bluuebunny/crossref_metadata_2025_split huggingface dataset:
T Cells Deficient in Diacylglycerol Kinase ζ Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia
Authors: Jing Weiqing , Gershan Jill A. , Holzhauer Sandra , Weber James , Palen Katie , McOlash Laura , Pulakanti Kirthi , Wesley Erin , Rao Sridhar , Johnson Bryon D. , Riese Matthew J. 
Published: September 2017

Abstract
Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ−/−) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ−/− T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676–86. ©2017 AACR.
Characterization of the Immune Microenvironment in Hepatocellular Carcinoma
Authors: Yarchoan Mark , Xing Dongmei , Luan Lan , Xu Haiying , Sharma Rajni B. , Popovic Aleksandra , Pawlik Timothy M. , Kim Amy K. , Zhu Qingfeng , Jaffee Elizabeth M. , Taube Janis M. , Anders Robert A. 
Published: September 2017

Abstract
Purpose: Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies.
Experimental Design: To characterize the immune microenvironment in HCC, IHC staining was performed for CD8-positive T lymphocytes, PD-1–positive, and LAG-3–positive lymphocytes, CD163-positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC.
Results: Expression of CD8 was reduced in tumor, and expression of CD163 was reduced at the tumor interface. Positive clusters of PD-L1 expression were identified in 24 of 29 cases (83%), and positive expression of LAG-3 on tumor-infiltrating lymphocytes was identified in 19 of 29 cases (65%). The expression of both PD-L1 and LAG-3 was increased in tumor relative to liver background. No association between viral status or other clinicopathologic features and expression of any of the IHC markers investigated was noted.
Conclusions: LAG-3 and PD-L1, two inhibitory molecules implicated in CD8 T-cell tolerance, are increased in most HCC tumors, providing a basis for investigating combinatorial checkpoint blockade with a LAG-3 and PD-L1 inhibitor in HCC. Clin Cancer Res; 23(23); 7333–9. ©2017 AACR.
Demethylation Therapy as a Targeted Treatment for Human Papillomavirus–Associated Head and Neck Cancer
Authors: Biktasova Asel , Hajek Michael , Sewell Andrew , Gary Cyril , Bellinger Gary , Deshpande Hari A. , Bhatia Aarti , Burtness Barbara , Judson Benjamin , Mehra Saral , Yarbrough Wendell G. , Issaeva Natalia 
Published: September 2017

Abstract
Purpose: DNA methylation in human papillomavirus–associated (HPV+) head and neck squamous cell carcinoma (HNSCC) may have importance for continuous expression of HPV oncogenes, tumor cell proliferation, and survival. Here, we determined activity of a global DNA-demethylating agent, 5-azacytidine (5-aza), against HPV+ HNSCC in preclinical models and explored it as a targeted therapy in a window trial enrolling patients with HPV+ HNSCC.
Experimental Design: Sensitivity of HNSCC cells to 5-aza treatment was determined, and then 5-aza activity was tested in vivo using xenografted tumors in a mouse model. Finally, tumor samples from patients enrolled in a window clinical trial were analyzed to identify activity of 5-aza therapy in patients with HPV+ HNSCC.
Results: Clinical trial and experimental data show that 5-aza induced growth inhibition and cell death in HPV+ HNSCC. 5-aza reduced expression of HPV genes, stabilized p53, and induced p53-dependent apoptosis in HNSCC cells and tumors. 5-aza repressed expression and activity of matrix metalloproteinases (MMP) in HPV+ HNSCC, activated IFN response in some HPV+ head and neck cancer cells, and inhibited the ability of HPV+ xenografted tumors to invade mouse blood vessels.
Conclusions: 5-aza may provide effective therapy for HPV-associated HNSCC as an alternative or complement to standard cytotoxic therapy. Clin Cancer Res; 23(23); 7276–87. ©2017 AACR.
HPV Integration in HNSCC Correlates with Survival Outcomes, Immune Response Signatures, and Candidate Drivers
Authors: Koneva Lada A. , Zhang Yanxiao , Virani Shama , Hall Pelle B. , McHugh Jonathan B. , Chepeha Douglas B. , Wolf Gregory T. , Carey Thomas E. , Rozek Laura S. , Sartor Maureen A. 
Published: September 2017

