bluuebunny/crossref_metadata_2025_split huggingface dataset:
Economic integration across Latin America: Evidence from labour markets, 1990–2013
Authors: Lederman Daniel , Robertson Raymond 
Published: January 2018

AbstractCombining macroeconomic and microeconomic data and three indicators of international market integration, this paper assesses the degree to which Latin American labour markets are integrated. The results suggest that relative to East Asia, Latin American labour markets are somewhat more integrated, but considerable differences across countries persist. In addition, the evidence indicates that the degree of labour market integration across Latin American borders is significantly less than that of labour markets within the United States in two of the three indicators. These differences may suggest opportunities for efficiency gains from further labour market integration.
Endotracheal tube placement during computed tomography of brachycephalic dogs alters upper airway dimensional measurements
Authors: Liu Nai‐Chieh , Troconis Eileen L. , McMillan Matthew , Genain Marie‐Aude , Kalmar Lajos , Price David J. , Sargan David R. , Ladlow Jane F. 
Published: January 2018

AbstractComputed tomography (CT) is used to document upper airway lesions in dogs with brachycephalic obstructive airway syndrome. The presence of an endotracheal tube during CT scanning is often required for general anesthesia. We hypothesized that the endotracheal tube placement would change the soft tissue dimensions of the upper airway. The aims of this prospective, method comparison study were to evaluate the reliability of the previously reported upper airway CT measurements with endotracheal tube placement, and to propose measurements that are minimally affected by the endotracheal tube. Twenty brachycephalic dogs were included in this study. Each dog underwent head/neck CT with an endotracheal tube, followed by a second scan without the endotracheal tube. Ten measurements of the soft palate, nasopharynx, and trachea were performed. Tracheal dimension was significantly larger with the endotracheal tube compared to without, whereas the soft palate cross‐sectional area was significantly smaller with the endotracheal tube than without the endotracheal tube. The influence of the endotracheal tube on the caudal nasopharynx cross‐sectional (transverse‐sectional) area varied with a mean proportional absolute difference of 35%. Rostral soft palate thickness, tracheal perimeter, and cross‐sectional area of the rostral nasopharynx were the measurements least affected by the endotracheal tube (intraclass correlation coefficient = 0.964, 0.967, and 0.951, respectively). Therefore, we proposed that these three measurements may be most useful for future brachycephalic obstructive airway syndrome studies that require CT scanning of intubated animals. However, with endotracheal tube placement, measurements of soft palate length, caudal nasopharyngeal cross‐sectional area, and trachea height and width may not be reliable.
S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense
Authors: Huang Yuefeng , Mao Kairui , Chen Xi , Sun Ming-an , Kawabe Takeshi , Li Weizhe , Usher Nicholas , Zhu Jinfang , Urban Joseph F. , Paul William E. , Germain Ronald N. 
Published: January 2018

Inflammatory ILC2s are itinerant sentinelsGroup 2 innate lymphoid cells (ILC2s) are a population of immune cells that play important roles in tissue homeostasis and barrier immunity to helminths. Recent work has suggested that ILC2s are primarily long-term residents of tissues that do not readily recirculate. Huanget al.now demonstrate, however, that these findings do not necessarily hold true for the interleukin-25 (IL-25)–responsive KLRG1hi“inflammatory” ILC2 (iILC2) subset (see the Perspective by Mjösberg and Rao). In response to exogenous IL-25 or helminth infection, iILC2 precursors in the small intestinal lamina propria proliferate and alter their expression of sphingosine 1-phosphate (S1P) receptors. They then traffic to both lymphatic and nonlymphatic organs in a partly S1P-dependent manner, participating in vital anti-helminth and tissue repair responses.Science, this issue p.114; see also p.36
Cardiac vanilloid receptor-1 afferent depletion enhances stellate ganglion neuronal activity and efferent sympathetic response to cardiac stress
Authors: Yoshie Koji , Rajendran Pradeep S. , Massoud Louis , Kwon OhJin , Tadimeti Vasudev , Salavatian Siamak , Ardell Jeffrey L. , Shivkumar Kalyanam , Ajijola Olujimi A. 
Published: January 2018

Afferent fibers expressing the vanilloid receptor 1 (VR1) channel have been implicated in cardiac nociception; however, their role in modulating reflex responses to cardiac stress is not well understood. We evaluated this role in Yorkshire pigs by percutaneous epicardial application of resiniferatoxin (RTX), a toxic activator of the VR1 channel, resulting in the depletion of cardiac VR1-expressing afferents. Hemodynamics, epicardial activation recovery intervals, and in vivo activity of stellate ganglion neurons (SGNs) were recorded in control and RTX-treated animals. Stressors included inferior vena cava or aortic occlusion and rapid right ventricular pacing (RVP) to induce dyssynchrony and ischemia. In the epicardium, stellate ganglia, and dorsal root ganglia, immunostaining for the VR1 channel, calcitonin gene-related peptide, and substance P was significantly diminished by RTX. RTX-treated animals exhibited higher basal systolic blood pressures and contractility than control animals. Reflex responses to epicardial bradykinin and capsaicin were mitigated by RTX. Cardiovascular reflex function, as assessed by inferior vena cava or aortic occlusion, was similar in RTX-treated versus control animals. RTX-treated animals exhibited resistance to hemodynamic collapse induced by RVP. Activation recovery interval shortening during RVP, a marker of cardiac sympathetic outflow, was greater in RTX-treated animals and exhibited significant delay in returning to baseline values after cessation of RVP. The basal firing rate of SGNs and firing rates in response to RVP were also greater in RTX-treated animals, as was the SGN network activity in response to cardiac stressors. These data suggest that elimination of cardiac nociceptive afferents reorganizes the central-peripheral nervous system interaction to enhance cardiac sympathetic outflow. NEW & NOTEWORTHY Our work demonstrates a role for cardiac vanilloid receptor-1-expressing afferents in reflex processing of cardiovascular stress. Current understanding suggests that elimination of vanilloid receptor-1 afferents would decrease reflex cardiac sympathetic outflow. We found, paradoxically, that sympathetic outflow to the heart is instead enhanced at baseline and during cardiac stress.
PHD3 Controls Lung Cancer Metastasis and Resistance to EGFR Inhibitors through TGFα
Authors: Dopeso Higinio , Jiao Hui-Ke , Cuesta Angel M. , Henze Anne-Theres , Jurida Liane , Kracht Michael , Acker-Palmer Amparo , Garvalov Boyan K. , Acker Till 
Published: January 2018

