bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestine-Specific Homeobox Gene ISX Integrates IL6 Signaling, Tryptophan Catabolism, and Immune Suppression
Authors: Wang Li-Ting , Chiou Shyh-Shin , Chai Chee-Yin , Hsi Edward , Yokoyama Kazunari K. , Wang Shen-Nien , Huang Shau-Ku , Hsu Shih-Hsien 
Published: June 2017

Abstract
The intestine-specific homeobox transcription factor intestine-specific homeobox (ISX) is an IL6-inducible proto-oncogene implicated in the development of hepatocellular carcinoma, but its mechanistic contributions to this process are undefined. In this study, we provide evidence that ISX mediates a positive feedback loop integrating inflammation, tryptophan catabolism, and immune suppression. We found that ISX-mediated IL6-induced expression of the tryptophan catabolic enzymes Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase in hepatocellular carcinoma cells, resulting in an ISX-dependent increase in the tryptophan catabolite kynurenine and its receptor aryl hydrocarbon receptor (AHR). Activation of this kynurenine/AHR signaling axis acted through a positive feedback mechanism to increase ISX expression and enhance cellular proliferation and tumorigenic potential. RNAi-mediated attenuation of ISX or AHR reversed these effects. In an IDO1-dependent manner, ectopic expression of ISX induced expression of genes encoding the critical immune modulators CD86 (B7-2) and programmed death ligand-1 (PD-L1), through which ISX conferred a significant suppressive effect on the CD8+ T-cell response. In hepatocellular carcinoma specimens, expression of IDO1, kynurenine, AHR, and PD-L1 correlated negatively with survival. Overall, our results identified a feed-forward mechanism of immune suppression in hepatocellular carcinoma organized by ISX, which involves kynurenine-AHR signaling and PD-L1, offering insights into immune escape by hepatocellular carcinoma, which may improve its therapeutic management. Cancer Res; 77(15); 4065–77. ©2017 AACR.
Potential Susceptibility Loci Identified for Renal Cell Carcinoma by Targeting Obesity-Related Genes
Authors: Shu Xiang , Purdue Mark P. , Ye Yuanqing , Tu Huakang , Wood Christopher G. , Tannir Nizar M. , Wang Zhaoming , Albanes Demetrius , Gapstur Susan M. , Stevens Victoria L. , Rothman Nathaniel , Chanock Stephen J. , Wu Xifeng 
Published: June 2017

Abstract
Background: Obesity is an established risk factor for renal cell carcinoma (RCC). Although genome-wide association studies (GWAS) of RCC have identified several susceptibility loci, additional variants might be missed due to the highly conservative selection.
Methods: We conducted a multiphase study utilizing three independent genome-wide scans at MD Anderson Cancer Center (MDA RCC GWAS and MDA RCC OncoArray) and National Cancer Institute (NCI RCC GWAS), which consisted of a total of 3,530 cases and 5,714 controls, to investigate genetic variations in obesity-related genes and RCC risk.
Results: In the discovery phase, 32,946 SNPs located at ±10 kb of 2,001 obesity-related genes were extracted from MDA RCC GWAS and analyzed using multivariable logistic regression. Proxies (R2 &gt; 0.8) were searched or imputation was performed if SNPs were not directly genotyped in the validation sets. Twenty-one SNPs with P &lt; 0.05 in both MDA RCC GWAS and NCI RCC GWAS were subsequently evaluated in MDA RCC OncoArray. In the overall meta-analysis, significant (P &lt; 0.05) associations with RCC risk were observed for SNP mapping to IL1RAPL2 [rs10521506-G: ORmeta = 0.87 (0.81–0.93), Pmeta = 2.33 × 10−5], PLIN2 [rs2229536-A: ORmeta = 0.87 (0.81–0.93), Pmeta = 2.33 × 10−5], SMAD3 [rs4601989-A: ORmeta = 0.86 (0.80–0.93), Pmeta = 2.71 × 10−4], MED13L [rs10850596-A: ORmeta = 1.14 (1.07–1.23), Pmeta = 1.50 × 10−4], and TSC1 [rs3761840-G: ORmeta = 0.90 (0.85–0.97), Pmeta = 2.47 × 10−3]. We did not observe any significant cis-expression quantitative trait loci effect for these SNPs in the TCGA KIRC data.
Conclusions: Taken together, we found that genetic variation of obesity-related genes could influence RCC susceptibility.
Impact: The five identified loci may provide new insights into disease etiology that reveal importance of obesity-related genes in RCC development. Cancer Epidemiol Biomarkers Prev; 26(9); 1436–42. ©2017 AACR.
The Impact of a Population-Based Screening Program on Income- and Immigration-Related Disparities in Colorectal Cancer Screening
Authors: Kiran Tara , Glazier Richard H. , Moineddin Rahim , Gu Sumei , Wilton Andrew S. , Paszat Lawrence 
Published: June 2017

