bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies
Authors: Dylgjeri Emanuela , McNair Christopher , Goodwin Jonathan F. , Raymon Heather K. , McCue Peter A. , Shafi Ayesha A. , Leiby Benjamin E. , de Leeuw Renée , Kothari Vishal , McCann Jennifer J. , Mandigo Amy C. , Chand Saswati N. , Schiewer Matthew J. , Brand Lucas J. , Vasilevskaya Irina , Gordon Nicolas , Laufer Talya S. , Gomella Leonard G. , Lallas Costas D. , Trabulsi Edouard J. , Feng Felix Y. , Filvaroff Ellen H. , Hege Kristin , Rathkopf Dana , Knudsen Karen E. 
Published: July 2019

Abstract

Purpose:
DNA-dependent protein kinase catalytic subunit (DNA-PK) is a pleiotropic kinase involved in DNA repair and transcriptional regulation. DNA-PK is deregulated in selected cancer types and is strongly associated with poor outcome. The underlying mechanisms by which DNA-PK promotes aggressive tumor phenotypes are not well understood. Here, unbiased molecular investigation in clinically relevant tumor models reveals novel functions of DNA-PK in cancer.
Experimental Design: DNA-PK function was modulated using both genetic and pharmacologic methods in a series of in vitro models, in vivo xenografts, and patient-derived explants (PDE), and the impact on the downstream signaling and cellular cancer phenotypes was discerned. Data obtained were used to develop novel strategies for combinatorial targeting of DNA-PK and hormone signaling pathways.

Results:
Key findings reveal that (i) DNA-PK regulates tumor cell proliferation; (ii) pharmacologic targeting of DNA-PK suppresses tumor growth both in vitro, in vivo, and ex vivo; (iii) DNA-PK transcriptionally regulates the known DNA-PK–mediated functions as well as novel cancer-related pathways that promote tumor growth; (iv) dual targeting of DNA-PK/TOR kinase (TORK) transcriptionally upregulates androgen signaling, which can be mitigated using the androgen receptor (AR) antagonist enzalutamide; (v) cotargeting AR and DNA-PK/TORK leads to the expansion of antitumor effects, uncovering the modulation of novel, highly relevant protumorigenic cancer pathways; and (viii) cotargeting DNA-PK/TORK and AR has cooperative growth inhibitory effects in vitro and in vivo.

Conclusions:
These findings uncovered novel DNA-PK transcriptional regulatory functions and led to the development of a combinatorial therapeutic strategy for patients with advanced prostate cancer, currently being tested in the clinical setting.
A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance
Authors: Olender Jacqueline , Wang Bi-Dar , Ching Travers , Garmire Lana X. , Garofano Kaitlin , Ji Youngmi , Knox Tessa , Latham Patricia , Nguyen Kenneth , Rhim Johng , Lee Norman H. 
Published: July 2019

AbstractAlternative splicing (AS) has been shown to participate in prostate cancer development and progression; however, a link between AS and prostate cancer health disparities has been largely unexplored. Here we report on the cloning of a novel splice variant of FGFR3 that is preferentially expressed in African American (AA) prostate cancer. This novel variant (FGFR3-S) omits exon 14, comprising 123 nucleotides that encode the activation loop in the intracellular split kinase domain. Ectopic overexpression of FGFR3-S in European American (EA) prostate cancer cell lines (PC-3 and LNCaP) led to enhanced receptor autophosphorylation and increased activation of the downstream signaling effectors AKT, STAT3, and ribosomal S6 compared with FGFR3-L (retains exon 14). The increased oncogenic signaling imparted by FGFR3-S was associated with a substantial gain in proliferative and antiapoptotic activities, as well as a modest but significant gain in cell motility. Moreover, the FGFR3-S–conferred proliferative and motility gains were highly resistant to the pan-FGFR small-molecule inhibitor dovitinib and the antiapoptotic gain was insensitive to the cytotoxic drug docetaxel, which stands in marked contrast with dovitinib- and docetaxel-sensitive FGFR3-L. In an in vivo xenograft model, mice injected with PC-3 cells overexpressing FGFR3-S exhibited significantly increased tumor growth and resistance to dovitinib treatment compared with cells overexpressing FGFR3-L. In agreement with our in vitro and in vivo findings, a high FGFR3-S/FGFR3-L expression ratio in prostate cancer specimens was associated with poor patient prognosis.Implications:This work identifies a novel FGFR3 splice variant and supports the hypothesis that differential AS participates in prostate cancer health disparities.
Upregulation of miR-130b Contributes to Risk of Poor Prognosis and Racial Disparity in African-American Prostate Cancer
Authors: Hashimoto Yutaka , Shiina Marisa , Dasgupta Pritha , Kulkarni Priyanka , Kato Taku , Wong Ryan K. , Tanaka Yuichiro , Shahryari Varahram , Maekawa Shigekatsu , Yamamura Soichiro , Saini Sharanjot , Deng Guoren , Tabatabai Z. Laura , Majid Shahana , Dahiya Rajvir 
Published: July 2019

