screening and colposcopy were 52% and 47%, respectively. Discordant follow-up was associated with factors including age, race/ethnicity, overweight/obese body mass index, and specific types of public payor coverage or being uninsured.

Conclusions:
Adherence to the recommended follow-up of cytologic and histopathologic abnormalities is inconsistent in clinical practice. Concordance was poor for mild abnormalities and improved, although suboptimal, for more severe abnormalities.

Impact:
There remain gaps in the cervical cancer screening process in clinical practice. Further study is needed to understand the barriers to the appropriate management of cervical abnormalities.
Exercise and QUality Diet after Leukemia: A Randomized Weight Loss Trial among Adult Survivors of Childhood Leukemia in the Childhood Cancer Survivor Study
Authors: Friedman Danielle N. , Chou Joanne F. , Clark Jeanne M. , Moskowitz Chaya S. , Ford Jennifer S. , Armstrong Gregory T. , Mubdi Nidha Z. , McDonald Aaron , Nathan Paul C. , Sklar Charles A. , Ramanathan Lakshmi V. , Robison Leslie L. , Oeffinger Kevin C. , Tonorezos Emily S. 
Published: April 2024

Abstract

Background:
Obesity is prevalent in childhood cancer survivors and interacts with cancer treatments to potentiate risk for cardiovascular (CV) death. We tested a remote weight-loss intervention trial that was effective among adults with CV risk factors in a cohort of adult survivors of childhood acute lymphoblastic leukemia (ALL) with overweight/obesity.

Methods:
In this phase III efficacy trial, survivors of ALL enrolled in the Childhood Cancer Survivor Study with a body mass index ≥25 kg/m2 were randomized to a remotely delivered weight-loss intervention versus self-directed weight loss, stratified by history of cranial radiotherapy. The primary endpoint was the difference in weight loss at 24 months in an intent-to-treat analysis. Analyses were performed using linear mixed-effects models.

Results:
Among 358 survivors (59% female; median attained age: 37 years; IQR: 33–43 years), the baseline mean (SD) weight was 98.6 kg (24.0) for the intervention group (n = 181) and 94.9 kg (20.3) for controls (n = 177). Adherence to the intervention was poor; 15% of individuals in the intervention group completed 24/30 planned coaching calls. Weight at 24 months was available for 274 (77%) participants. After controlling for cranial radiotherapy, sex, race/ethnicity, and age, the mean (SE) change in weight from baseline to 24 months was −0.4 kg (0.8) for the intervention group and 0.2 kg (0.6) for control participants (P = 0.59).

Conclusions:
A remote weight-loss intervention that was successful among adults with CV conditions did not result in significant weight loss among adult survivors of childhood ALL.

Impact:
Future interventions in this population must be tailored to the unique needs of survivors to encourage engagement and adherence.
See related In the Spotlight, p. 1147
A First-in-Human Phase 1 Study of a Tumor-Directed RNA-Interference Drug against HIF2α in Patients with Advanced Clear Cell Renal Cell Carcinoma
Authors: Brugarolas James , Obara Gregory , Beckermann Kathryn E. , Rini Brian , Lam Elaine T. , Hamilton James , Schluep Thomas , Yi Min , Wong So , Mao Zhongping Lily , Gamelin Erick , Tannir Nizar M. 
Published: April 2024

Abstract

Purpose:
ARO-HIF2 is an siRNA drug designed to selectively target hypoxia-inducible factor-2α (HIF2α) interrupting downstream pro-oncogenic signaling in clear cell renal cell carcinoma (ccRCC). The aims of this Phase 1 study (AROHIF21001) were to evaluate safety, tolerability, pharmacokinetics, and establish a recommended Phase 2 dose.

Patients and Methods:
Subjects with ccRCC and progressive disease after at least 2 prior therapies that included VEGF and immune checkpoint inhibitors were progressively enrolled into dose-escalation cohorts of ARO-HIF2 administered intravenously at 225, 525, or 1,050 mg weekly.

