bluuebunny/crossref_metadata_2025_split huggingface dataset:
αvβ6 Integrin Promotes Castrate-Resistant Prostate Cancer through JNK1-Mediated Activation of Androgen Receptor
Authors: Lu Huimin , Wang Tao , Li Jing , Fedele Carmine , Liu Qin , Zhang Jianzhong , Jiang Zhong , Jain Dhanpat , Iozzo Renato V. , Violette Shelia M. , Weinreb Paul H. , Davis Roger J. , Gioeli Daniel , FitzGerald Thomas J. , Altieri Dario C. , Languino Lucia R. 
Published: July 2016

AbstractAndrogen receptor signaling fuels prostate cancer and is a major therapeutic target. However, mechanisms of resistance to therapeutic androgen ablation are not well understood. Here, using a prostate cancer mouse model, Ptenpc−/−, carrying a prostate epithelial-specific Pten deletion, we show that the αvβ6 integrin is required for tumor growth in vivo of castrated as well as of noncastrated mice. We describe a novel signaling pathway that couples the αvβ6 integrin cell surface receptor to androgen receptor via activation of JNK1 and causes increased nuclear localization and activity of androgen receptor. This downstream kinase activation by αvβ6 is specific for JNK1, with no involvement of p38 or ERK kinase. In addition, differential phosphorylation of Akt is not observed under these conditions, nor is cell morphology affected by αvβ6 expression. This pathway, which is specific for αvβ6, because it is not regulated by a different αv-containing integrin, αvβ3, promotes upregulation of survivin, which in turn supports anchorage-independent growth of αvβ6-expressing cells. Consistently, both αvβ6 and survivin are significantly increased in prostatic adenocarcinoma, but are not detected in normal prostatic epithelium. Neither XIAP nor Bcl-2 is affected by αvβ6 expression. In conclusion, we show that αvβ6 expression is required for prostate cancer progression, including castrate-resistant prostate cancer; mechanistically, by promoting activation of JNK1, the αvβ6 integrin causes androgen receptor–increased activity in the absence of androgen and consequent upregulation of survivin. These preclinical results pave the way for further clinical development of αvβ6 antagonists for prostate cancer therapy. Cancer Res; 76(17); 5163–74. ©2016 AACR.
Validation of a Novel Biomarker Panel for the Detection of Ovarian Cancer
Authors: Leung Felix , Bernardini Marcus Q. , Brown Marshall D. , Zheng Yingye , Molina Rafael , Bast Robert C. , Davis Gerard , Serra Stefano , Diamandis Eleftherios P. , Kulasingam Vathany 
Published: July 2016

Abstract
Background: Ovarian cancer is the most lethal gynecological malignancy. Our integrated -omics approach to ovarian cancer biomarker discovery has identified kallikrein 6 (KLK6) and folate-receptor 1 (FOLR1) as promising candidates but these markers require further validation.
Methods: KLK6, FOLR1, CA125, and HE4 were investigated in three independent serum cohorts with a total of 20 healthy controls, 150 benign controls, and 216 ovarian cancer patients. The serum biomarker levels were determined by ELISA or automated immunoassay.
Results: All biomarkers demonstrated elevations in the sera of ovarian cancer patients compared with controls (P &lt; 0.01). Overall, CA125 and HE4 displayed the strongest ability (AUC 0.80 and 0.82, respectively) to identify ovarian cancer patients and the addition of HE4 to CA125 improved the sensitivity from 36% to 67% at a set specificity of 95%. In addition, the combination of HE4 and FOLR1 was a strong predictor of ovarian cancer diagnosis, displaying comparable sensitivity (65%) to the best-performing CA125-based models (67%) at a set specificity of 95%.
Conclusions: The markers identified through our integrated -omics approach performed similarly to the clinically approved markers CA125 and HE4. Furthermore, HE4 represents a powerful diagnostic marker for ovarian cancer and should be used more routinely in a clinical setting.
Impact: The implications of our study are 2-fold: (i) we have demonstrated the strengths of HE4 alone and in combination with CA125, lending credence to increasing its usage in the clinic; and (ii) we have demonstrated the clinical utility of our integrated -omics approach to identifying novel serum markers with comparable performance to clinical markers. Cancer Epidemiol Biomarkers Prev; 25(9); 1333–40. ©2016 AACR.
The Prediction of Clinical Outcome in Hepatocellular Carcinoma Based on a Six-Gene Metastasis Signature
Authors: Yuan Shengxian , Wang Jie , Yang Yuan , Zhang Jin , Liu Hui , Xiao Juanjuan , Xu Qingguo , Huang Xinhui , Xiang Bangde , Zhu Shaoliang , Li Lequn , Liu Jingfeng , Liu Lei , Zhou Weiping 
Published: July 2016