Abstract
Prostate cancer incidence and mortality rates are higher in African-American (AA) than in European-American (EA) men. The main objective of this study was to elucidate the role of miR-130b as a contributor to prostate cancer health disparity in AA patients. We also determined whether miR-130b is a prognostic biomarker and a new therapeutic candidate for AA prostate cancer. A comprehensive approach of using cell lines, tissue samples, and the TCGA database was employed. We performed a series of functional assays such as cell proliferation, migration, invasion, RT2-PCR array, qRT-PCR, cell cycle, luciferase reporter, immunoblot, and IHC. Various statistical approaches such as Kaplan–Meier, uni-, and multivariate analyses were utilized to determine the clinical significance of miR-130b. Our results showed that elevated levels of miR-130b correlated with race disparity and PSA levels/failure and acted as an independent prognostic biomarker for AA patients. Two tumor suppressor genes, CDKN1B and FHIT, were validated as direct functional targets of miR-130b. We also found race-specific cell-cycle pathway activation in AA patients with prostate cancer. Functionally, miR-130b inhibition reduced cell proliferation, colony formation, migration/invasion, and induced cell-cycle arrest. Inhibition of miR-130b modulated critical prostate cancer–related biological pathways in AA compared with EA prostate cancer patients. In conclusion, attenuation of miR-130b expression has tumor suppressor effects in AA prostate cancer. miR-130b is a significant contributor to prostate cancer racial disparity as its overexpression is a risk factor for poor prognosis in AA patients with prostate cancer. Thus, regulation of miR-130b may provide a novel therapeutic approach for the management of prostate cancer in AA patients.
An Anticancer Drug Cocktail of Three Kinase Inhibitors Improved Response to a Dendritic Cell–Based Cancer Vaccine
Authors: Guo Jitao , Muse Elena , Christians Allison J. , Swanson Steven J. , Davila Eduardo 
Published: July 2019

Abstract
Monocyte-derived dendritic cell (moDC)–based cancer therapies intended to elicit antitumor T-cell responses have limited efficacy in most clinical trials. However, potent and sustained antitumor activity in a limited number of patients highlights the therapeutic potential of moDCs. In vitro culture conditions used to generate moDCs can be inconsistent, and moDCs generated in vitro are less effective than natural DCs. On the basis of our study highlighting the ability for certain kinase inhibitors to enhance tumor antigenicity, we therefore screened kinase inhibitors for their ability to improve DC immunogenicity. We identified AKT inhibitor MK2206, DNA-PK inhibitor NU7441, and MEK inhibitor trametinib as the compounds most effective at modulating moDC immunogenicity. The combination of these drugs, referred to as MKNUTRA, enhanced moDC activity over treatment with individual drugs while exhibiting minimal toxicity. An evaluation of 335 activation and T-cell–suppressive surface proteins on moDCs revealed that MKNUTRA treatment more effectively matured cells and reduced the expression of tolerogenic proteins as compared with control moDCs. MKNUTRA treatment imparted to ICT107, a glioblastoma (GBM) DC-based vaccine that has completed phase II trials, an increased ability to stimulate patient-derived autologous CD8+ T cells against the brain tumor antigens IL13Rα2(345-354) and TRP2(180-188). In vivo, treating ICT107 with MKNUTRA, prior to injection into mice with an established GBM tumor, reduced tumor growth kinetics. This response was associated with an increased frequency of tumor-reactive lymphocytes within tumors and in peripheral tissues. These studies broaden the application of targeted anticancer drugs and highlight their ability to increase moDC immunogenicity.
MERTK Acts as a Costimulatory Receptor on Human CD8+ T Cells
Authors: Peeters Marlies J.W. , Dulkeviciute Donata , Draghi Arianna , Ritter Cathrin , Rahbech Anne , Skadborg Signe K. , Seremet Tina , Carnaz Simões Ana Micaela , Martinenaite Evelina , Halldórsdóttir Hólmfridur R. , Andersen Mads Hald , Olofsson Gitte Holmen , Svane Inge Marie , Rasmussen Lene Juel , Met Özcan , Becker Jürgen C. , Donia Marco , Desler Claus , thor Straten Per 
Published: July 2019