Results:
Twenty-six subjects received ARO-HIF2. The most common treatment emergent adverse events (AE) irrespective of causality were fatigue (50.0%), dizziness (26.9%), dyspnea (23.1%), and nausea (23.1%). Four subjects (15.4%) had treatment-related serious AEs. AEs of special interest included neuropathy, hypoxia, and dyspnea. ARO-HIF2 was almost completely cleared from plasma circulation within 48 hours with minimal renal clearance. Reductions in HIF2α were observed between pre- and post-dosing tumor biopsies, but the magnitude was quite variable. The objective response rate was 7.7% and the disease control rate was 38.5%. Responses were accompanied by ARO-HIF2 uptake in tumor cells, HIF2α downregulation, as well as rapid suppression of tumor produced erythropoietin (EPO) in a patient with paraneoplastic polycythemia.

Conclusions:
ARO-HIF2 downregulated HIF2α in advanced ccRCC—inhibiting tumor growth in a subset of subjects. Further development was hampered by off-target neurotoxicity and low response rate. This study provides proof of concept that siRNA can target tumors in a specific manner.
Immunologic Profiling of Immune-Related Cutaneous Adverse Events with Checkpoint Inhibitors Reveals Polarized Actionable Pathways
Authors: Lacouture Mario E. , Goleva Elena , Shah Neil , Rotemberg Veronica , Kraehenbuehl Lukas , Ketosugbo Kwami F. , Merghoub Taha , Maier Tara , Bang Alexander , Gu Stephanie , Salvador Trina , Moy Andrea P. , Lyubchenko Taras , Xiao Olivia , Hall Clifton F. , Berdyshev Evgeny , Crooks James , Weight Ryan , Kern Jeffrey A. , Leung Donald Y.M. 
Published: April 2024

Abstract

Purpose:
Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood.

Experimental Design:
Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays.

Results:
Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P &lt; 0.0001) and psoriasiform dermatitis (P &lt; 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P &lt; 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P &lt; 0.001), lichenoid (P &lt; 0.0001), bullous dermatitis (P &lt; 0.05), and MPR (P &lt; 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine–targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo.

Conclusions:
Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.
Classifying Glioma via Liquid Biopsy: Progress toward an Unmet Clinical Need
Authors: Abdullah Kalil G. 
Published: April 2024

Summary
The diagnosis and classification of glioma by liquid biopsy represent a critical unmet need in neuro-oncology. A recent study demonstrates targeted next-generation sequencing of cell-free DNA from cerebrospinal fluid as an evolving option for liquid biopsy in patients with glioma.
See related article by Iser et al., p. 2974
FLT3 Agonists and Secondary Hematopoietic Malignancies: A Potential Class Effect
Authors: Raeder Henry W. , Drazer Michael W. 
Published: April 2024

SummaryExpansion of conventional dendritic cells via FMS-like tyrosine kinase 3 agonism has promising therapeutic potential in the treatment of advanced solid tumors. In this study, we discuss the results of a clinical trial using GS-3583, an FMS-like tyrosine kinase 3 agonist, that was stopped after a patient in the study developed acute myeloid leukemia.See related article by Tolcher et al., p. 2954
Abstract 605: ERK5 Activation Regulates PPARalpha Activity and Subsequent Cardioprotection After Ischemia/Reperfusion
Authors: Ding Bo , Yan Chen , Liu Weiming , Shishido Tetsuro , Woo Chang Hoon , McClain Carolyn , Abe Jun-Ichi 
Published: April 2024