Abstract
Purpose: The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict hepatocellular carcinoma prognosis.
Experimental Design: Using microarrays, sequencing, and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model.
Results: Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of five mRNAs and one lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% [95% confidence interval (CI), 85%–99%] and 74% (95% CI, 58%–86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (P &lt; 0.05 for each cohort). Early HCC patients also have a poorer outcome for multicenter HRM patients. Finally, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (HR 2.98–16.6, P &lt; 0.05).
Conclusions: We developed an applicable six-gene metastasis signature, which is robust and reproducible in multicenter cohorts for HCC prognosis. Clin Cancer Res; 23(1); 289–97. ©2016 AACR.
The Novel KLF4/MSI2 Signaling Pathway Regulates Growth and Metastasis of Pancreatic Cancer
Authors: Guo Kun , Cui Jiujie , Quan Ming , Xie Dacheng , Jia Zhiliang , Wei Daoyan , Wang Liang , Gao Yong , Ma Qingyong , Xie Keping 
Published: July 2016

Abstract
Purpose: Musashi 2 (MSI2) is reported to be a potential oncoprotein in cases of leukemia and several solid tumors. However, its expression, function, and regulation in pancreatic ductal adenocarcinoma (PDAC) cases have yet to be demonstrated. Therefore, in the current study, we investigated the clinical significance and biologic effects of MSI2 expression in PDAC cases and sought to delineate the clinical significance of the newly identified Krüppel-like factor 4 (KLF4)/MSI2 regulatory pathway.
Experimental Design: MSI2 expression and its association with multiple clinicopathologic characteristics in human PDAC specimens were analyzed immunohistochemically. The biological functions of MSI2 regarding PDAC cell growth, migration, invasion, and metastasis were studied using gain- and loss-of-function assays both in vitro and in vivo. Regulation of MSI2 expression by KLF4 was examined in several cancer cell lines, and the underlying mechanisms were studied using molecular biologic methods.
Results: MSI2 expression was markedly increased in both PDAC cell lines and human PDAC specimens, and high MSI2 expression was associated with poor prognosis for PDAC. Forced MSI2 expression promoted PDAC proliferation, migration, and invasion in vitro and growth and metastasis in vivo, whereas knockdown of MSI2 expression did the opposite. Transcriptional inhibition of MSI2 expression by KLF4 occurred in multiple PDAC cell lines as well as mouse models of PDAC.
Conclusions: Lost expression of KLF4, a transcriptional repressor of MSI2 results in overexpression of MSI2 in PDACs, which may be a biomarker for accurate prognosis. A dysregulated KLF4/MSI2 signaling pathway promotes PDAC progression and metastasis. Clin Cancer Res; 23(3); 687–96. ©2016 AACR.
Abstract 2890: ERCC5 variant rs2296147 T-allele creates a predicted TP53 binding site and up-regulates transcript abundance in normal bronchial epithelial cells, while rs17655 C-allele is linked to miRNA binding site variant and down regulates
Authors: Zhang Xiaolu , Crawford Erin L. , Blomquist Thomas M. , Khuder Sadik A. , Yeo Jiyoun , Levin Albert M. , Willey James C. 
Published: July 2016