Abstract
The incidence of human papillomavirus (HPV)–related oropharynx cancer has steadily increased over the past two decades and now represents a majority of oropharyngeal cancer cases. Integration of the HPV genome into the host genome is a common event during carcinogenesis that has clinically relevant effects if the viral early genes are transcribed. Understanding the impact of HPV integration on clinical outcomes of head and neck squamous cell carcinoma (HNSCC) is critical for implementing deescalated treatment approaches for HPV+ HNSCC patients. RNA sequencing (RNA-seq) data from HNSCC tumors (n = 84) were used to identify and characterize expressed integration events, which were overrepresented near known head and neck, lung, and urogenital cancer genes. Five genes were recurrent, including CD274 (PD-L1). A significant number of genes detected to have integration events were found to interact with Tp63, ETS, and/or FOX1A. Patients with no detected integration had better survival than integration-positive and HPV− patients. Furthermore, integration-negative tumors were characterized by strongly heightened signatures for immune cells, including CD4+, CD3+, regulatory, CD8+ T cells, NK cells, and B cells, compared with integration-positive tumors. Finally, genes with elevated expression in integration-negative specimens were strongly enriched with immune-related gene ontology terms, while upregulated genes in integration-positive tumors were enriched for keratinization, RNA metabolism, and translation.
Implications: These findings demonstrate the clinical relevancy of expressed HPV integration, which is characterized by a change in immune response and/or aberrant expression of the integration-harboring cancer-related genes, and suggest strong natural selection for tumor cells with expressed integration events in key carcinogenic genes. Mol Cancer Res; 16(1); 90–102. ©2017 AACR.
Use of Cloud Radar Doppler Spectra to Evaluate Stratocumulus Drizzle Size Distributions in Large-Eddy Simulations with Size-Resolved Microphysics
Authors: Rémillard J. , Fridlind A. M. , Ackerman A. S. , Tselioudis G. , Kollias P. , Mechem D. B. , Chandler H. E. , Luke E. , Wood R. , Witte M. K. , Chuang P. Y. , Ayers J. K. 
Published: September 2017

AbstractA case study of persistent stratocumulus over the Azores is simulated using two independent large-eddy simulation (LES) models with bin microphysics, and forward-simulated cloud radar Doppler moments and spectra are compared with observations. Neither model is able to reproduce the monotonic increase of downward mean Doppler velocity with increasing reflectivity that is observed under a variety of conditions, but for differing reasons. To a varying degree, both models also exhibit a tendency to produce too many of the largest droplets, leading to excessive skewness in Doppler velocity distributions, especially below cloud base. Excessive skewness appears to be associated with an insufficiently sharp reduction in droplet number concentration at diameters larger than ~200 μm, where a pronounced shoulder is found for in situ observations and a sharp reduction in reflectivity size distribution is associated with relatively narrow observed Doppler spectra. Effectively using LES with bin microphysics to study drizzle formation and evolution in cloud Doppler radar data evidently requires reducing numerical diffusivity in the treatment of the stochastic collection equation; if that is accomplished sufficiently to reproduce typical spectra, progress toward understanding drizzle processes is likely.
A Field Study of Footprint-Scale Variability of Raindrop Size Distribution
Authors: Tokay Ali , D’Adderio Leo Pio , Porcù Federico , Wolff David B. , Petersen Walter A. 
Published: September 2017

Abstract
A network of seven two-dimensional video disdrometers (2DVD), which were operated during the Midlatitude Continental Convective Clouds Experiment (MC3E) in northern Oklahoma, are employed to investigate the spatial variability of raindrop size distribution (DSD) within the footprint of the dual-frequency precipitation radar (DPR) on board the National Aeronautics and Space Administration’s Global Precipitation Measurement (GPM) mission core satellite. One-minute 2DVD DSD observations were interpolated uniformly to 13 points distributed within a nearly circular DPR footprint through an inverse distance weighting method. The presence of deep continental showers was a unique feature of the dataset resulting in a higher mean rain rate R with respect to previous studies. As a measure of spatial variability for the interpolated data, a three-parameter exponential function was applied to paired correlations of three parameters of normalized gamma DSD, R, reflectivity, and attenuation at Ka- and Ku-band frequencies of DPR (Z_Ka, Z_Ku, k_Ka, and k_Ku, respectively). The symmetry of the interpolated sites allowed quantifying the directional differences in correlations at the same distance. The correlation distances d0 of R, k_Ka, and k_Ku were approximately 10 km and were not sensitive to the choice of four rain thresholds used in this study. The d0 of Z_Ku, on the other hand, ranged from 29 to 20 km between different rain thresholds. The coefficient of variation (CV) remained less than 0.5 for most of the samples for a given physical parameter, but a CV of greater than 1.0 was also observed in noticeable samples, especially for the shape parameter and Z_Ku.
Combination of Multimodel Probabilistic Forecasts Using an Optimal Weighting System
Authors: Chen Li-Chuan Gwen , van den Dool Huug 
Published: September 2017