Abstract
Background: A population-based program promoting the Fecal Occult Blood Test (FOBT) for colorectal cancer screening was introduced in 2008 in Ontario, Canada, where opportunistic screening with colonoscopy had been increasing in frequency. We evaluated the impact of the program on income and immigration-related disparities in screening.
Methods: We used linked administrative data to calculate colorectal cancer screening rates for eligible Ontarians in each year between 2001/02 (n = 2,852,619) and 2013/14 (n = 4,139,304). We quantified disparities using an “inequality ratio” of screening rates in the most disadvantaged group relative to the most advantaged group. We performed segmented logistic regression analyses stratified by screening modality and adjusted for age, sex, rurality, comorbidity, and morbidity.
Results: Between 2001/02 and 2013/14, the income and immigration inequality ratios narrowed from 0.74 to 0.80 and 0.55 to 0.69, respectively. Before the screening program, the income inequality ratio was widening by 1% per year (95% CI 1% to 1%); in the year it was introduced, it narrowed by 4% (95% CI 2% to 7%) and in the years following, it remained stable [0% decrease (95% CI 1% decrease to 0% decrease) per year]. Results were similar for immigration-related disparities. After program introduction, disparities in receiving FOBT were narrowing at a faster rate while disparities in receiving colonoscopy were widening at a slower rate.
Conclusions: Introduction of a population-based screening program promoting FOBT for colorectal cancer was associated with only modest improvements in immigration and income-related disparities.
Impact: Reducing immigration and income-related disparities should be a focus for future research and policy work. Disparities in Ontario seem to be driven by a higher uptake of colonoscopy among more advantaged groups. Cancer Epidemiol Biomarkers Prev; 26(9); 1401–10. ©2017 AACR.
Fractionated Dosing Improves Preclinical Therapeutic Index of Pyrrolobenzodiazepine-Containing Antibody Drug Conjugates
Authors: Hinrichs Mary Jane Masson , Ryan Pauline M. , Zheng Bo , Afif-Rider Shameen , Yu Xiang Qing , Gunsior Michele , Zhong Haihong , Harper Jay , Bezabeh Binyam , Vashisht Kapil , Rebelatto Marlon , Reed Molly , Ryan Patricia C. , Breen Shannon , Patel Neki , Chen Cui , Masterson Luke , Tiberghien Arnaud , Howard Phillip W. , Dimasi Nazzareno , Dixit Rakesh 
Published: June 2017

AbstractPurpose: To use preclinical models to identify a dosing schedule that improves tolerability of highly potent pyrrolobenzodiazepine dimers (PBDs) antibody drug conjugates (ADCs) without compromising antitumor activity.Experimental Design: A series of dose-fractionation studies were conducted to investigate the pharmacokinetic drivers of safety and efficacy of PBD ADCs in animal models. The exposure–activity relationship was investigated in mouse xenograft models of human prostate cancer, breast cancer, and gastric cancer by comparing antitumor activity after single and fractionated dosing with tumor-targeting ADCs conjugated to SG3249, a potent PBD dimer. The exposure–tolerability relationship was similarly investigated in rat and monkey toxicology studies by comparing tolerability, as assessed by survival, body weight, and organ-specific toxicities, after single and fractionated dosing with ADCs conjugated to SG3249 (rats) or SG3400, a structurally related PBD (monkeys).Results: Observations of similar antitumor activity in mice treated with single or fractionated dosing suggests that antitumor activity of PBD ADCs is more closely related to total exposure (AUC) than peak drug concentrations (Cmax). In contrast, improved survival and reduced toxicity in rats and monkeys treated with a fractionated dosing schedule suggests that tolerability of PBD ADCs is more closely associated with Cmax than AUC.Conclusions: We provide the first evidence that fractionated dosing can improve preclinical tolerability of at least some PBD ADCs without compromising efficacy. These findings suggest that preclinical exploration of dosing schedule could be an important clinical strategy to improve the therapeutic window of highly potent ADCs and should be investigated further. Clin Cancer Res; 23(19); 5858–68. ©2017 AACR.
SLC45A2: A Melanoma Antigen with High Tumor Selectivity and Reduced Potential for Autoimmune Toxicity
Authors: Park Jungsun , Talukder Amjad H. , Lim Seon A. , Kim Kwanghee , Pan Ke , Melendez Brenda , Bradley Sherille D. , Jackson Kyle R. , Khalili Jahan S. , Wang Junmei , Creasy Caitlin , Pan Bih-Fang , Woodman Scott E. , Bernatchez Chantale , Hawke David , Hwu Patrick , Lee Kyung-Mi , Roszik Jason , Lizée Gregory , Yee Cassian 
Published: June 2017

