bluuebunny/crossref_metadata_2025_split huggingface dataset:
TGFβ Promotes Genomic Instability after Loss of RUNX3
Authors: Krishnan Vaidehi , Chong Yu Lin , Tan Tuan Zea , Kulkarni Madhura , Bin Rahmat Muhammad Bakhait , Tay Lavina Sierra , Sankar Haresh , Jokhun Doorgesh S. , Ganesan Amudha , Chuang Linda Shyue Huey , Voon Dominic C. , Shivashankar GV , Thiery Jean-Paul , Ito Yoshiaki 
Published: October 2017

Abstract
Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFβ is the most abundantly secreted cytokine in the TME, where it imparts various aggressive characteristics including invasive migration, drug resistance, and epithelial-to-mesenchymal transition (EMT). Here we show that TGFβ also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harboring a TGFβ gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFβ-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell–extrinsic TGFβ signaling and cancer cell–intrinsic RUNX3 inactivation as aggravating factors for genomic instability.
Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFβ expressed in the tumor microenvironment. Cancer Res; 78(1); 88–102. ©2017 AACR.
Type I IFN Receptor Signaling Controls IL7-Dependent Accumulation and Activity of Protumoral IL17A-Producing γδT Cells in Breast Cancer
Authors: Patin Emmanuel C. , Soulard Daphnée , Fleury Sébastien , Hassane Maya , Dombrowicz David , Faveeuw Christelle , Trottein François , Paget Christophe 
Published: October 2017

Abstract
The protumoral activity of γδT17 cells has recently emerged in a wide variety of solid malignancies, including breast cancer. These cells exert their detrimental functions by promoting tumor growth, angiogenesis, and subsequent metastasis development. However, the intratumoral factors that regulate the biology of γδT17cells within the tumor microenvironment are less well understood. Here, using two experimental models of breast cancer, we reinforced the concept that tumor-infiltrating γδT17 cells are endowed with protumoral functions, which promote tumor progression and metastasis development. More importantly, we demonstrated a critical role for type I IFN signaling in controlling the preferential accumulation in the tumor bed of a peculiar subset of γδT17 cells displaying a CD27− CD3bright phenotype (previously associated with the invariant Vγ6Vδ1+ TCR). Interestingly, this effect was indirect and partially relied on the IFNAR1-dependent control of IL7 secretion, a factor that triggers proliferation and activating functions of deleterious γδT17 cells. Our work therefore identifies a key role of the type I IFN/IL7 axis in the regulation of intratumoral γδT17-cell functions and in the development of primary breast tumor growth and metastasis.
Significance: Tumor-derived IL7 can represent a therapeutic target to prevent accumulation of immune cells endowed with potent protumoral activities. Cancer Res; 78(1); 195–204. ©2017 AACR.
Mitochondrial Haplotype Alters Mammary Cancer Tumorigenicity and Metastasis in an Oncogenic Driver–Dependent Manner
Authors: Brinker Amanda E. , Vivian Carolyn J. , Koestler Devin C. , Tsue Trevor T. , Jensen Roy A. , Welch Danny R. 
Published: October 2017

AbstractUsing a novel mouse model, a mitochondrial-nuclear exchange model termed MNX, we tested the hypothesis that inherited mitochondrial haplotypes alter primary tumor latency and metastatic efficiency. Male FVB/N-Tg(MMTVneu)202Mul/J (Her2) transgenic mice were bred to female MNX mice having FVB/NJ nuclear DNA with either FVB/NJ, C57BL/6J, or BALB/cJ mtDNA. Pups receiving the C57BL/6J or BALB/cJ mitochondrial genome (i.e., females crossed with Her2 males) showed significantly (P &lt; 0.001) longer tumor latency (262 vs. 293 vs. 225 days), fewer pulmonary metastases (5 vs. 7 vs. 15), and differences in size of lung metastases (1.2 vs. 1.4 vs. 1.0 mm diameter) compared with FVB/NJ mtDNA. Although polyoma virus middle T–driven tumors showed altered primary and metastatic profiles in previous studies, depending upon nuclear and mtDNA haplotype, the magnitude and direction of changes were not the same in the HER2-driven mammary carcinomas. Collectively, these results establish mitochondrial polymorphisms as quantitative trait loci in mammary carcinogenesis, and they implicate distinct interactions between tumor drivers and mitochondria as critical modifiers of tumorigenicity and metastasis. Cancer Res; 77(24); 6941–9. ©2017 AACR.
PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia
Authors: Zhou Jingfeng , Nie Danian , Li Juan , Du Xin , Lu Yuhong , Li Yangqiu , Liu Chang , Dai Wei , Wang Yun , Jin Yanli , Pan Jingxuan 
Published: October 2017