Abstract
In this study, an optimal weighting system is developed that combines multiple seasonal probabilistic forecasts in the North American Multimodel Ensemble (NMME). The system is applied to predict temperature and precipitation over the North American continent, and the analysis is conducted using the 1982–2010 hindcasts from eight NMME models, including the CFSv2, CanCM3, CanCM4, GFDL CM2.1, Forecast-Oriented Low Ocean Resolution (FLOR), GEOS5, CCSM4, and CESM models, with weights determined by minimizing the Brier score using ridge regression. Strategies to improve the performance of ridge regression are explored, such as eliminating a priori models with negative skill and increasing the effective sample size by pooling information from neighboring grids. A set of constraints is put in place to confine the weights within a reasonable range or restrict the weights from departing wildly from equal weights. So when the predictor–predictand relationship is weak, the multimodel ensemble forecast returns to an equal-weight combination. The new weighting system improves the predictive skill from the baseline, equally weighted forecasts. All models contribute to the weighted forecasts differently based upon location and forecast start and lead times. The amount of improvement varies across space and corresponds to the average model elimination percentage. The areas with higher elimination rates tend to show larger improvement in cross-validated verification scores. Some local improvements can be as large as 0.6 in temporal probability anomaly correlation (TPAC). On average, the results are about 0.02–0.05 in TPAC for temperature probabilistic forecasts and 0.03–0.05 for precipitation probabilistic forecasts over North America. The skill improvement is generally greater for precipitation probabilistic forecasts than for temperature probabilistic forecasts.
In vivo MR spectroscopy predicts high tumor grade in endometrial cancer
Authors: Ytre-Hauge Sigmund , Esmaeili Morteza , Sjøbakk Torill E , Grüner Renate , Woie Kathrine , Werner Henrica M , Krakstad Camilla , Bjørge Line , Salvesen Øyvind O , Stefansson Ingunn M , Trovik Jone , Bathen Tone F , Haldorsen Ingfrid S 
Published: September 2017

Background In vivo magnetic resonance spectroscopy (MRS) enables non-invasive measurements of tumor metabolites. Choline-containing metabolites play a key role in tumor metabolism. Purpose To explore whether preoperative MRS-derived tumor choline levels are associated with clinical and histological features in endometrial carcinomas. Material and Methods Preoperative pelvic magnetic resonance imaging (MRI) (1.5T), including structural and diffusion-weighted imaging and localized multivoxel proton MR (1H-MR) spectroscopy, was performed in 77 prospectively included patients with histologically confirmed endometrial carcinomas. Relative levels of total choline-containing metabolites (tCho) in tumor and myometrium were measured using the ratios: tCho/Creatine; tCho/Water; and tCho/Noise. MRS parameters were analyzed in relation to histological subtype and grade, surgicopathological staging parameters, MRI-measured tumor volume, and tumor apparent diffusion coefficient (ADC) value and clinical outcome. Results Tumor tissue had significantly higher ratios for tCho/Creatine, tCho/Water, and tCho/Noise than normal myometrial tissue ( P < 0.001 for all). High tumor tCho/Water ratio was significantly associated with high tumor grade in endometrioid tumors ( P = 0.02). Tumor tCho/Creatine ratio was positively correlated to MRI-measured tumor volume (rs = 0.25; P = 0.03). Conclusion High choline levels in tumor are associated with high-risk features. In vivo MRS may potentially aid in the preoperative risk stratification in endometrial cancer.
Correlations between polymorphisms in the uridine diphosphate-glucuronosyltransferase 1A and C-C motif chemokine receptor 5 genes and infection with the hepatitis B virus in three ethnic groups in China
Authors: Zhang Chan , He Yan , Shan Ke-Ren , Tan Kui , Zhang Ting , Wang Chan-Juan , Guan Zhi-Zhong 
Published: September 2017

