bluuebunny/crossref_metadata_2025_split huggingface dataset:
STAT3 Establishes an Immunosuppressive Microenvironment during the Early Stages of Breast Carcinogenesis to Promote Tumor Growth and Metastasis
Authors: Jones Laura M. , Broz Miranda L. , Ranger Jill J. , Ozcelik John , Ahn Ryuhjin , Zuo Dongmei , Ursini-Siegel Josie , Hallett Michael T. , Krummel Matthew , Muller William J. 
Published: January 2016

Abstract
Immunosurveillance constitutes the first step of cancer immunoediting in which developing malignant lesions are eliminated by antitumorigenic immune cells. However, the mechanisms by which neoplastic cells induce an immunosuppressive state to evade the immune response are still unclear. The transcription factor STAT3 has been implicated in breast carcinogenesis and tumor immunosuppression in advanced disease, but its involvement in early disease development has not been established. Here, we genetically ablated Stat3 in the tumor epithelia of the inducible PyVmT mammary tumor model and found that Stat3-deficient mice recapitulated the three phases of immunoediting: elimination, equilibrium, and escape. Pathologic analyses revealed that Stat3-deficient mice initially formed hyperplastic and early adenoma-like lesions that later completely regressed, thereby preventing the emergence of mammary tumors in the majority of animals. Furthermore, tumor regression was correlated with massive immune infiltration into the Stat3-deficient lesions, leading to their elimination. In a minority of animals, focal, nonmetastatic Stat3-deficient mammary tumors escaped immune surveillance after a long latency or equilibrium period. Taken together, our findings suggest that tumor epithelial expression of Stat3 plays a critical role in promoting an immunosuppressive tumor microenvironment during breast tumor initiation and progression, and prompt further investigation of Stat3-inhibitory strategies that may reactivate the immunosurveillance program. Cancer Res; 76(6); 1416–28. ©2015 AACR.
Factors Associated with Multiple Biomarkers of Systemic Inflammation
Authors: Navarro Sandi L. , Kantor Elizabeth D. , Song Xiaoling , Milne Ginger L. , Lampe Johanna W. , Kratz Mario , White Emily 
Published: January 2016

AbstractBackground: While much is known about correlates of C-reactive protein (CRP), little is known about correlates of other inflammation biomarkers. As these measures are increasingly being used in epidemiologic studies, it is important to determine what factors affect inflammation biomarker concentrations.Methods: Using age, sex, and body mass index (BMI) adjusted linear regression, we examined 38 exposures (demographic and anthropometric measures, chronic disease history, NSAIDs, dietary factors, and supplement use) of 8 inflammation biomarkers [CRP, IL1β, IL6, IL8, TNFα, and soluble TNF receptors (sTNFR) in plasma; and prostaglandin E2 metabolite (PGE-M) in urine] in 217 adults, ages 50 to 76 years.Results: Increasing age was associated with higher concentrations of all biomarkers except IL1β. BMI was positively associated with CRP and sTNFR I and II. Saturated fat intake was associated with increased CRP, sTNFRII, TNFα, and IL1β, whereas eicosapentaenoic acid + docosahexaenoic acid (EPA+DHA) intake (diet or total) was associated with decreased CRP, TNFα, and IL1β. Results for sex were varied: CRP and IL6 were lower among men, whereas PGE-M and sTNFRI were higher. Higher CRP was also associated with smoking, hormone replacement therapy use, and γ-tocopherol intake; lower CRP with physical activity, and intakes of dietary vitamin C and total fiber.Conclusions: Although the associations varied by biomarker, the factors having the greatest number of significant associations (P ≤ 0.05) with the inflammation biomarkers were age, BMI, dietary saturated fat, and EPA+DHA omega-3 fatty acids.Impact: Our results suggest that potential confounders in epidemiologic studies assessing associations with inflammation biomarkers vary across specific biomarkers. Cancer Epidemiol Biomarkers Prev; 25(3); 521–31. ©2016 AACR.
Augmentation of Immune Checkpoint Cancer Immunotherapy with IL18
Authors: Ma Zhifeng , Li Wen , Yoshiya Shinichi , Xu Yunfeng , Hata Masaki , El-Darawish Yosif , Markova Tzvetanka , Yamanishi Kyosuke , Yamanishi Hiromichi , Tahara Hideaki , Tanaka Yoshimasa , Okamura Haruki 
Published: January 2016