Abstract
Purpose: Leukemia stem cells (LSCs) are an important source of tyrosine kinase inhibitor resistance and disease relapse in patients with chronic myelogenous leukemia (CML). Targeting LSCs may be an attractive strategy to override this thorny problem. Given that EZH2 was overexpressed in primary CML CD34+ cells, our purpose in this study was to evaluate the effects of targeting EZH2 on CML LSCs and clarify its underlying mechanism.
Experimental Design: Human primary CML CD34+ cells and retrovirally BCR–ABL-driven CML mouse models were employed to evaluate the effects of suppression of EZH2 by GSK126- or EZH2-specific shRNA in vitro and in vivo. Recruitment of EZH2 and H3K27me3 on the promoter of tumor-suppressor gene PTEN in CML cells was measured by chromatin immunoprecipitation assay.
Results: Our results showed that pharmacologic inhibition of EZH2 by GSK126 not only elicited apoptosis and restricted cell growth in CML bulk leukemia cells, but also decreased LSCs in CML CD34+ cells while sparing those from normal bone marrow CD34+ cells. Suppression of EZH2 by GSK126 or specific shRNA prolonged survival of CML mice and reduced the number of LSCs in mice. EZH2 knockdown resulted in elevation of PTEN and led to impaired recruitment of EZH2 and H3K27me3 on the promoter of PTEN gene. The effect of EZH2 knockdown in the CML mice was at least partially reversed by PTEN knockdown.
Conclusions: These findings improve the understanding of the epigenetic regulation of stemness in CML LSCs and warrant clinical trial of GSK126 in refractory patients with CML. Clin Cancer Res; 24(1); 145–57. ©2017 AACR.
Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation
Authors: Kapoor Shivani , Natarajan Karthika , Baldwin Patrick R. , Doshi Kshama A. , Lapidus Rena G. , Mathias Trevor J. , Scarpa Mario , Trotta Rossana , Davila Eduardo , Kraus Manfred , Huszar Dennis , Tron Adriana E. , Perrotti Danilo , Baer Maria R. 
Published: October 2017

Abstract
Purpose: fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition.
Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo.
Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor–induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML.
Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234–47. ©2017 AACR.
Extracellular Vesicles Released by Cardiomyocytes in a Doxorubicin-Induced Cardiac Injury Mouse Model Contain Protein Biomarkers of Early Cardiac Injury
Authors: Yarana Chontida , Carroll Dustin , Chen Jing , Chaiswing Luksana , Zhao Yanming , Noel Teresa , Alstott Michael , Bae Younsoo , Dressler Emily V. , Moscow Jeffrey A. , Butterfield D. Allan , Zhu Haining , St. Clair Daret K. 
Published: October 2017