Objective To determine whether genetic polymorphisms in the uridine diphosphate-glucuronosyltransferase 1A ( UGT1A) and the C-C motif chemokine receptor 5 ( CCR5) genes are associated with hepatitis B virus (HBV) infection in Yi, Yao and Han ethnic groups in the Guizhou Province of China. Methods The study enrolled subjects with and without HBV infection. Whole blood was used for DNA genotyping using standard techniques. The study determined the frequencies of several polymorphic alleles ( UGT1A6 [rs2070959], UGT1A1 [rs8175347], CCR5-59029 [rs1799987] and CCR5Δ32 [rs333]) and then characterized their relationship with HBV infection. Results A total of 404 subjects were enrolled in the study: 138 from the Yao group, 101 from the Yi group and 165 from the Han group. There was a significant difference in the frequency of UGT1A1 rs8175347 polymorphisms among the three groups. The rates of 7TA carriers of UGT1A1 rs8175347 in all three groups were significantly higher than the other genotypes. Individuals with genotype AA of UGT1A6 rs2070959 in the Yi group had a higher risk for HBV infection than in the Yao and Han groups. The frequency of genotype GG in CCR5-59029 in the Yao group was significantly higher than in the Yi group. The genotypes of CCR5Δ32 were not associated with HBV infection. Conclusion These findings provide genetic and epidemiological evidence for an association of UGT1A and CCR5-59029 polymorphisms with HBV infection in Chinese Yi and Yao populations.
Worse renal outcome of subclass IV-G lupus nephritis patients over IV-S
Authors: Duque de Sá Carneiro Filho E J , Jorge L B , Testagrossa L , Bitencourt C , Yu L , Woronik V 
Published: September 2017

Background International Society of Nephrology/ Renal Pathology Society (ISN/RPS) consensus on the classification of lupus nephritis (LN) subdivided class IV into diffuse segmental (IV-S) and diffuse global (IV-G). Nephrologists and nephropathologists believe that this subclassification would be clinically relevant based on hypothetical distinct immunopathogenesis of those subclasses guiding therapy as well as judging prognosis. Methods All adult patients with a renal biopsy-confirmed diagnosis of LN class IV undergoing regular follow-up in the Nephrology Division between January 2004 and December 2014 were enrolled excluding those with diabetes, hepatitis B, hepatitis C, HIV as well as those with insufficient clinical and hystopathological data. Biopsies were reviewed and reclassified according to ISN/RPS 2003 classification by two experienced pathologists and were examined by light microscopy and direct immunofluorescence. Results On baseline subclass IV-G compared to IV-S showed higher frequency of males and histologically higher activity (7.5 ± 2.8 vs 5.1 ± 2.3, p = 0.004) and chronicity index (3.4 ± 1.6 vs 2.4 ± 1.8, p = 0.016) as well as a higher percentage of epithelial crescents (12.9 vs 5.1, p = 0.0001) and vessel abnormalities (72% vs 42%, p = 0.017). Although renal function on baseline was not different between subclasses, IV-G showed lower levels, although not significant, of estimated glomerular filtration based on CKD-EPI formula (91.0 ± 34.8 vs 64.4 ± 44.5, p = 0.059) at the end of follow-up. In addition, we observed a higher rate of patients reaching CKD-EPI under 60 mL/min/1.73 m2 in subclass IV-G over IV-S on last follow-up. Conclusion Subclasses IV-S and IV-G patients show some clinical and pathological differences that might represent distinct stages of the same disease and they should thus be treated the same.
False-positive screens and lung cancer risk in the National Lung Screening Trial: Implications for shared decision-making
Authors: Pinsky Paul F , Bellinger Christina R , Miller David P 
Published: September 2017