Abstract
Cytotoxic T lymphocyte (CTL)–based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopeptidomes of 55 melanoma patient–derived cell lines, we identified a number of shared HLA class I–bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A*0201- and HLA-A*2402–restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity. Cancer Immunol Res; 5(8); 618–29. ©2017 AACR.
Experimental, Pathologic, and Clinical Findings of Radiofrequency Catheter Ablation of Para-Hisian Region From the Right Ventricle in Dogs and Humans
Authors: Xue Yumei , Zhan Xianzhang , Wu Shulin , Wang Hongyue , Liu Yang , Liao Zili , Deng Hai , Duan Xuejing , Zeng Shaoying , Liang Dongpo , Elvan Arif , Fang Xianhong , Liao Hongtao , Ramdat Misier Anand R. , Smit Jaap Jan J. , Metzner Andreas , Heeger Christian-Hendrik , Liu Fangzhou , Wang Feng , Zhang Zhiwei , Kuck Karl-Heinz , Yen Ho Siew , Ouyang Feifan 
Published: June 2017

Background—
Ablation of para-Hisian accessory pathway (AP) poses high risks of atrioventricular block. We developed a pacing technique to differentiate the near-field (NF) from far-field His activations to avoid the complication.

Methods and Results—
Three-dimensional mapping of the right ventricle was performed in 15 mongrel dogs and 23 patients with para-Hisian AP. Using different pacing outputs, the NF- and far-field His activation was identified on the ventricular aspect. Radiofrequency application was delivered at the NF His site in 8 (group 1) and the far-field His site in 7 dogs (group 2), followed by pathologic examination after 14 days. NF His activation was captured with 5 mA/1 ms in 10 and 10 mA/1 ms in 5 dogs. In group 1, radiofrequency delivery resulted in complete atrioventricular block in 3, right bundle branch block with HV (His-to-ventricular) interval prolongation in 1, and only right bundle branch block in 2 dogs, whereas no changes occurred in group 2. Pathologic examination in group-1 dogs showed complete or partial necrosis of the His bundle in 4 and complete necrosis of the right bundle branch in 5 dogs. In group 2, partial necrosis in the right bundle branch was found only in 1 dog. Using this pacing technique, the APs were 5.7±1.2 mm away from the His bundle located superiorly in 20 or inferiorly in 3 patients. All APs were successfully eliminated with 1 to 3 radiofrequency applications. No complications and recurrence occurred during a follow-up of 11.8±1.4 months.

Conclusions—
Differentiating the NF His from far-field His activations led to a high ablation success without atrioventricular block in para-Hisian AP patients.
Incidence and Time Course for Developing Heart Failure With High-Burden Right Ventricular Pacing
Authors: Merchant Faisal M. , Hoskins Michael H. , Musat Dan L. , Prillinger Julie B. , Roberts Gregory J. , Nabutovsky Yelena , Mittal Suneet 
Published: June 2017

Background—
Although right ventricular pacing can contribute to cardiomyopathy, the impact of complete atrioventricular block (cAVB) on heart failure (HF) development in pacemaker patients has not been well characterized. We evaluated the incidence and time course for developing HF after pacemaker implantation for cAVB.