AbstractPurpose: Cardiac injury is a major cause of death in cancer survivors, and biomarkers for it are detectable only after tissue injury has occurred. Extracellular vesicles (EV) remove toxic biomolecules from tissues and can be detected in the blood. Here, we evaluate the potential of using circulating EVs as early diagnostic markers for long-term cardiac injury.Experimental Design: Using a mouse model of doxorubicin (DOX)-induced cardiac injury, we quantified serum EVs, analyzed proteomes, measured oxidized protein levels in serum EVs released after DOX treatment, and investigated the alteration of EV content.Results: Treatment with DOX caused a significant increase in circulating EVs (DOX_EV) compared with saline-treated controls. DOX_EVs exhibited a higher level of 4-hydroxynonenal adducted proteins, a lipid peroxidation product linked to DOX-induced cardiotoxicity. Proteomic profiling of DOX_EVs revealed the distinctive presence of brain/heart, muscle, and liver isoforms of glycogen phosphorylase (GP), and their origins were verified to be heart, skeletal muscle, and liver, respectively. The presence of brain/heart GP (PYGB) in DOX_EVs correlated with a reduction of PYGB in heart, but not brain tissues. Manganese superoxide dismutase (MnSOD) overexpression, as well as pretreatment with cardioprotective agents and MnSOD mimetics, resulted in a reduction of EV-associated PYGB in mice treated with DOX. Kinetic studies indicated that EVs containing PYGB were released prior to the rise of cardiac troponin in the blood after DOX treatment, suggesting that PYGB is an early indicator of cardiac injury.Conclusions: EVs containing PYGB are an early and sensitive biomarker of cardiac injury. Clin Cancer Res; 24(7); 1644–53. ©2017 AACR.See related commentary by Zhu and Gius, p. 1516
Low PD-1 Expression in Cytotoxic CD8+ Tumor-Infiltrating Lymphocytes Confers an Immune-Privileged Tissue Microenvironment in NSCLC with a Prognostic and Predictive Value
Authors: Mazzaschi Giulia , Madeddu Denise , Falco Angela , Bocchialini Giovanni , Goldoni Matteo , Sogni Francesco , Armani Giovanna , Lagrasta Costanza Annamaria , Lorusso Bruno , Mangiaracina Chiara , Vilella Rocchina , Frati Caterina , Alfieri Roberta , Ampollini Luca , Veneziani Michele , Silini Enrico Maria , Ardizzoni Andrea , Urbanek Konrad , Aversa Franco , Quaini Federico , Tiseo Marcello 
Published: October 2017

Abstract
Purpose: The success of immune checkpoint inhibitors strengthens the notion that tumor growth and regression are immune regulated. To determine whether distinct tissue immune microenvironments differentially affect clinical outcome in non–small cell lung cancer (NSCLC), an extended analysis of PD-L1 and tumor-infiltrating lymphocytes (TIL) was performed.
Experimental Design: Samples from resected adenocarcinoma (ADC 42), squamous cell carcinoma (SCC 58), and 26 advanced diseases (13 ADC and 13 SCC) treated with nivolumab were analyzed. PD-L1 expression and the incidence of CD3, CD8, CD4, PD-1, CD57, FOXP3, CD25, and Granzyme B TILs were immunohistochemically assessed.
Results: PD-L1 levels inversely correlated with N involvement, although they did not show a statistically significant prognostic value in resected patients. The incidence and phenotype of TILs differed in SCC versus ADC, in which EGFR and KRAS mutations conditioned a different frequency and tissue localization of lymphocytes. NSCLC resected patients with high CD8pos lymphocytes lacking PD-1 inhibitory receptor had a longer overall survival (OS: HR = 2.268; 95% CI, 1.056–4.871, P = 0.03). PD-1-to-CD8 ratio resulted in a prognostic factor both on univariate (HR = 1.952; 95% CI, 1.34–3.12, P = 0.001) and multivariate (HR = 1.943; 95% CI, 1.38–2.86, P = 0.009) analysis. Moreover, low PD-1 incidence among CD8pos cells was a distinctive feature of nivolumab-treated patients, showing clinical benefit with a prolonged progression-free survival (PFS: HR = 4.51; 95% CI, 1.45–13.94, P = 0.004).
Conclusions: In the presence of intrinsic variability in PD-L1 expression, the reservoir of PD-1–negative effector T lymphocytes provides an immune-privileged microenvironment with a positive impact on survival of patients with resected disease and response to immunotherapy in advanced NSCLC. Clin Cancer Res; 24(2); 407–19. ©2017 AACR.
Interleukin-12 from CD103+ Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis
Authors: Mittal Deepak , Vijayan Dipti , Putz Eva M. , Aguilera Amelia R. , Markey Kate A. , Straube Jasmin , Kazakoff Stephen , Nutt Stephen L. , Takeda Kazuyoshi , Hill Geoffrey R. , Waddell Nicola , Smyth Mark J. 
Published: October 2017