Abstract
The TAM family of receptor tyrosine kinases (TYRO3, AXL, and MERTK) is known to be expressed on antigen-presenting cells and function as oncogenic drivers and as inhibitors of inflammatory responses. Both human and mouse CD8+ T cells are thought to be negative for TAM receptor expression. In this study, we show that T-cell receptor (TCR)–activated human primary CD8+ T cells expressed MERTK and the ligand PROS1 from day 2 postactivation. PROS1-mediated MERTK signaling served as a late costimulatory signal, increasing proliferation and secretion of effector and memory-associated cytokines. Knockdown and inhibition studies confirmed that this costimulatory effect was mediated through MERTK. Transcriptomic and metabolic analyses of PROS1-blocked CD8+ T cells demonstrated a role of the PROS1–MERTK axis in differentiation of memory CD8+ T cells. Finally, using tumor-infiltrating lymphocytes (TIL) from melanoma patients, we show that MERTK signaling on T cells improved TIL expansion and TIL-mediated autologous cancer cell killing. We conclude that MERTK serves as a late costimulatory signal for CD8+ T cells. Identification of this costimulatory function of MERTK on human CD8+ T cells suggests caution in the development of MERTK inhibitors for hematologic or solid cancer treatment.
Immunologic Profiling of Mutational and Transcriptional Subgroups in Pediatric and Adult High-Grade Gliomas
Authors: Bockmayr Michael , Klauschen Frederick , Maire Cecile L. , Rutkowski Stefan , Westphal Manfred , Lamszus Katrin , Schüller Ulrich , Mohme Malte 
Published: July 2019

Abstract
Immunologic treatment strategies are under investigation for high-grade gliomas. Determining relevant immunologic pathways is required for invigorating a tumor-specific immune response. We therefore investigated the immunologic phenotypes within different subgroups of high-grade gliomas, with a focus on rare genetic subgroups of pediatric and adolescent patients to identify potentially targetable mechanisms. We gathered published gene-expression data from 1,135 high-grade glioma patients and applied a machine-learning technique to determine their transcriptional (mesenchymal, classic, neural, and proneural) and mutational [K27, G34, IDH, and wild type (WT)] subtypes. Gene signatures of infiltrating immune cells and functional immune pathways were evaluated in correlation to histologic diagnosis, age, and transcriptional and mutational subgroups. Our analysis identified four distinct microenvironmental signatures of immune cell infiltration (immune 1–4), which can be stratified into vascular, monocytic/stromal, monocytic/T-cell–, and antigen-presenting cell (APC)/natural killer (NK) cell/T-cell–dominated immune clusters. Immune cell expression profiles correlated with transcriptional and mutational subgroups but were independent of age and histologic diagnosis. By including functional pathways and correlating the expression of immunostimulatory and -inhibitory receptor–ligand interactions, we were able to define the immunologic microenvironment and identify possible immunologic subtypes associated with poor prognosis. In addition, comparison of overall survival with the immunologic landscape and with checkpoint molecules revealed correlations within the transcriptional and mutational subgroups, highlighting the potential application of PD-1/PD-L1 checkpoint inhibition in K27-mutated tumors. Our study shows that transcriptional and mutational subgroups are characterized by distinct immunologic tumor microenvironments, demonstrating the immunologic heterogeneity within high-grade gliomas and suggesting an immune-specific stratification for upcoming immunotherapy trials.
A Phase I Study of Neoadjuvant Capecitabine, Oxaliplatin, and Irinotecan (XELOXIRI) in Patients with Locally Advanced Rectal Cancer
Authors: Kudo Toshihiro , Takemasa Ichiro , Hata Tsuyoshi , Sakai Daisuke , Takahashi Hidekazu , Haraguchi Naotsugu , Nishimura Junichi , Hata Taishi , Matsuda Chu , Satoh Taroh , Mizushima Tsunekazu , Mori Masaki , Doki Yuichiro 
Published: July 2019