Methods and Results—

A MarketScan database identified patients undergoing dual-chamber pacemaker implantation from 2008 to 2014. Patients with cAVB were identified by an atrioventricular node ablation or diagnosis of third-degree AVB. Patients with ≥1 year of continuous MarketScan enrollment before and after implant and without a previous diagnosis of HF were dichotomized into those with cAVB and without AVB. The primary end point was new HF assessed over acute (0–6 months) and chronic (6 months to 4 years) phases post–pacemaker implantation. The cohort included 6994 cAVB patients and 14 208 patients without AVB, followed for 2.35 years (interquartile range, 1.62–3.39 years). After adjustment for baseline covariates, patients with cAVB experienced an increased risk of new-onset HF in the acute phase (hazard ratio, 1.62; 95% confidence interval, 1.48–1.79;
P
<0.001). Although the risk of HF remained elevated among those with cAVB in the chronic phase, the effect was attenuated (hazard ratio, 1.16; 95% confidence interval, 1.08–1.25;
P
<0.001). After pacemaker implantation, younger patients (≤55 years of age) and those with an antecedent history of atrial fibrillation experienced the highest risk of HF associated with cAVB.

Conclusions—
Patients with a diagnosis of cAVB, and thus presumed to have a higher burden of right ventricular pacing, experienced an increased risk of new-onset HF after pacemaker implantation compared with those without AVB. Better tools are needed to identify patients at high risk of developing HF in the setting of right ventricular pacing and to determine whether these patients benefit from upfront biventricular pacing.
Ischemic Stroke
Authors: Sporns Peter B. , Hanning Uta , Schwindt Wolfram , Velasco Aglaé , Minnerup Jens , Zoubi Tarek , Heindel Walter , Jeibmann Astrid , Niederstadt Thomas Ulrich 
Published: June 2017

Background and Purpose—
The introduction of stent retrievers allows for a complete extraction and histological analysis of human thrombi. Ischemic stroke is a major health issue, and differentiation of underlying causes is highly relevant to prevent recurrent stroke. Therefore, histopathologic analysis of the embolic clots after removal may provide valuable information about underlying pathologies. This study analyzes histological clot composition and aims to identify specific patterns that might help to distinguish causes of ischemic stroke.

Methods—
Patients with occlusion of the carotid-T or middle cerebral artery who underwent thrombectomy at our university medical center between December 2013 and February 2016 were included. Samples were histologically analyzed (hematoxylin and eosin, Elastica van Gieson, and Prussian blue), additionally immunohistochemistry for CD3, CD20, and CD68/KiM1P was performed. These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification.

Results—

One hundred eighty-seven patients were included, of these, in 77 patients, cardioembolic; in 46 patients, noncardioembolic; and in 64 patients, cryptogenic pathogenesis was determined. Cardioembolic thrombi had higher proportions of fibrin/platelets (
P
=0.027), less erythrocytes (
P
=0.005), and more leucocytes (
P
=0.026) than noncardioembolic thrombi. We observed a strong overlap of cryptogenic strokes and cardioembolic strokes concerning thrombus histology. The immunohistochemical parameters CD3, CD20, and CD68/KiM1P showed no statistically noticeable differences between stroke subtypes.

Conclusions—
Histological thrombus features vary significantly according to the underlying cause and may help to differentiate between cardioembolic and noncardioembolic stroke. In addition, our study supports the hypothesis that most cryptogenic strokes have a cardioembolic cause.
Dose-Dependent Effect of Statin Pretreatment on Preventing the Periprocedural Complications of Carotid Artery Stenting
Authors: Hong Jeong-Ho , Sohn Sung-Il , Kwak Jaehyuk , Yoo Joonsang , Chang Hyuk Won , Kwon O-Ki , Jung Cheolkyu , Chung Inyoung , Bae Hee-Joon , Lee Ji Sung , Han Moon-Ku 
Published: June 2017

Background and Purpose—
We investigated whether statin pretreatment can dose dependently reduce periprocedural complications in patients undergoing carotid artery stenting because of symptomatic carotid artery stenosis.