AbstractSeveral host factors may affect the spread of cancer to distant organs; however, the intrinsic role of dendritic cells (DC) in controlling metastasis is poorly described. Here, we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not different from primary tumors in wild-type (WT) control mice, Batf3-deficient mice had increased experimental and spontaneous metastasis and poorer survival. The increased metastasis was independent of CD4+ and CD8+ T lymphocytes, but required NK cells and IFNγ. Chimeric mice in which Batf3-dependent DCs uniformly lacked the capacity to produce IL12 had metastatic burdens similar to the Batf3-deficient mice, suggesting that Batf3+ DCs were the only cell type whose IL12 production was critical for controlling metastasis. We found that IL12-YFP reporter mice, whose lungs were injected with B16F10 melanoma, had increased numbers of IL12-expressing CD103+ DCs with enhanced CD86 expression. Bone-marrow–derived DCs from WT, but not Batf3-deficient, mice activated NK cells to produce IFNγ in an IL12-dependent manner and therapeutic injection of recombinant mouse IL12 decreased metastasis in both WT and Batf3-deficient mice. Analysis of TCGA datasets revealed an association between high expression of BATF3 and IRF8 and improved survival of breast cancer patients; BATF3 expression also significantly correlated with NK-cell receptor genes, IL12, and IFNG. Collectively, our findings show that IL12 from CD103+ DCs is critical for NK cell–mediated control of tumor metastasis. Cancer Immunol Res; 5(12); 1098–108. ©2017 AACR.
Impact of the FloTrac/Vigileo<sup>TM</sup> Monitoring on Intraoperative Fluid Management and Outcome after Liver Resection
Authors: Giustiniano Enrico , Procopio Fabio , Ruggieri Nadia , Grimaldi Stefania , Torzilli Guido , Raimondi Ferdinando 
Published: October 2017

<b><i>Backgrounds:</i></b> Perioperative fluid-therapy is a still a debated issue. In hepatic surgery, volume load must be strictly monitored to assure both a safe hemodynamics and low central venous pressure (CVP) to limit the backflow bleeding. Retrospectively, we compared intraoperative fluid management before and after the adoption of a semi-invasive hemodynamic monitoring. <b><i>Methods:</i></b> We compared patients submitted to liver resection monitored by FloTrac/Vigileo<sup>TM</sup> (group A) vs. patients who did not (group B). We searched for differences about hemodynamics, fluid therapy and outcome. <b><i>Results:</i></b> Three hundred fifty-five patients underwent hepatic resection due to neoplasm: group A – <i>n</i> = 179 and group B – <i>n</i> = 176. At the end of the resection, patients of group A showed a higher mean arterial pressure (MAP) than group B (74 ± 12 vs. 49.4 ± 8 mm Hg, respectively; <i>p</i> &#x3c; 0.001). Cardiac index and stroke volume variation in group A were within a normal range. Fluid input was higher in group B than in group A (12.0 ± 3.4 vs. 7.6 ± 3.1 mL/kg/h, respectively; <i>p</i> &#x3c; 0.001) and fluid balance was significantly different: group A –400 ± 1,527 vs. group B 326 ± 1,527 mL (<i>p</i> &#x3c; 0.001). Group B showed a greater number of cases complicated outcomes (36 vs. 20; <i>p</i> = 0.014). Considering only those subjects who were able to reach their hemodynamic targets (MAP ≥65 mm Hg and CVP ≤7 mm Hg), we found similar data. <b><i>Conclusions:</i></b> Patients who received a monitored fluid therapy experienced a safer outcome.
Early Cognitive Impairment after Intracerebral Hemorrhage in the INTERACT1 Study
Authors: You Shoujiang , Wang Xia , Lindley Richard I. , Robinson Thompson , Anderson Craig S. , Cao Yongjun , Chalmers John 
Published: October 2017

<b><i>Background:</i></b> Data on cognitive impairment after acute intracerebral hemorrhage (ICH) are limited. This study is aimed at determining the frequency and predictors of cognitive impairment among participants of the pilot phase, Intensive Blood Pressure (BP) Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1). <b><i>Methods:</i></b> INTERACT1 was an open randomized trial of early intensive (target systolic BP &#x3c;140 mm Hg) compared with contemporaneous guideline-recommended BP lowering in 404 patients with elevated systolic BP (150–220 mm Hg) within 6 h of ICH onset. Cognitive impairment was defined by scores ≤24 on the Mini-Mental State Examination (MMSE) assessed by interview on follow-up at 90 days. <b><i>Results:</i></b> A total of 231 (64.5%) of 358 90-day survivors had MMSE scores for analyses, and 75 (32.5%) had cognitive impairment. In multivariable analysis, older age (OR 2.48, 95% CI 1.73–3.56 per 10-year increase; <i>p</i> &#x3c; 0.001), female sex (OR 2.06, 95% CI 1.00–4.23; <i>p</i> = 0.049), prior ICH (OR 2.87, 95% CI 1.08–7.65; <i>p</i> = 0.035), high baseline National Institute of Health Stroke Scale score (OR 1.06, 95% CI 1.00–1.13; <i>p</i> = 0.044), and high mean systolic BP over the first 24 h post-randomization (OR 1.34, 95% CI 1.07–1.68/10 mm Hg increase; <i>p</i> = 0.011) were independently associated with cognitive impairment. <b><i>Conclusions:</i></b> One third of patients have significant cognitive impairment early after ICH, which is more frequent in the elderly, females, those with prior ICH, and more severe initial neurological deficit and with persistently high early systolic BP.
Lenin Studies: Method and Organisation
Authors: Le Blanc Paul 
Published: October 2017