<b><i>Objectives:</i></b> The aim of this study was to determine the recommended dose (RD) of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer. <b><i>Method:</i></b> Patients received irinotecan and oxaliplatin (85 mg/m<sup>2</sup>) on day 1, and capecitabine (1,000 mg/m<sup>2</sup> orally twice daily) on days 1–7 of a biweekly schedule. Three dose levels, ranging from 100 to 150 mg/m<sup>2</sup>, were explored for irinotecan in sequential cohorts of 6 patients. Dose-limiting toxicities (DLTs) were assessed in the first cycle to determine the RD. <b><i>Results:</i></b> Six patients were enrolled. The DLT was grade 3 febrile neutropenia, which was observed in 2 of the 6 patients at dose level 1. The RD of irinotecan was defined as 150 mg/m<sup>2</sup>. Toxicity was manageable: the most common grade ≥3 toxicities were neutropenia (2 patients), anemia (1 patient), and anorexia (1 patient). Nodal downstaging (cN+ to ypN0) was detected in 2 patients and the T stage was downstaged in 3 patients. <b><i>Conclusions:</i></b> XELOXIRI is a feasible and active regimen for patients with locally advanced rectal cancer. Febrile neutropenia was the DLT, and the RD of irinotecan is 150 mg/m<sup>2</sup>.
Silencing of GPR82 with Interference RNA Improved Metabolic Profiles in Rats with High Fructose Intake
Authors: Romero-Nava Rodrigo , Aguayo-Cerón Karla Aidee , Ruiz-Hernández Armando , Huang Fengyang , Hong Enrique , Aguilera-Mendez Asdrubal  , Villafaña Rauda Santiago 
Published: July 2019

Metabolic syndrome (MS) is a clinical condition, constituted by alterations that lead to the onset of type II diabetes and cardiovascular disease. It has been reported that orphan G-protein-coupled receptor 82 (GPR82) participates in metabolic processes. The aim of this study was to evaluate the function of GPR82 in MS using a small interfering RNA (siRNA) against this receptor. We used Wistar rats of 10–12 weeks of age fed with a high-fructose solution (70%) for 9 weeks to induce MS. Subsequently, the rats were treated with an intrajugular dose of an siRNA against GPR82 and the effects were evaluated on day 3 and 7 after administration. On day 3 the siRNA had a transient effect on decreasing blood pressure and triglycerides and increasing high-density lipoprotein cholesterol, which recovered to the MS control on day 7. Decreased gene expressions of GPR82 mRNA in the aorta and heart were observed on day 3; moreover, decreased gene expression was maintained in the aorta on day 7. Therefore, we conclude that the orphan receptor GPR82 participates in the development of MS induced by fructose and the silencing of this receptor could ameliorate metabolic components.
CHA2DS2-VASC Score Predicts Risk of Contrast-Induced Nephropathy in Non-ST Elevation Myocardial Infarction Patients Undergoing Percutaneous Coronary Interventions
Authors: Baydar Onur , Kilic Alparslan 
Published: July 2019

<b><i>Backround:</i></b> The CHA2DS2-VASC score, used for embolic risk stratiﬁcation in atrial ﬁbrillation, has been reported recently to predict adverse clinical outcomes in patients with coronary artery disease. We investigated the correlation between the CHA2DS2-VASC score and contrast-induced nephropathy (CIN) in patients with non-ST elevation myocardial infarction (NSTEMI) who underwent percutaneous coronary intervention (PCI). <b><i>Methods:</i></b> We retrospectively enrolled 363 (191; 52.6% men) NSTEMI patients undergoing PCI. The CHA2 DS2-VASC score was calculated for each patient, and the study population was divided into 2 groups: CHA2DS2-VASC score &#x3c;2 group (low score; <i>n</i> = 259, 71.3%) and CHA2DS2-VASC score ≥2 group (high score; <i>n</i> = 104, 28.6%). Patients were then reallocated to 2 groups according to the presence or absence of CIN. CIN was deﬁned as a rise in serum creatinine &#x3e;0.5 mg/dL or &#x3e;25% increase in baseline within 72 h after PCI. <b><i>Results:</i></b> Overall, 56 cases (15.4%) of CIN were diagnosed. When patients with a CHA2DS2-VASC score of &#x3c;2 were compared with those with a CHA2DS2-VASC score of ≥2, patients with a high score had a higher frequency of CIN (33) 31.7% versus (23) 8.9%; <i>p</i> &#x3c; 0.001. Also patients with CIN had higher CHADS2 VASC score (3.94 ± 1.13 vs. 1.68 ± 0.46, <i>p</i> &#x3c; 0.001). Additionally, in-hospital mortality, length of hospital stay, major bleeding, requirement of mechanical ventilation, and dialysis were observed significantly higher in patients with CHA2DS2-VASC score of ≥2 (<i>p</i> = 0.001, <i>p</i> = 0.002, <i>p</i> = 0.006, <i>p</i> = 0.001, <i>p</i> = 0.001, respectively). In receiver operating characteristic curve analysis, the area under the curve for predicting CIN was 0.702 (<i>p</i> &#x3c; 0.001, 95% CI 0.617–0.787) and cutoff value was 2.5 (sensitivity 58.9%, specificity 76.9%) for the number of CHA2DS2-VASC score. <b><i>Conclusion:</i></b> In NSTEMI patients undergoing PCI, CHADS2 VASC score is associated with an increased risk for CIN and in-hospital morbidity and mortality.
Causes of Dimming and Brightening in China Inferred from Homogenized Daily Clear-Sky and All-Sky in situ Surface Solar Radiation Records (1958–2016)
Authors: Yang Su , Wang Xiaolan L. , Wild Martin 
Published: July 2019

