bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-1/SHP-2 Inhibits Tc1/Th1 Phenotypic Responses and the Activation of T Cells in the Tumor Microenvironment
Authors: Li Jing , Jie Hyun-Bae , Lei Yu , Gildener-Leapman Neil , Trivedi Sumita , Green Tony , Kane Lawrence P. , Ferris Robert L. 
Published: December 2014

Abstract
Immune rejection of tumors is mediated by IFNγ production and T-cell cytolytic activity. These processes are impeded by PD-1, a coinhibitory molecule expressed on T cells that is elevated in tumor-infiltrating lymphocytes (TIL). PD-1 elevation may reflect T-cell exhaustion marked by decreased proliferation, production of type I cytokines, and poor cytolytic activity. Although anti–PD-1 antibodies enhance IFNγ secretion after stimulation of the T-cell receptor (TCR), the mechanistic link between PD-1 and its effects on T-cell help (Tc1/Th1 skewing) remains unclear. In prospectively collected cancer tissues, we found that TIL exhibited dampened Tc1/Th1 skewing and activation compared with peripheral blood lymphocytes (PBL). When PD-1 bound its ligand PD-L1, we observed a marked suppression of critical TCR target genes and Th1 cytokines. Conversely, PD-1 blockade reversed these suppressive effects of PD-1:PD-L1 ligation. We also found that the TCR-regulated phosphatase SHP-2 was expressed higher in TIL than in PBL, tightly correlating with PD-1 expression and negative regulation of TCR target genes. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment. Cancer Res; 75(3); 508–18. ©2014 AACR.
Identification of a Functional SNP in the 3′UTR of CXCR2 That Is Associated with Reduced Risk of Lung Cancer
Authors: Ryan Bríd M. , Robles Ana I. , McClary Andrew C. , Haznadar Majda , Bowman Elise D. , Pine Sharon R. , Brown Derek , Khan Mohammed , Shiraishi Kouya , Kohno Takashi , Okayama Hirokazu , Modali Ramakrishna , Yokota Jun , Harris Curtis C. 
Published: December 2014

Abstract
Global changes in gene expression accompany the development of cancer. Thus, inherited variants in miRNA-binding sites are likely candidates for conferring inherited susceptibility. Using an in silico approach, we compiled a comprehensive list of SNPs predicted to modulate miRNA binding in genes from several key lung cancer pathways. We then investigated whether these SNPs were associated with lung cancer risk in two independent populations. In general, SNPs in miRNA-binding sites are rare. However, some allelic variation was observed. We found that rs1126579 in CXCR2 was associated with a reduced risk of lung cancer in both European American [ORTT vs. CC 0.56 (0.37–0.88); P = 0.008] and Japanese [ORTT vs. CC 0.62 (0.38–1.00); P = 0.049] populations. Furthermore, we found that the SNP disrupted a novel binding site for miR-516a-3p, led to a moderate increase in CXCR2 mRNA and protein expression, and increased MAPK signaling. Moreover, analysis of rs1126579 with serum levels of IL8, its endogenous ligand, supported an interaction whereby rs1126579-T and high serum IL8 conferred synergistic protection from lung cancer. Our findings demonstrate a function for a 3′UTR SNP in modulating CXCR2 expression, signaling, and susceptibility to lung cancer. Cancer Res; 75(3); 566–75. ©2014 AACR.
TUSC4 Functions as a Tumor Suppressor by Regulating BRCA1 Stability
Authors: Peng Yang , Dai Hui , Wang Edward , Lin Curtis Chun-Jen , Mo Wei , Peng Guang , Lin Shiaw-Yih 
Published: December 2014