Abstract
Background: Excision repair cross-complementation group 5 (ERCC5) gene plays an important role in nucleotide excision repair (NER) and dysregulation of ERCC5 is associated with increased lung cancer risk. This study was conducted to characterize cis-acting genetic variants responsible for inter-individual variation in ERCC5 transcript regulation in normal bronchial epithelial cells (NBEC).
Methods: We determined genotypes at putative ERCC5 cis-regulatory single nucleotide polymorphic sites (SNP) rs751402 and rs2296147, and marker SNPs rs1047768 and rs17655. Using a recently developed targeted sequencing method, ERCC5 allele-specific transcript abundance was assessed in NBEC RNA from 55 individuals heterozygous for rs1047768 and 21 subjects heterozygous for rs17655. Syntenic relationships among alleles at rs751402, rs2296147 and rs1047768 were assessed by allele-specific PCR followed by Sanger sequencing. We assessed association of NBEC ERCC5 allele-specific expression at rs1047768 with haplotype and diplotype structure at putative ERCC5 promoter cis-regulatory SNPs rs751402 and rs2296147.
Results: Genotype analysis revealed higher inter-individual variation in allelic ratios in cDNA samples relative to matched gDNA samples at both rs1047768 and rs17655 (p&lt;0.0001 and p = 0.0005 respectively). By haplotype analysis, mean expression was higher at the rs1047768 alleles syntenic with rs2296147 T allele compared to rs2296147 C allele (p = 0.0030). Sequence analysis predicts that T allele at SNP rs2296147 creates a TP53 binding site. Mean expression was higher at rs17655 G allele (p&lt;0.0001) which is syntenic with G allele at a linked SNP rs873601 (r2 = 0.74). C allele at SNP rs873601 is predicted to create a miRNA binding site.
Conclusions: These data support the conclusion that T allele at SNP rs2296147 creates a TP53 binding site and up-regulates ERCC5 while C allele at SNP rs873601 creates a miRNA binding site and down-regulates ERCC5. Variation in ERCC5 transcript abundance associated with allelic variation at these SNPs is likely associated with variation in NER function in NBEC and lung cancer risk.
Citation Format: Xiaolu Zhang, Erin L. Crawford, Thomas M. Blomquist, Sadik A. Khuder, Jiyoun Yeo, Albert M. Levin, James C. Willey. ERCC5 variant rs2296147 T-allele creates a predicted TP53 binding site and up-regulates transcript abundance in normal bronchial epithelial cells, while rs17655 C-allele is linked to miRNA binding site variant and down regulates. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2890.
Abstract 3621: High efficiency detection of low frequency alleles in cell-free DNA
Authors: Shazand Kamran , Ning Jing , Popkie Anthony , Ranghini Egon , Jerome John Paul 
Published: July 2016

Abstract
Cancer is a genetic disease, caused by a variety of alterations to a cell's genome. One specific type of alteration associated with cancer is point mutations, and Next-generation sequencing (NGS) is a key tool to identify those mutations. Unlike inherited mutations, cancer mutations can be found at very low frequencies, mainly because of tumor heterogeneity and their dilution in the germline background. Cell-free DNA (cfDNA) derived from blood plasma, is a promising material for cancer research and diagnosis, and can be readily obtained via non-invasive procedures. However, the amount of tumor DNA and, hence, the amount of rare allele in the cfDNA are typically very low. Sensitive methods are therefore needed for the detection of somatic, cancer-associated mutations in cfDNA isolated from liquid biopsies to support both discovery and clinical decision making in oncology.
To overcome these challenges, we developed at Rubicon Genomics an NGS library preparation kit, namely ThruPLEX® Plasma-seq, optimized specifically for cfDNA at input levels from less than 1 ng to 30 ng. We designed experiments to determine the lower limit of SNV detection under these assay conditions. Six individual ThruPLEX® Plasma-seq libraries generated from 10 ng cfDNA were enriched with the Agilent SureSelect XT2 reagents and ClearSeq Comprehensive Cancer panel (151 genes). After sequencing to &gt;500X coverage, SNP calling was performed using Agilent SureCall software to identify the SNPs specific to each sample. In a second step, the cfDNA isolated from two of these plasma samples with known SNP differences were mixed to generate various spike-in frequencies (10%, 5%, 2% and 0.5%) prior to preparing libraries and enrichment. This is to simulate low allele frequency, and to determine the sensitivity of ThruPLEX® Plasma-seq under the outlined assay conditions.
Our results showed that it was possible to detect specific alleles down to an actual 0.6% with the theoretical 0.5% spike-in ratio. The percent of on­target bases was over 45%. The sensitivity (SNPs detected/total SNPs analyzed) of our test was above 97% for 10%, 5%, and 2% frequencies and 70% for 0.5%. This is a demonstration of ThruPLEX® Plasma-seq to produce libraries with high enough complexity to detect low frequency alleles from limited amounts of cfDNA from plasma.
Citation Format: Kamran Shazand, Jing Ning, Anthony Popkie, Egon Ranghini, John Paul Jerome. High efficiency detection of low frequency alleles in cell-free DNA. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3621.
Abstract LB-057: 1-Benzylquinazoline-2,4(1H,3H)-diones as potent PARP inhibitors. SAR of the quinazoline group and in vivo efficacy of clinical candidate IMP4297
Authors: Cai Sui Xiong , Xu Qingbing , Hu Xiuhua , Jiang Yangzhen , Wang Guoxiang , Tian Ed 
Published: July 2016