AbstractThis paper presents a study on long-term surface solar radiation (SSR) changes over China under clear- and all-sky conditions and analyzes the causes of the “dimming” and “brightening.” To eliminate the nonclimatic signals in the historical records, the daily SSR dataset was first homogenized using quantile-matching (QM) adjustment. The results reveal rapid dimming before 2000 not only under all-sky conditions, but also under clear-sky conditions, at a decline rate of −9.7 ± 0.4 W m−2 decade−1 (1958–99). This is slightly stronger than that under all-sky conditions at −7.4 ± 0.4 W m−2 decade−1, since the clear-sky dimming stopped 15 years later. A rapid “wettening” of about 40-Pa surface water vapor pressure (SWVP) from 1985 to 2000 was found over China. It contributed 2.2% to the SSR decline under clear-sky conditions during the whole dimming period (1958–99). Therefore, water vapor cannot be the main cause of the long-term dimming in China. After a stable decade (1999–2008), an intensive brightening appeared under the clear-sky conditions at a rate of 10.6 ± 2.0 W m−2 decade−1, whereas a much weaker brightening (−0.8 ± 3.1 W m−2 decade−1) has been observed under all-sky conditions between 2008 and 2016. The remarkable divergence between clear- and all-sky trends in recent decades indicates that the clouds played two opposite roles in the SSR changes during the past 30 years, by compensating for the declining SSR under the cloud-free conditions in 1985–99 and by counteracting the increasing SSR under cloud-free conditions in 2008–16. Aerosols remain as the main cause of dimming and brightening over China in the last 60 years, although the clouds counteract the effects of aerosols after 2000.
Class Politics and Social Protection: A Comparative Analysis of Local Governments in India
Authors: Roy Indrajit 
Published: July 2019

Dramatic differences in the quality of human life are a prominent feature of today’s world. In response, many governments and international development agencies have begun to formulate and implement agendas for social protection. Nevertheless, the outcomes of such initiatives remain vastly varied. What explains such variations? In this article, I direct attention to the role of class politics in shaping the implementation of social protection by local governments that implement India’s Mahatma Gandhi National Rural Employment Guarantee Act (MGNREGA). Based on a synthesis of official data, interviews with beneficiaries of social protections and elites, and direct observations in two Indian States, the author illustrates the ways in which variations in class politics influence the supply of employment works. This article departs from existing analysis of factors that favour the implementation of social protections, namely commitment of bureaucrats and politicians, political party linkages and clientelism, and civil society activism. It also nuances extant class-focused analysis which tend to adopt a polarized model of class conflict between dominant classes and the laboring poor. This article, by contrast, appreciates the conflicts within dominant classes, and emphasizes the role of coalitions and competitions between elite fractions. Where elite fractions successfully co-opt or eliminate one another, they successfully sabotage the labour-friendly MGNREGA. On the other hand, where elite fractions conflict with one another, labour-friendly programs such as the MGNREGA have a chance of being implemented. However, the transformative aspect of the program’s intent, in terms of dissolving the relations of power that bolster poverty, appears to be more in evidence in localities where precarious elites align with the laboring poor to challenge the influence of the entrenched elites. As we examine alternative means of addressing the dramatic differences in the quality of life that continue to blight the contemporary world, the imperative to analyze class politics becomes greater than ever before.