AbstractBRCA1 expression is lost frequently in breast cancers in which it promotes malignant development. In the present study, we performed a global expression analysis of breast cancer cells in which the tumor-suppressor candidate gene TUSC4 was silenced to gain insights into its function. TUSC4 silencing affected genes involved in cell cycle and cell death, which have broad reaching influence on cancer development. Most importantly, we found a cluster pattern of gene-expression profiles in TUSC4-silenced cells that defined a homologous recombination (HR) repair defect signature. Mechanistic investigations indicated that TUSC4 protein could physically interact with the E3 ligase Herc2, which prevents BRCA1 degradation through the ubiquitination pathway. TUSC4 silencing enhanced BRCA1 polyubiquitination, leading to its degradation and a marked reduction in HR repair efficiency. Notably, ectopic expression of TUSC4 suppressed the proliferation, invasion, and colony formation of breast cancer cells in vitro and tumorigenesis in vivo. Furthermore, TUSC4 silencing was sufficient to transform normal mammary epithelial cells and to enhance sensitivity to PARP inhibitors. Our results provide a set of genetic and biologic proofs that TUSC4 functions as a bona fide tumor suppressor by regulating the protein stability and function of BRCA1 in breast cancer. Cancer Res; 75(2); 378–86. ©2014 AACR.
Kinome-wide Functional Screen Identifies Role of PLK1 in Hormone-Independent, ER-Positive Breast Cancer
Authors: Bhola Neil E. , Jansen Valerie M. , Bafna Sangeeta , Giltnane Jennifer M. , Balko Justin M. , Estrada Mónica V. , Meszoely Ingrid , Mayer Ingrid , Abramson Vandana , Ye Fei , Sanders Melinda , Dugger Teresa C. , Allen Eliezer V. , Arteaga Carlos L. 
Published: December 2014

Abstract
Estrogen receptor (ER) α–positive breast cancers initially respond to antiestrogens but eventually become estrogen independent and recur. ER+ breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki-67 score in primary ER+ breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth, and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacologic inhibition of PLK1 with volasertib, a small-molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity, and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared with parental MCF7 cells. Furthermore, JUNB and BCL2L1 (which encodes antiapoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells, while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER+ human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy. Cancer Res; 75(2); 405–14. ©2014 AACR.
DNA-PK—A Candidate Driver of Hepatocarcinogenesis and Tissue Biomarker That Predicts Response to Treatment and Survival
Authors: Cornell Liam , Munck Joanne M. , Alsinet Clara , Villanueva Augusto , Ogle Laura , Willoughby Catherine E. , Televantou Despina , Thomas Huw D. , Jackson Jennifer , Burt Alastair D. , Newell David , Rose John , Manas Derek M. , Shapiro Geoffrey I. , Curtin Nicola J. , Reeves Helen L. 
Published: December 2014

Abstract
Purpose: Therapy resistance and associated liver disease make hepatocellular carcinomas (HCC) difficult to treat with traditional cytotoxic therapies, whereas newer targeted approaches offer only modest survival benefit. We focused on DNA-dependent protein kinase, DNA-PKcs, encoded by PRKDC and central to DNA damage repair by nonhomologous end joining. Our aim was to explore its roles in hepatocarcinogenesis and as a novel therapeutic candidate.
Experimental Design: PRKDC was characterized in liver tissues from of 132 patients [normal liver (n = 10), cirrhotic liver (n = 13), dysplastic nodules (n = 18), HCC (n = 91)] using Affymetrix U133 Plus 2.0 and 500 K Human Mapping SNP arrays (cohort 1). In addition, we studied a case series of 45 patients with HCC undergoing diagnostic biopsy (cohort 2). Histological grading, response to treatment, and survival were correlated with DNA-PKcs quantified immunohistochemically. Parallel in vitro studies determined the impact of DNA-PK on DNA repair and response to cytotoxic therapy.
Results: Increased PRKDC expression in HCC was associated with amplification of its genetic locus in cohort 1. In cohort 2, elevated DNA-PKcs identified patients with treatment-resistant HCC, progressing at a median of 4.5 months compared with 16.9 months, whereas elevation of activated pDNA-PK independently predicted poorer survival. DNA-PKcs was high in HCC cell lines, where its inhibition with NU7441 potentiated irradiation and doxorubicin-induced cytotoxicity, whereas the combination suppressed HCC growth in vitro and in vivo.
Conclusions: These data identify PRKDC/DNA-PKcs as a candidate driver of hepatocarcinogenesis, whose biopsy characterization at diagnosis may impact stratification of current therapies, and whose specific future targeting may overcome resistance. Clin Cancer Res; 21(4); 925–33. ©2014 AACR.
A Phase I Study of Oral ARRY-614, a p38 MAPK/Tie2 Dual Inhibitor, in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes
Authors: Garcia-Manero Guillermo , Khoury Hanna J. , Jabbour Elias , Lancet Jeffrey , Winski Shannon L. , Cable LouAnn , Rush Selena , Maloney Lara , Hogeland Grant , Ptaszynski Mieke , Calvo Monica Cabrero , Bohannan Zach , List Alan , Kantarjian Hagop , Komrokji Rami 
Published: December 2014