Background: The strong cardioprotective effect of erythropoietin (EPO) and heme oxygenase-1 (HO-1) have been reported, but the mechanism are not understood. Previously we found that activation of big MAP kinase 1 (BMK1/ERK5) inhibits cardiac injury after myocardial ischemia and reperfusion. The hinge-helix 1 region of peroxisome proliferator-activated receptor gamma1 (PPARgamma1) mediates interaction with extra-cellular signal-regulated kinase 5(ERK5). We hypothesize that ERK5 activation induced by insulin growth factor-1(IGF-1), erythropoietin(EPO) and heme oxygenase-1(HO-1) is a “key modulator” of PPARa activity and provides a cardioprotective effect after I/R. Thus the aim of this study was to explore the mechanism of the protective effect of EPO, HO-1 and IGF-1 via ERK5 activation.
Method and Results: We have found that EPO, HO-1 and IGF-1 stimulate ERK5 activation in the heart, and increase PPARa activity via an ERK5 dependent manner. To prove the role of ERK5 kinase/PPARa activation in IGF-1, EPO and HO-1 mediated cardioprotection after I/R, we characterized the unique role of ERK5 in IGF-1, EPO and HO-1-mediated PPARa activation. In cardiomyocytes, IGF-1, EPO and HO-1 mediate endogenous ERK5 association with endogenous PPARa but not phosphorylation of the PPARa. Activation of ERK5 by Ad-CA-MEK5a trigged the induction of mCPT-1 and PDK4, which promote fatty acid beta-oxidation (FAO) enzyme pathway via increasing PPARa transcriptional activation. Also we found that increased apoptosis in cardiomyocytes incubated by H2O2 compared to non-treated group( 3– 4 times increase H2O2 group vs. wildtype group). However HO-1 induction, EPO and IGF-1 treatment blocked the increased apoptosis induced by H2O2 stimulation. To determine the role of ERK5 kinase in EPO-mediated cardioprotection in vivo, we used the I/R mouse model in CA-MEK5a transgenic mice. Our preliminary experiments suggest a smaller infarction size in CA-MEK5a transgenic mice hearts compared to control hearts.
Conclusion: We propose a key role for PPARa and subsequent activation of FAO enzyme induced by EPO and HO-1 mediated cardioprotection. These factors are induced by ERK5 activation. These data suggest that ERK5 is a critical factor and therefore a future therapeutic target.
Abstract 5041: Insulin Resistance Reduces Circulating Endothelial Progenitor Cells and Impairs Endothelial Regeneration Following Wire-induced Vascular Injury
Authors: Kahn Matthew B , Cubbon Richard , Visvambharan Hema , Yuldasheva Nadira , Kearney Mark T , Wheatcroft Stephen 
Published: April 2024

Introduction: Endothelial progenitor cells (EPCs) contribute to endothelial regeneration following damage accrued through exposure to various risk factors. Type 2 diabetes is associated with reduced EPC numbers, EPC dysfunction and delayed endothelial repair. However, it remains unknown whether insulin resistance per se has an effect on EPCs or endothelial regeneration.
Methods: We assessed metabolic and endothelial function, circulating, spleen- and bone marrow-derived EPCs and endothelial regeneration following wire-injury in mice hemizygous for deletion of the insulin receptor (IR+/−) and their littermate wild type (WT) controls. Results: The metabolic phenotype of IR+/− mice was consistent with compensated insulin resistance, with hyperinsulinaemia after a glucose challenge but a normal blood glucose response to a glucose tolerance test. Endothelial function was impaired in aorta from IR+/− mice, with decreased basal nitric oxide production and blunted eNOS activity in response to insulin. Sca-1/VEGFR-2 positive EPCs, measured in peripheral blood by flow cytometry, were reduced in IR+/− mice compared to WT controls (67±6 vs 87±6 cells/100 000 events; P<0.05). Culture of mononuclear cells from peripheral blood, spleen and bone marrow revealed significantly reduced numbers of circulating EPCs in IR+/− mice compared to WT controls (P<0.05), however there was no difference in the number of spleen- and bone marrow-derived EPCs. Endothelial regeneration, assessed by Evan’s blue staining of femoral artery at intervals following denuding wire-injury, was significantly delayed in IR+/− mice compared to WT controls (reendothelialised area 35.8±4.8% vs 66.6±5.2% at day 5 following injury and 35.6±4.8% vs 59.8±6.6% at day 7 following injury; P<0.05).
Conclusions: These novel data demonstrate that mild insulin resistance reduces the number of basal circulating EPCs and delays endothelial regeneration following injury. The findings support the hypothesis that insulin resistance may promote atherosclerosis by adversely affecting the balance between endothelial damage and repair.
Abstract 5088: Exercise Training Increases Endothelial Progenitor Cells and Decreases Asymmetrical Dimethylarginine in Patients With Intermittent Claudication
Authors: Schlager Oliver , Giurgea Aura , Schuhfried Othmar , Gschwandtner Michael , Koppensteiner Renate , Steiner Sabine 
Published: April 2024