Abstract
Poly (ADP-ribose) polymerase (PARP) is a critical enzyme for DNA repair and PARP-1 inhibitors have been found to be efficacious against cancers with BRCA mutations. Olaparib (AZD2281) has been approved as the first PARP-1 inhibitor for the treatment of ovarian cancers with BRCA mutations.
In this presentation, we will report the SAR studies of 1-benzylquinazoline-2,4(1H,3H)-diones (BQD) as potent PARP inhibitors. We will present data for substituents at the quinazoline group of BQD, as well as in vivo efficacy data of IMP4297 which has been selected as clinical candidate for development. In a human triple negative breast cancer PDX model (BR-05-0028) with BRCA1 mutations, IMP4297 is highly efficacious against tumor growth with potency that is about 20-fold that of AZD2281. An IND for IMP4297 has been filed in China recently.
Citation Format: Sui Xiong Cai, Qingbing Xu, Xiuhua Hu, Yangzhen Jiang, Guoxiang Wang, Ed Tian. 1-Benzylquinazoline-2,4(1H,3H)-diones as potent PARP inhibitors. SAR of the quinazoline group and in vivo efficacy of clinical candidate IMP4297. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-057.
Longer Duration and Earlier Age of Onset of Paternal Betel Chewing and Smoking Increase Metabolic Syndrome Risk in Human Offspring, Independently, in a Community-Based Screening Program in Taiwan
Authors: Yen Amy Ming-Fang , Boucher Barbara J. , Chiu Sherry Yueh-Hsia , Fann Jean Ching-Yuan , Chen Sam Li-Sheng , Huang Kuo-Chin , Chen Hsiu-Hsi 
Published: July 2016

Background:

Transgenerational effects of paternal
Areca
catechu
nut chewing on offspring metabolic syndrome (MetS) risk in humans, on obesity and diabetes mellitus experimentally, and of paternal smoking on offspring obesity, are reported, likely attributable to genetic and epigenetic effects previously reported in betel-associated disease. We aimed to determine the effects of paternal smoking, and betel chewing, on the risks of early MetS in human offspring.

Methods:
The 13 179 parent-child trios identified from 238 364 Taiwanese aged ≥20 years screened at 2 community-based integrated screening sessions were tested for the effects of paternal smoking, areca nut chewing, and their duration prefatherhood on age of detecting offspring MetS at screen by using a Cox proportional hazards regression model.

Results:

Offspring MetS risks increased with prefatherhood paternal areca nutusage (adjusted hazard ratio, 1.77; 95% confidence interval [CI], 1.23–2.53) versus nonchewing fathers (adjusted hazard ratio, 3.28; 95% CI, 1.67–6.43) with >10 years paternal betel chewing, 1.62 (95% CI, 0.88–2.96) for 5 to 9 years, and 1.42 (95% CI, 0.80–2.54) for <5 years betel usage prefatherhood (
P
trend
=0.0002), with increased risk (adjusted hazard ratio, 1.95; 95% CI, 1.26–3.04) for paternal areca nut usage from 20 to 29 years of age, versus from >30 years of age (adjusted hazard ratio,1.61; 95% CI, 0.22–11.69). MetS offspring risk for paternal smoking increased dosewise (
P
trend
<0.0001) with earlier age of onset (
P
trend
=0.0009), independently.