Abstract
Purpose: Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria.
Experimental Design: Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts.
Results: The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1–2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI.
Conclusions: ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study. Clin Cancer Res; 21(5); 985–94. ©2014 AACR.
CD25 Identifies a Subset of CD4+FoxP3− TIL That Are Exhausted Yet Prognostically Favorable in Human Ovarian Cancer
Authors: deLeeuw Ronald J. , Kroeger David R. , Kost Sara E. , Chang Pheh-Ping , Webb John R. , Nelson Brad H. 
Published: December 2014

Abstract
CD25, the alpha subunit of the IL2 receptor, is a canonical marker of regulatory T cells (Treg) and hence has been implicated in immune suppression in cancer. However, CD25 is also required for optimal expansion and activity of effector T cells in peripheral tissues. Thus, we hypothesized that CD25, in addition to demarcating Tregs, might identify effector T cells in cancer. To investigate this possibility, we used multiparameter flow cytometry and IHC to analyze tumor-infiltrating lymphocytes (TIL) in primary high-grade serous carcinomas, the most common and fatal subtype of ovarian cancer. CD25 was expressed primarily by CD4+ TIL, with negligible expression by CD8+ TIL. In addition to conventional CD25+FoxP3+ Tregs, we identified a subset of CD25+FoxP3− T cells that comprised up to 13% of CD4+ TIL. In tumors with CD8+ TIL, CD25+FoxP3− T cells showed a strong positive association with patient survival (HR, 0.56; P = 0.02), which exceeded the negative effect of Tregs (HR, 1.55; P = 0.09). Among CD4+ TIL subsets, CD25+FoxP3− cells expressed the highest levels of PD-1. Moreover, after in vitro stimulation, they failed to produce common T-helper cytokines (IFNγ, TNFα, IL2, IL4, IL10, or IL17A), suggesting that they were functionally exhausted. In contrast, the more abundant CD25−FoxP3− subset of CD4+ TIL expressed low levels of PD-1 and produced T-helper 1 cytokines, yet conferred no prognostic benefit. Thus, CD25 identifies a subset of CD4+FoxP3− TIL that, despite being exhausted at diagnosis, have a strong, positive association with patient survival and warrant consideration as effector T cells for immunotherapy. Cancer Immunol Res; 3(3); 245–53. ©2014 AACR.
Utilization and Adverse Outcomes of Percutaneous Left Atrial Appendage Closure for Stroke Prevention in Atrial Fibrillation in the United States
Authors: Badheka Apurva O. , Chothani Ankit , Mehta Kathan , Patel Nileshkumar J. , Deshmukh Abhishek , Hoosien Michael , Shah Neeraj , Singh Vikas , Grover Peeyush , Savani Ghanshyambhai T. , Panaich Sidakpal S. , Rathod Ankit , Patel Nilay , Arora Shilpkumar , Bhalara Vipulkumar , Coffey James O. , O’Neill William , Makkar Raj , Grines Cindy L. , Schreiber Theodore , Di Biase Luigi , Natale Andrea , Viles-Gonzalez Juan F. 
Published: December 2014

Background—
Safety data on percutaneous left atrial appendage closure arises from centers with considerable expertise in the procedure or from clinical trial, which might not be reproducible in clinical practice. We sought to estimate the frequency and predictors of adverse outcomes and costs of percutaneous left atrial appendage closure procedure in the US.