Background - Exercise training is a well-established, non-invasive method to improve peripheral arterial perfusion and walking capacity in PAD patients.
Hypothesis - We designed a prospective randomized controlled trial to test the effect of training on laboratory markers of angiogenesis.
Methods - Thirty patients with intermittent claudication were randomized to supervised training twice a week for 6 months or standard medical therapy. Endothelial progenitor cells (EPC) were assessed by whole-blood flow cytometry (co-expression of CD34+CD133+KDR+) and cell culture assays (colony forming units/CFU and circulating angiogenic cells/CAC) at baseline, 3-months and 6-months after training as well as 12-months after study begin. Plasma ADMA was determined by immunoassay. In addition, changes in maximum walking distance were recorded.

Results - EPC measured by flow cytometry increased significantly three and six months after training paralleled by a significant decrease of ADMA (asymmetric dimethylarginine), a major endogenous inhibitor of NO synthase (see table

). The number of CFUs and CACs were significantly higher after 6-months compared to baseline upon exercise (P<0.05). No differences were observed in the standard group in timecourse. However, 6-months after training cessation the number of EPC and ADMA levels were similar to baseline. Exercise training showed a benefit on treadmill maximum walking distance with a trendwise increase at 6-months (training: baseline 116.6m±12.8 (mean±SEM) vs. 6-months 149.1m±17.8, P=0.08; standard: baseline 125.2m±23.9 vs. 6-months 108m±19.9, P=0.3). The benefit was sustained 6 months after training cessation in the exercise group (training: 12-months 157.5m±18.4, P=0.07; standard: 12-months 129.5m±26.9).

Conclusions - The beneficial effect of exercise training in PAD patients might partly be due to EPC mobilization mediated by improved NO synthesis as we observed reduced ADMA levels.

EPC and ADMA levels in timecourse
Abstract 5090: Nadph Oxidase-mediated Arterial Dysfunction in Patients With Peripheral Arterial Disease
Authors: Loffredo Lorenzo , Carnevale Roberto , Cangemi Roberto , Perri Ludovica , Di Santo Serena , Mormina Paola , Basili Stefania , Pignatelli Pasquale , Violi Francesco 
Published: April 2024