AbstractThe growing field of Lenin Studies has been nurtured by the growth of crises and struggles in our own time and may contribute to present-day activists’ efforts at developing revolutionary strategy, organisation and struggle. Surveying this field, it is worth focusing on three recent studies by Antonio Negri, Tamás Krausz and Alan Shandro which give attention to the methodological core of what can be called ‘Leninism’. All three distinguish Lenin’s approach to Marxism from that of such prominent Marxists as Kautsky. The result, highlighted by aspects of Lenin’s functioning in the early Communist International, provides a more consistent activist- and revolutionary edge that might have relevance for future struggles, particularly in relation to the question of organisation.
Climate Similarity Search: GeoWeb Tool for Exploring Climate Variability
Authors: Netzel Pawel , Stepinski Tomasz 
Published: October 2017

Abstract
Climate and climate change are among the scientific topics most widely recognized by the public. Thus, climatologists seek out effective ways of communicating results of their research to various constituencies—a task made difficult by the complexity of the concept of climate. The current standard for communicated variability of climate on the global scale is a map based on the Köppen-Geiger classification (KGC) of climates, and maps of change in average annual temperatures and total annual precipitation for communicating climate change. The ClimateEx (Climate Explorer) project (http://sil.uc.edu/webapps/climateex/) communicates spatial variability and temporal change of global climate in a novel way by using the data science concept of similarity-based query. ClimateEx is implemented as a web-based visual spatial search tool. Users select a location (query), and ClimatEx returns a similarity map that visually communicates locations of places in the world having climates similar to the climate at a query location. ClimateEx can also inform about magnitude of temporal climate change by calculating a global map of local magnitudes of climate change. It offers personalized means of communicating climate heterogeneity and conveying magnitude of climate change in a single map. It has the advantage of relating climate to a user’s own experience, and is well-suited for communicating character of global climate to specialists and nonspecialists alike.
Northern Westerlies during the Last Glacial Maximum: Results from CMIP5 Simulations
Authors: Wang Na , Jiang Dabang , Lang Xianmei 
Published: October 2017

Abstract
Based upon simulations from phase 5 of the Coupled Model Intercomparison Project (CMIP5), the vertical and regional characteristics of the northern westerlies during the Last Glacial Maximum (LGM) are investigated in this study. At the Northern Hemispheric scale, all nine available models simulate a poleward shift of the 200-hPa jet, and eight models simulate an equatorward shift of the 850-hPa jet compared to the preindustrial period; these shifts are of approximately 2°–3° latitude for the arithmetic multimodel mean. The upper-tropospheric cooling in the tropics, possibly due to reduced latent heat release, is expected to account for the poleward shift of the 200-hPa jet through the thermal wind relationship. Changes in the midlatitude baroclinic instability in response to the amplified polar cooling are associated with the jet stream in the lower troposphere through anomalous eddy activity. In particular, the types of predominant baroclinic eddies are regionally dependent. The behavior of the 850-hPa jet over the North Pacific is steered by transient eddies and characterized by a southward displacement during the LGM. By contrast, the remarkable enhancement of the North Atlantic jet stream throughout the troposphere is associated with the notably increased stationary eddy momentum convergence, presumably due to the presence of the Laurentide ice sheet over North America. In comparison with the proxy records, although there is no observational evidence explicitly indicating changes of the upper-level northern westerlies, the simulated LGM 850-hPa westerly wind field is indirectly concordant with the reconstructed moisture conditions over the Mediterranean region and southwestern North America.