Methods and Results—

The data were obtained from the Nationwide Inpatient Sample from the years 2006 to 2010. The Nationwide Inpatient Sample is the largest all-payer inpatient data set in the US. Complications were calculated using patient safety indicators and
International Classification of Diseases
-Ninth Revision, Clinical Modification codes. Annual hospital volume was calculated using unique hospital identifiers. Weights provided by the Nationwide Inpatient Sample were used to generate national estimates. A total of 268 (weighted=1288) procedures were analyzed. The overall composite rate of mortality or any adverse event was 24.3% (65), with 3.4% patients required open cardiac surgery after procedure. Average length of stay was 4.61±1.05 days and cost of care was 26 024±34 651. Annual hospital procedural volume was significantly associated with reduced complications and mortality (every unit increase: odds ratio, 0.89; 95% confidence interval, 0.85–0.94;
P
<0.001), decrease in length of stay (every unit increase: hazard ratio, 0.95; 95% confidence interval, 0.92–0.98;
P
<0.001) and cost of care (every unit increase: hazard ratio, 0.96; 95% confidence interval, 0.93–0.98;
P
<0.001).

Conclusions—
Our study demonstrates that the frequency of inhospital adverse outcomes associated with percutaneous left atrial appendage closure is higher in the real-world population than in clinical trials. We also demonstrate that higher annual hospital volume is associated with safer procedures, with lower length of stay and cost.
Mapping Genetic Contributions to Cardiac Pathology Induced by Beta-Adrenergic Stimulation in Mice
Authors: Rau Christoph D. , Wang Jessica , Avetisyan Rozeta , Romay Milagros C. , Martin Lisa , Ren Shuxun , Wang Yibin , Lusis Aldons J. 
Published: December 2014

Background—
Chronic stress-induced cardiac pathology exhibits both a wide range in severity and a high degree of heterogeneity in clinical manifestation in human patients. This variability is contributed to by complex genetic and environmental etiologies within the human population. Genetic approaches to elucidate the genetics underlying the acquired forms of cardiomyopathies, including genome-wide association studies, have been largely unsuccessful, resulting in limited knowledge as to the contribution of genetic variations for this important disease.

Methods and Results—

Using the β-adrenergic agonist isoproterenol as a specific pathological stressor to circumvent the problem of etiologic heterogeneity, we performed a genome-wide association study for genes influencing cardiac hypertrophy and fibrosis in a large panel of inbred mice. Our analyses revealed 7 significant loci and 17 suggestive loci, containing an average of 14 genes, affecting cardiac hypertrophy, fibrosis, and surrogate traits relevant to heart failure. Several loci contained candidate genes which are known to contribute to Mendelian cardiomyopathies in humans or have established roles in cardiac pathology based on molecular or genetic studies in mouse models. In particular, we identify
Abcc6
as a novel gene underlying a fibrosis locus by validating that an allele with a splice mutation of
Abcc6
dramatically and rapidly promotes isoproterenol-induced cardiac fibrosis.

Conclusions—

Genetic variants significantly contribute to the phenotypic heterogeneity of stress-induced cardiomyopathy. Systems genetics is an effective approach to identify genes and pathways underlying the specific pathological features of cardiomyopathies.
Abcc6
is a previously unrecognized player in the development of stress-induced cardiac fibrosis.
Cardiomyocyte p65 Nuclear Factor-κB Is Necessary for Compensatory Adaptation to Pressure Overload
Authors: Javan Hadi , Szucsik Amanda M. , Li Ling , Schaaf Christin L. , Salama Mohamed E. , Selzman Craig H. 
Published: December 2014

Background—
Nuclear factor κB (NF-κB) is often implicated in contributing to the detrimental effects of cardiac injury. This ostensibly negative view of NF-κB competes with its important role in the normal host inflammatory and immune response. We have previously demonstrated that pharmacological inhibition of NF-κB at the time of acute pressure overload accelerates the progression of left ventricular hypertrophy to heart failure in mice. NF-κB regulates angiogenesis and other factors responsible for compensatory reaction to intracellular hypoxia. We hypothesized that impaired angiogenesis may be the trigger, not the result, of pathological left ventricular hypertrophy through NF-κB–related pathways.