Objectives Low-dose computed tomography lung cancer screening has been shown to reduce lung cancer mortality but has a high false-positive rate. The precision medicine approach to low-dose computed tomography screening assesses subjects’ benefits versus harms based on their personal lung cancer risk, where harms include false-positive screens and resultant invasive procedures. We assess the relationship between lung cancer risk and the rate of false-positive LDCT screens. Methods The National Lung Screening Trial randomized high-risk subjects to three annual screens with low-dose computed tomography or chest radiographs. Following the completion of National Lung Screening Trial, the Lung CT Screening Reporting and Data System (Lung-RADS) classification system was developed and retrospectively applied to National Lung Screening Trial low-dose computed tomography findings. The rate of false-positive screens (by Lung-RADS) and the resultant invasive procedures were examined as a function of lung cancer risk estimated by a model. Results Of 26,722 subjects randomized to the low-dose computed tomography arm, 26,309 received a baseline screen and were included in the analysis. The proportion with any false positive over three screening rounds increased from 12.9% to 25.9% from lowest to highest risk decile, and the proportion with an invasive procedure following a false positive also significantly increased from 0.7% to 2.0% from lowest to highest risk decile. Conclusion These findings indicate a need for personalized low-dose computed tomography lung cancer screening decision aids to accurately convey the benefits to harm trade-off.
Long-term predictors of stroke in healthy middle-aged men
Authors: Prestgaard Erik , Hodnesdal Christian , Engeseth Kristian , Erikssen Jan , Bodegård Johan , Liestøl Knut , Gjesdal Knut , Kjeldsen Sverre E. , Grundvold Irene , Berge Eivind 
Published: September 2017

Background There are few data on risk factors for stroke during long-term follow-up of healthy individuals. Aims We aimed to investigate the long-term predictive impact on stroke risk of baseline variables including hemodynamic variables measured at rest and during exercise in middle-aged, healthy men. Methods We performed a prospective cohort study of 2014 healthy Norwegian men aged 40–59 years, recruited during the period 1972–1975 and followed until 2007. Participants underwent a comprehensive clinical assessment at baseline, including a bicycle exercise test. Data on stroke, transient ischemic attack, and death were collected on all participants from follow-up visits, medical records, and the National Cause of Death Registry. We used Cox regression for analysis and estimated hazard ratios with 95% confidence intervals, adjusting for traditional risk factors and hemodynamic variables measured at rest and during exercise. Results During 35 years’ follow-up, 316 participants (16%) had stroke, of which 287 (91%) were ischemic and 29 (9%) were hemorrhagic. Age (hazard ratio 2.70 per increase in one standard deviation, 95% confidence interval 2.13–3.43), resting systolic blood pressure (hazard ratio 1.24, 95% confidence interval 1.11–1.39), body mass index (hazard ratio 1.14, 95% confidence interval 1.02–1.29), and atrioventricular conduction time (hazard ratio 1.11, 95% confidence interval 1.03–1.19) were significantly associated with long-term risk of stroke, as were maximal systolic blood pressure and heart rate during exercise (hazard ratio 1.28, 95% confidence interval 1.13–1.46, and hazard ratio 0.86, 95% confidence interval 0.74–0.99, respectively). Conclusions Hemodynamic variables at rest and during exercise testing add to the predictive value of clinical variables in healthy, middle-aged men, and should be included in the assessment of long-term risk of stroke, when available.
Emerging mechanisms of long noncoding RNA function during normal and malignant hematopoiesis
Authors: Alvarez-Dominguez Juan R. , Lodish Harvey F. 
Published: September 2017

AbstractLong noncoding RNAs (lncRNAs) are increasingly recognized as vital components of gene programs controlling cell differentiation and function. Central to their functions is an ability to act as scaffolds or as decoys that recruit or sequester effector proteins from their DNA, RNA, or protein targets. lncRNA-modulated effectors include regulators of transcription, chromatin organization, RNA processing, and translation, such that lncRNAs can influence gene expression at multiple levels. Here we review the current understanding of how lncRNAs help coordinate gene expression to modulate cell fate in the hematopoietic system. We focus on a growing number of mechanistic studies to synthesize emerging principles of lncRNA function, emphasizing how they facilitate diversification of gene programming during development. We also survey how disrupted lncRNA function can contribute to malignant transformation, highlighting opportunities for therapeutic intervention in specific myeloid and lymphoid cancers. Finally, we discuss challenges and prospects for further elucidation of lncRNA mechanisms.