Conclusions:
Longer duration of paternal betel quid chewing and smoking, prefatherhood, independently predicted early occurrence of incident MetS in offspring, corroborating previously reported transgenerational effects of these habits, and supporting the need for habit-cessation program provision.
Investigating Possible Arctic–Midlatitude Teleconnections in a Linear Framework
Authors: Sellevold Raymond , Sobolowski Stefan , Li Camille 
Published: July 2016

Abstract
There is an ongoing debate over whether accelerated Arctic warming [Arctic amplification (AA)] is altering the large-scale circulation responsible for the anomalous weather experienced by midlatitude regions in recent years. Among the proposed mechanisms is the idea that local processes associated with sea ice loss heat the lower troposphere at high latitudes, thus weakening the equator-to-pole temperature gradient and driving changes in quasi-stationary waves, the midlatitude jets, and storm tracks. It is further hypothesized that these circulation changes are conducive to persistent weather patterns. Because of the short observational record and large atmospheric internal variability, it is difficult to identify robust relationships and infer causality. Here, a simplified, linear, steady-state model is used to investigate the direct response of the midlatitude atmospheric circulation to thermal forcing in the Arctic. The results suggest that there is a weak midlatitude circulation response to an idealized, but representative, Arctic heating perturbation. Further, the stationary wave responses are shown to be well within the bounds of internal variability. A midlatitude response is excited if the idealized heating penetrates up to the tropopause. Such deep, persistent heating is not observed on average during the AA period but does suggest a pathway for Arctic–midlatitude linkages under specific conditions. This study adds to the growing body of work suggesting that warming in the lower troposphere associated with Arctic amplification is not currently a direct driver of anomalous midlatitude circulation changes.
Haemostatic factors do not account for worse outcomes from ischaemic stroke in patients with higher C-reactive protein concentrations
Authors: Słomka Artur , Świtońska Milena , Sinkiewicz Władysław , Żekanowska Ewa 
Published: July 2016

Background Although the role of microparticles was recently implicated in stroke pathophysiology, the association between microparticles and inflammation is still not fully understood. The aim of this cohort study of 66 patients was to assess a relation between haemostatic factors, C-reactive protein and clinical outcome of ischaemic stroke. Methods Plasma microparticles procoagulant activity, concentrations of tissue factor-bearing microparticles, tissue factor and tissue factor pathway inhibitor in ischaemic stroke patients were determined with enzyme-linked immunosorbent assays at the time of initial diagnosis, along with serum C-reactive protein concentrations. Patients were divided into two groups depending on their C-reactive protein concentrations (C-reactive protein <3 mg/L; n = 28 vs. C-reactive protein ≥3 mg/L; n = 38). The analysed clinical outcome measures included the National Institutes of Health Stroke Scale and the Barthel Index. Results The two C-reactive protein groups did not differ significantly in terms of microparticles procoagulant activities, tissue factor-bearing microparticles, tissue factor and tissue factor pathway inhibitor concentrations. A significant correlation was observed between tissue factor pathway inhibitor and National Institutes of Health Stroke Scale score at admission ( R = 0.3, P = 0.03). Patients with C-reactive protein ≥3 mg/L presented with significantly higher National Institutes of Health Stroke Scale scores (median, 9.00 vs. 5.50, P = 0.002) and lower Barthel Index scores (median, 20.00 vs. 65.00, P = 0.002) than individuals with C-reactive protein <3 mg/L. The C-reactive protein concentrations correlated positively with National Institutes of Health Stroke Scale scores ( R = 0.3, P = 0.02) and inversely with Barthel Index scores ( R = − 0.4, P = 0.002). Conclusions Altogether, these findings imply that haemostatic parameters (microparticles, tissue factor-bearing microparticles, tissue factor, tissue factor pathway inhibitor) do not account for elevated C-reactive protein concentrations in ischaemic stroke patients.