Abstract
Purpose: Recent clinical trials and animal models demonstrated that immune checkpoint blockade enhanced effector cell responses and tumor rejection; however, further development and improvement of cancer immunotherapy is necessary for more favorable objective responses. In this study, we examined the effect of IL18 on the antitumor effect of immune checkpoint inhibitors.
Experimental Design: We examined the effect of IL18 on the peritoneal dissemination of CT-26 cells or tail vein injection metastasis of B16/F10 cells using antiprogrammed death-1 ligand-1 (αPD-L1) and/or anti-CTL–associated antigen-4 (αCTLA-4) mAbs.
Result: Massive ascites developed after intraperitoneal inoculation of CT-26, resulting in animal death within 30 days. Treatment of mice with αPD-L1 and/or αCTLA-4 significantly prolonged their survival, and a combination of the antibodies and IL18 provided a much greater therapeutic benefit. The combination modality led to the accumulation of precursor of mature natural killer (pre-mNK) cells in the peritoneal cavity together with increased CD8+ T and decreased CD4+CD25+Foxp3+ T cells. Depletion of the pre-mNK cells abrogated the therapeutic effects and increased the number of CD4+CD25+Foxp3+ T cells. The combination treatment also suppressed tail vein injection metastasis of B16/F10 cells.
Conclusions: The results demonstrated that IL18 enhanced therapeutic effects of immune checkpoint blockade against peritoneal dissemination of carcinoma or tail vein injection metastasis of melanoma through accumulation of pre-mNK cells, memory-type CD8+ T cells, and suppression of CD4+CD25+Foxp3+ T cells. A combination of immune checkpoint inhibitors with IL18 may give a suggestion to the development of next-generation cancer immunotherapy. Clin Cancer Res; 22(12); 2969–80. ©2016 AACR.
Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(−) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG
Authors: Linge Annett , Löck Steffen , Gudziol Volker , Nowak Alexander , Lohaus Fabian , von Neubeck Cläre , Jütz Martin , Abdollahi Amir , Debus Jürgen , Tinhofer Inge , Budach Volker , Sak Ali , Stuschke Martin , Balermpas Panagiotis , Rödel Claus , Avlar Melanie , Grosu Anca-Ligia , Bayer Christine , Belka Claus , Pigorsch Steffi , Combs Stephanie E. , Welz Stefan , Zips Daniel , Buchholz Frank , Aust Daniela E. , Baretton Gustavo B. , Thames Howard D. , Dubrovska Anna , Alsner Jan , Overgaard Jens , Baumann Michael , Krause Mechthild 
Published: January 2016

Abstract
Purpose: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
Experimental Design: Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control.
Results: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA–negative but not with HPV16 DNA–positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA–negative subgroup.
Conclusions: We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA–negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639–49. ©2016 AACR.
Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations
Authors: Bianchi-Frias Daniella , Basom Ryan , Delrow Jeffrey J. , Coleman Ilsa M. , Dakhova Olga , Qu Xiaoyu , Fang Min , Franco Omar E. , Ericson Nolan G. , Bielas Jason H. , Hayward Simon W. , True Lawrence , Morrissey Colm , Brown Lisha , Bhowmick Neil A. , Rowley David , Ittmann Michael , Nelson Peter S. 
Published: January 2016

Abstract
Prostate cancer–associated stroma (CAS) plays an active role in malignant transformation, tumor progression, and metastasis. Molecular analyses of CAS have demonstrated significant changes in gene expression; however, conflicting evidence exists on whether genomic alterations in benign cells comprising the tumor microenvironment (TME) underlie gene expression changes and oncogenic phenotypes. This study evaluates the nuclear and mitochondrial DNA integrity of prostate carcinoma cells, CAS, matched benign epithelium and benign epithelium–associated stroma by whole-genome copy-number analyses, targeted sequencing of TP53, and FISH. Array comparative genomic hybridization (aCGH) of CAS revealed a copy-neutral diploid genome with only rare and small somatic copy-number aberrations (SCNA). In contrast, several expected recurrent SCNAs were evident in the adjacent prostate carcinoma cells, including gains at 3q, 7p, and 8q, and losses at 8p and 10q. No somatic TP53 mutations were observed in CAS. Mitochondrial DNA (mtDNA) extracted from carcinoma cells and stroma identified 23 somatic mtDNA mutations in neoplastic epithelial cells, but only one mutation in stroma. Finally, genomic analyses identified no SCNAs, LOH, or copy-neutral LOH in cultured cancer-associated fibroblasts, which are known to promote prostate cancer progression in vivo.
Implications: The gene expression changes observed in prostate cancer–adjacent stroma and the attendant contribution of the stroma to the development and progression of prostate cancer are not due to frequent or recurrent genomic alterations in the TME. Mol Cancer Res; 14(4); 374–84. ©2016 AACR.
Vaccines Combined with Immune Checkpoint Antibodies Promote Cytotoxic T-cell Activity and Tumor Eradication
Authors: Ali Omar A. , Lewin Sarah A. , Dranoff Glenn , Mooney David J. 
Published: January 2016