Methods—
We enrolled a consecutive series of 397 symptomatic carotid artery stenosis (≥50% stenosis on conventional angiography) treated with carotid artery stenting at 2 tertiary university hospitals over a decade. Definition of periprocedural complications included any stroke, myocardial infarction, and death within 1 month after or during the procedure. Statin pretreatment was divided into 3 categories according to the atorvastatin equivalent dose: none (n=158; 39.8%), standard dose (<40 mg of atorvastatin, n=155; 39.0%), and high dose (≥40 mg; n=84; 21.2%). A multivariable logistic regression analysis with the generalized estimating equation method was used to investigate independent factors in periprocedural complications.

Results—

The patients’ mean age was 68.7 years (81.6% men). The periprocedural complication rates across the 3 categories of statin use were 12.0%, 4.5%, and 1.2%. After adjustment, a change in the atorvastatin dose category was associated with reduction in the odds of periprocedural complications for each change in dose category (standard-dose statin: odds ratio, 0.24; 95% confidence interval, 0.07−0.81; high-dose statin: odds ratio, 0.11; 95% confidence interval, 0.01−0.96;
P
for trend=0.01). Administration of antiplatelet drugs was also an independent factor in periprocedural complications (OR, 0.18; 95% CI, 0.05−0.69).

Conclusions—
This study shows that statin pretreatment may reduce the incidence of periprocedural complications dose dependently in patients with symptomatic carotid artery stenting.
Early Reperfusion After Brain Ischemia Has Beneficial Effects Beyond Rescuing Neurons
Authors: Tachibana Masaki , Ago Tetsuro , Wakisaka Yoshinobu , Kuroda Junya , Shijo Masahiro , Yoshikawa Yoji , Komori Motohiro , Nishimura Ataru , Makihara Noriko , Nakamura Kuniyuki , Kitazono Takanari 
Published: June 2017

Background and Purpose—
Recent studies show that successful endovascular thrombectomy 6 to 12 hours after stroke onset enhances functional outcomes 3 months later. In this study, we investigated the effects of reperfusion after ischemia on repair processes in the ischemic areas, as well as on functional recovery, using mouse stroke models.

Methods—
We examined time-dependent histological changes and functional recovery after transient middle cerebral artery occlusion of different durations, including permanent middle cerebral artery occlusion, using the CB-17 (CB-17/lcr-+/+Jcl) mouse strain, which has poor pial collateral blood flow.

Results—
Large microtubule-associated protein 2-negative areas of neuronal death were produced in mice subjected to ≥60 minutes of ischemia followed by reperfusion on day 1, while restricted microtubule-associated protein 2-negative regions were observed in mice subjected to a 45-minute period of ischemia. A substantial reduction in microtubule-associated protein 2-negative areas was observed on day 7 in mice given early reperfusion and was associated with better functional recovery. Klüver–Barrera staining demonstrated that white matter injury on day 1 was significantly lesser in mice with reperfusion. Immunohistochemistry and electron microscopy revealed that a greater number of endothelial cells were present in the infarct areas in mice with earlier reperfusion and were associated with a more rapid recruitment of platelet-derived growth factor receptor β-positive pericytes and subsequent intrainfarct fibrosis. Early reperfusion also resulted in a greater accumulation of glial fibrillary acidic protein–positive astrocytes in peri-infarct areas. Peri-infarct astrogliosis was attenuated in platelet-derived growth factor receptor β heterozygous knockout mice.

Conclusions—
Early reperfusion after ischemia enhances the survival of endothelial cells and pericytes within ischemic areas even after the infarct is established, resulting in efficient intrainfarct fibrosis and peri-infarct astrogliosis. These effects might be associated with efficient peri-infarct reorganization and functional recovery.
Trust and Patience after a Tornado
Authors: Shupp Robert , Loveridge Scott , Skidmore Mark , Lim Jungmin , Rogers Cynthia 
Published: June 2017

Abstract
This study examines how individuals’ trust levels and patience are affected by a tornado event. Affected and unaffected people were surveyed after a 2013 tornado in Moore, Oklahoma, that resulted in 24 fatalities. Findings suggest that those who self-identified as affected became more trusting in general as well as more trusting of police and fire authorities. Affected homeowners also exhibited less patience than their unaffected counterparts. The evaluation of differences in trust and patience enables us to learn about how underlying propensities to invest (or reinvest) in critical private and public infrastructure may be influenced by extreme events. Disasters alter trust levels and patience of affected residents, and documenting the direction and magnitude of these changes may help agencies involved in the recovery process.