BACKGROUND. Peripheral arterial disease (PAD) is a clinical setting characterized by endothelial dysfunction and atherosclerosis. NADPH oxidase is believed to modulate arterial tone and oxidative stress but its role in PAD is still unclear.
OBJECTIVE. The aim of this study was to evaluate whether NADPH oxidase is implicated in determining reduced FMD and to assess if the administration of an antioxidant was able to improve arterial dilatation and gp91phox, the catalytic core of NADPH oxidase, serum levels in PAD patients.
METHODS. We performed a cross-sectional study comparing flow-mediated dilation, oxidative stress, by serum levels of 8-Hydroxy-2-deoxy-2-deoxyguanosine (8-OHdG), and NO generation, by serum levels of nitrite/nitrate (NOx), and serum gp91phox in a population of PAD patients (n=25; mean age: 63.7±7.9 years) and controls (n=40; mean age: 64.2±11.2 years). In the second part, we performed an interventional cross-over study in PAD patients to assess if the infusion of an antioxidant, propionyl-L-carnitine (PLC), vs placebo, was able to improve endothelial dysfunction and serum gp91phox levels in 20 PAD patients.
RESULTS. Compared with controls, patients with PAD had enhanced gp91phox (mean±S.E.: 21.3±3.6 vs 71.7±14; p<0.001) and 8-OHdG serum levels (mean±SD: 2.4+1.2 vs. 4.24+3.11 ng/mL; P<0.001), reduced NOx (mean±SD:17.02+6.11 vs.11.28+6.02 mM; P<0.001), and lowered FMD (mean±SD: 10.34+2.14 vs. 6.69+2.95%; P<0.001). General linear model analysis for repeated measures showed that PLC infusion was associated with an increase of FMD (from 6.6±0.6 to 11.1±1.2%, F=9.98, p=0.005) and with a reduction of serum gp91phox (from 88.2±13 to 38.6±5.9, F=9.98, p=0.006). No changes were observed after placebo treatment.
CONCLUSIONS. This study shows that in PAD patients, gp91phox is overexpressed and may contribute to reduce FMD.
Abstract 5322: Donepezil, an Acetylcholinesterase Inhibitor, Attenuates Atherogenesis in Apolipoprotein E Knockout Mice Through Antioxidative and Anti-inflammatory Effects
Authors: Inanaga Keita , Ichiki Toshihiro , Takeda Kotaro , Sunagawa Kenji 
Published: April 2024

Objective Donepezil, a reversible acetylcholinesterase inhibitor, improves cognitive function of Alzheimer’s disease. Vagus nerve stimulation is known to attenuate inflammatory responses in mice with lipopolysaccharide-induced sepsis, which is designated cholinergic anti-inflammatory system. We investigated whether the pharmacological stimulation of cholinergic system by donepezil affects atherogenesis in apolipoprotein (Apo) E-knockout (KO) mice.
Methods and Results Male ApoE-KO mice (10-week-old) were fed a high fat diet (HFD) and received infusion of angiotensin (Ang) II (1.9 mg/kg/day). Oral administration of donepezil (5 mg/kg/day) or infusion of physostigmine (2mg/kg/day), another acetylcholinesterase inhibitor, for 4 weeks did not change hemodynamics or cholesterol level, but significantly reduced Oil Red O-positive area of en face aorta (Control 3.8±0.4%, AngII + HFD 13.6±2.2%, AngII + HFD and donepezil 6.9±0.9%*, AngII + HFD and physostigmine 8.2±0.6%*, *P<0.05 vs AngII + HFD) and macrophage infiltration into the aortic root (p<0.05). Donepezil also decreased monocyte chemoattractant protein (MCP)-1-positive area by 45% (p<0.05) in the aortic sinus. Donepezil administration also attenuated atherogenesis in ApoE-KO mice fed a HFD for 8 weeks without AngII infusion. Quantitative RT-PCR revealed that administration of donepezil to ApoE-KO mice treated with AngII and a HFD significantly suppressed expression of MCP-1 and tumor necrosis factor-alpha 52% and 70% reduction, respectively, P<0.05) in the aorta. Donepezil significantly suppressed NADPH oxidase activity (43% reduction, P<0.05) and production of reactive oxygen species in the aorta. Preincubation with acetylcholine completely inhibited AngII-induced NADPH oxidase 1 expression in cultured vascular smooth muscle cells (P<0.05).
Conclusion The present study revealed a novel anti-atherosclerotic effect of pharmacological stimulation of cholinergic system by donepezil. Donepezil may increase acetylcholine availability and downregulate NADPH oxidase followed by suppression of inflammatory cytokine production and atherogenesis. Cholinergic stimulation may be a novel therapeutic strategy for atherosclerotic cardiovascular diseases.