Abstract
We demonstrate that a poly(lactide-co-glycolide) (PLG) cancer vaccine can be used in combination with immune checkpoint antibodies, anti–CTLA-4 or anti–PD-1, to enhance cytotoxic T-cell (CTL) activity and induce the regression of solid B16 tumors in mice. Combination therapy obviated the need for vaccine boosting and significantly skewed intratumoral reactions toward CTL activity, resulting in the regression of B16 tumors up to 50 mm2 in size and 75% survival rates. These data suggest that combining material-based cancer vaccines with checkpoint antibodies has the potential to mediate tumor regression in humans. Cancer Immunol Res; 4(2); 95–100. ©2015 AACR.
Hypomethylation of the Treg-Specific Demethylated Region inFOXP3Is a Hallmark of the Regulatory T-cell Subtype in Adult T-cell Leukemia
Authors: Shimazu Yayoi , Shimazu Yutaka , Hishizawa Masakatsu , Hamaguchi Masahide , Nagai Yuya , Sugino Noriko , Fujii Sumie , Kawahara Masahiro , Kadowaki Norimitsu , Nishikawa Hiroyoshi , Sakaguchi Shimon , Takaori-Kondo Akifumi 
Published: January 2016

AbstractAdult T-cell leukemia (ATL) is an aggressive T-cell malignancy caused by human T-cell leukemia virus type 1. Because of its immunosuppressive property and resistance to treatment, patients with ATL have poor prognoses. ATL cells possess the regulatory T cell (Treg) phenotype, such as CD4 and CD25, and usually express forkhead box P3 (FOXP3). However, the mechanisms of FOXP3 expression and its association with Treg-like characteristics in ATL remain unclear. Selective demethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene leads to stable FOXP3 expression and defines natural Tregs. Here, we focus on the functional and clinical relationship between the epigenetic pattern of the TSDR and ATL. Analysis of DNA methylation in specimens from 26 patients with ATL showed that 15 patients (58%) hypomethylated the TSDR. The FOXP3+ cells were mainly observed in the TSDR-hypomethylated cases. The TSDR-hypomethylated ATL cells exerted more suppressive function than the TSDR-methylated ATL cells. Thus, the epigenetic analysis of the FOXP3 gene identified a distinct subtype with Treg properties in heterogeneous ATL. Furthermore, we observed that the hypomethylation of TSDR was associated with poor outcomes in ATL. These results suggest that the DNA methylation status of the TSDR is an important hallmark to define this heterogeneous disease and to predict ATL patient prognosis. Cancer Immunol Res; 4(2); 136–45. ©2015 AACR.
Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells
Authors: Van Lint Sandra , Renmans Dries , Broos Katrijn , Goethals Lode , Maenhout Sarah , Benteyn Daphné , Goyvaerts Cleo , Du Four Stephanie , Van der Jeught Kevin , Bialkowski Lukasz , Flamand Véronique , Heirman Carlo , Thielemans Kris , Breckpot Karine 
Published: January 2016

AbstractModulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α+ cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We show in various mouse cancer models that i.t. delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we show that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such, we provide a platform and a mechanistic rationale for the clinical testing of i.t. administration of TriMix mRNA. Cancer Immunol Res; 4(2); 146–56. ©2015 AACR.
Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction
Authors: Zile Michael R. , Jhund Pardeep S. , Baicu Catalin F. , Claggett Brian L. , Pieske Burkert , Voors Adriaan A. , Prescott Margaret F. , Shi Victor , Lefkowitz Martin , McMurray John J.V. , Solomon Scott D. 
Published: January 2016

Background—
Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction.

Methods and Results—
Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6–48.1] ng/mL) and galectin 3 (17.8 [14.1–22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5–230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3–6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B-type natriuretic peptide, E/E′, and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N-terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time.

Conclusions—
In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00887588.
Clopidogrel Versus Aspirin as an Antiplatelet Monotherapy After 12-Month Dual-Antiplatelet Therapy in the Era of Drug-Eluting Stents
Authors: Park Taek Kyu , Song Young Bin , Ahn Joonghyun , Carriere K.C. , Hahn Joo-Yong , Yang Jeong Hoon , Choi Seung-Hyuk , Choi Jin-Ho , Lee Sang Hoon , Gwon Hyeon-Cheol 
Published: January 2016

Background—
The use of dual-antiplatelet therapy (DAPT) exceeding 12 months may increase a bleeding risk despite a lower risk of ischemic events. There is no study to compare clinical outcomes in patients treated with a single-antiplatelet drug after DAPT in the era of drug-eluting stents (DES). We sought to investigate the efficacy and safety of clopidogrel versus aspirin monotherapy after 12-month DAPT after DES implantation using an institutional registry.