Methods and Results—
Transgenic mice were generated with cardiomyocyte-specific deletion of the p65 subunit of NF-κB. Mice underwent transverse aortic constriction and serially followed up with echocardiography for 6 weeks. Cardiomyocyte p65 NF-κB deletion promoted maladaptive left ventricular hypertrophy and accelerated progression toward heart failure as measured by ejection fraction, left ventricular mass, and lung congestion. Transgenic mice had higher levels of fibrosis and periostin expression. Whole-field digital microscopy revealed increased capillary domain areas in knockout mice while concurrently demonstrating decreased microvessel density. This observation was associated with decreased expression of hypoxia-inducible factor 1α.

Conclusions—
Rather than developing compensatory left ventricular hypertrophy, pressure overload in cardiomyocyte NF-κB–deficient mice resulted in functional deterioration that was associated with increased fibrosis, decreased hypoxia-inducible factor expression, and decreased microvessel density. These observations mechanistically implicate NF-κB, and its regulation of hypoxic stress, as an important factor determining the path between adaptive hypertrophy and maladaptive heart failure.
Characteristics and Outcomes of Patients With Advanced Chronic Systolic Heart Failure Receiving Care at the Veterans Affairs Versus Other Hospitals
Authors: Jones Linda G. , Sin Mo-Kyung , Hage Fadi G. , Kheirbek Raya E. , Morgan Charity J. , Zile Michael R. , Wu Wen-Chih , Deedwania Prakash , Fonarow Gregg C. , Aronow Wilbert S. , Prabhu Sumanth D. , Fletcher Ross D. , Ahmed Ali , Allman Richard M. 
Published: December 2014

Background—
Characteristics and outcomes of patients with heart failure and reduced ejection fraction receiving care at Veterans Affairs (VA) versus non-VA hospitals have not been previously reported.

Methods and Results—
In the randomized controlled Beta-blocker Evaluation of Survival Trial (BEST; 1995-1999), of the 2707 (bucindolol=1353; placebo=1354) patients with heart failure and left ventricular ejection fraction ≤35%, 918 received care at VA hospitals, of which 98% (n=898) were male. Of the 1789 receiving care at non-VA hospitals, 68% (n=1216) were male. Our analyses were restricted to these 2114 male patients. VA patients were older with higher symptom and comorbidity burdens. There was no significant between-group difference in unadjusted primary end point of 2-year all-cause mortality (35% VA versus 32% non-VA; hazard ratio associated with VA hospitals, 1.09; 95% confidence interval, 0.94–1.26), which remained unchanged after adjustment for age and race (hazard ratio, 1.00; 95% confidence interval, 0.86–1.16) or multivariable adjustment, including cardiovascular morbidities (hazard ratio, 0.94; 95% confidence interval, 0.80–1.10). There was no between-group difference in cause-specific mortalities or hospitalizations. Chronic kidney disease, pulmonary edema, left ventricular ejection fraction <20%, and peripheral arterial disease were significant predictors of mortality for both groups. African America race, New York Heart Association class IV symptoms, atrial fibrillation, and right ventricular ejection fraction <20% were associated with higher mortality among non-VA hospital patients only; however, these differences from VA patients were not significant.

Conclusions—
Patients with heart failure and reduced ejection fraction receiving care at VA hospitals were older and sicker; yet their risk of mortality and hospitalization was similar to younger and healthier patients receiving care at non-VA hospitals.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00000560.