Methods and Results—

This observational study was conducted on consecutive patients receiving DES between January 2003 and December 2010. A total of 3243 patients receiving 12-month DAPT after DES implantation without adverse clinical outcomes were divided into 2 groups based on prescribed antiplatelet status: aspirin (n=2472) and clopidogrel (n=771). Clinical, angiographic, and procedural characteristics revealed more comorbidities and more complex lesions in the clopidogrel group than in the aspirin group. At 36 months after initiation of antiplatelet monotherapy, clopidogrel was associated with a reduction in risk for a composite of cardiac death, myocardial infarction, or stroke (aspirin versus clopidogrel; 3.8% versus 2.6%; hazard ratio, 0.54; 95% confidence interval, 0.32–0.92;
P
=0.02). The risk of cardiac death was lower with clopidogrel monotherapy than with aspirin monotherapy (1.4% versus 0.5%; hazard ratio, 0.31; 95% confidence interval, 0.11–0.93;
P
=0.04). Thrombolysis in myocardial infarction major bleeding occurred similarly between both groups (0.9% versus 1.3%; hazard ratio, 1.03; 95% confidence interval, 0.46–2.32;
P
=0.95).

Conclusions—
After 12-month DAPT, clopidogrel monotherapy, when compared with aspirin monotherapy, might be associated with a reduced risk of recurrent ischemic events in patients receiving DES.
Estimating the Bowen Ratio for Application in Air Quality Models by Integrating a Simplified Analytical Expression with Measurement Data
Authors: Lin K. M. , Juang J. Y. , Shiu Y.-W. , Chang L. F. W. 
Published: January 2016

AbstractIn air quality models, daytime sensible and latent heat fluxes are important factors that influence atmospheric stability. These heat fluxes originate from heat that is generated from solar radiation and is then released from the earth’s surface. Different climates and surface conditions may lead to varying heat flux distributions. Because latent heat flux is influenced by both solar radiation and plant evapotranspiration, it is often difficult to estimate. The objective of this study was to apply thermodynamic concepts to determine an equation that could be used to estimate the Bowen ratio in the absence of latent and sensible heat fluxes. This study showed that, using two meteorological parameters (i.e., absolute temperature and relative humidity), the Bowen ratio for the climate in Taiwan could be obtained and then used to estimate sensible and latent heat fluxes in a series of equations. Furthermore, the approach’s applicability was determined by testing the sensitivities of parameters used in the Bowen ratio equation. A comparison of results determined through the Priestly–Taylor and Penman–Monteith methods with meteorological data for Yilan and Chiayi counties, Taiwan, for the 2006 summer and winter is performed. The results of this study showed that, among the simulated latent heat fluxes in the two study areas, the values estimated using the Penman–Monteith method were the largest, followed by those estimated using the Priestly–Taylor method. Values estimated using the Bowen ratio method were the smallest. Predictions generated by the proposed Bowen ratio equation correlated with those generated by the other models; however, the values estimated with the Priestly–Taylor method were closest to the simulated values.
Long-Lead Seasonal Prediction of China Summer Rainfall Using an EOF–PLS Regression-Based Methodology*,+
Authors: Xing Wen , Wang Bin , Yim So-Young 
Published: January 2016

Abstract
Considerable year-to-year variability of summer rainfall exposes China to threats of frequent droughts and floods. Objective prediction of the summer rainfall anomaly pattern turns out to be very challenging. As shown in the present study, the contemporary state-of-the-art dynamical models’ 1-month-lead prediction of China summer rainfall (CSR) anomalies has insignificant skills. Thus, there is an urgent need to explore other ways to improve CSR prediction. The present study proposes a combined empirical orthogonal function (EOF)–partial least squares (PLS) regression method to offer a potential long-lead objective prediction of spatial distribution of CSR anomalies. The essence of the methodology is to use PLS regression to predict the principal component (PC) of the first five leading EOF modes of CSR. The preceding December–January mean surface temperature field [ST; i.e., SST over ocean and 2-m air temperature (T2m) over land] is selected as the predictor field for all five PCs because SST and snow cover, which is reflected by 2-m air temperature, are the most important factors that affect CSR and because the correlation between each mode and ST during winter is higher than in spring. The 4-month-lead forecast models are established by using the data from 1979 to 2004. A 9-yr independent forward-rolling prediction is made for the latest 9 yr (2005–13) as a strict forecast validation. The pattern correlation coefficient skill (0.32) between the observed and the 4-month-lead predicted patterns during the independent forecast period of 2005–13 is significantly higher than the dynamic models’ 1-month-lead hindcast skill (0.04), which indicates that the EOF–PLS regression is a useful tool for improving the current seasonal rainfall prediction. Issues related to the EOF–PLS method are also discussed.