Abstract
Lung cancer is the leading cause of cancer-related death worldwide, in large part due to its high propensity to metastasize and to develop therapy resistance. Adaptive responses to hypoxia and epithelial–mesenchymal transition (EMT) are linked to tumor metastasis and drug resistance, but little is known about how oxygen sensing and EMT intersect to control these hallmarks of cancer. Here, we show that the oxygen sensor PHD3 links hypoxic signaling and EMT regulation in the lung tumor microenvironment. PHD3 was repressed by signals that induce EMT and acted as a negative regulator of EMT, metastasis, and therapeutic resistance. PHD3 depletion in tumors, which can be caused by the EMT inducer TGFβ or by promoter methylation, enhanced EMT and spontaneous metastasis via HIF-dependent upregulation of the EGFR ligand TGFα. In turn, TGFα stimulated EGFR, which potentiated SMAD signaling, reinforcing EMT and metastasis. In clinical specimens of lung cancer, reduced PHD3 expression was linked to poor prognosis and to therapeutic resistance against EGFR inhibitors such as erlotinib. Reexpression of PHD3 in lung cancer cells suppressed EMT and metastasis and restored sensitivity to erlotinib. Taken together, our results establish a key function for PHD3 in metastasis and drug resistance and suggest opportunities to improve patient treatment by interfering with the feedforward signaling mechanisms activated by PHD3 silencing.
Significance: This study links the oxygen sensor PHD3 to metastasis and drug resistance in cancer, with implications for therapeutic improvement by targeting this system. Cancer Res; 78(7); 1805–19. ©2018 AACR.
STAT3/PIAS3 Levels Serve as “Early Signature” Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube
Authors: Saini Uksha , Suarez Adrian A. , Naidu Shan , Wallbillich John J. , Bixel Kristin , Wanner Ross A. , Bice Jason , Kladney Raleigh D. , Lester Jenny , Karlan Beth Y. , Goodfellow Paul J. , Cohn David E. , Selvendiran Karuppaiyah 
Published: January 2018

Abstract
The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states.
Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739–50. ©2018 AACR.
E6 Protein Expressed by High-Risk HPV Activates Super-Enhancers of the EGFR and c-MET Oncogenes by Destabilizing the Histone Demethylase KDM5C
Authors: Chen Xiaohua , Loo Jun Xian , Shi Xin , Xiong Wenjun , Guo Yong , Ke Haiqiang , Yang Mingkun , Jiang Yanping , Xia Siyu , Zhao Min , Zhong Shan , He Chunjiang , Fu Li , Li Feng 
Published: January 2018

Abstract
The high-risk (HR) human papillomaviruses (HPV) are causative agents of anogenital tract dysplasia and cancers and a fraction of head and neck cancers. The HR HPV E6 oncoprotein possesses canonical oncogenic functions, such as p53 degradation and telomerase activation. It is also capable of stimulating expression of several oncogenes, but the molecular mechanism underlying these events is poorly understood. Here, we provide evidence that HPV16 E6 physically interacts with histone H3K4 demethylase KDM5C, resulting in its degradation in an E3 ligase E6AP- and proteasome-dependent manner. Moreover, we found that HPV16-positive cancer cell lines exhibited lower KDM5C protein levels than HPV-negative cancer cell lines. Restoration of KDM5C significantly suppressed the tumorigenicity of CaSki cells, an HPV16-positive cervical cancer cell line. Whole genome ChIP-seq and RNA-seq results revealed that CaSki cells contained super-enhancers in the proto-oncogenes EGFR and c-MET. Ectopic KDM5C dampened these super-enhancers and reduced the expression of proto-oncogenes. This effect was likely mediated by modulating H3K4me3/H3K4me1 dynamics and decreasing bidirectional enhancer RNA transcription. Depletion of KDM5C or HPV16 E6 expression activated these two super-enhancers. These results illuminate a pivotal relationship between the oncogenic E6 proteins expressed by HR HPV isotypes and epigenetic activation of super-enhancers in the genome that drive expression of key oncogenes like EGFR and c-MET.
Significance: This study suggests a novel explanation for why infections with certain HPV isotypes are associated with elevated cancer risk by identifying an epigenetic mechanism through which E6 proteins expressed by those isotypes can drive expression of key oncogenes. Cancer Res; 78(6); 1418–30. ©2018 AACR.
The Hippo Pathway Component TAZ Promotes Immune Evasion in Human Cancer through PD-L1
Authors: Janse van Rensburg Helena J. , Azad Taha , Ling Min , Hao Yawei , Snetsinger Brooke , Khanal Prem , Minassian Lori M. , Graham Charles H. , Rauh Michael J. , Yang Xiaolong 
Published: January 2018

AbstractThe Hippo pathway component WW domain-containing transcription regulator 1 (TAZ) is a transcriptional coactivator and an oncogene in breast and lung cancer. Transcriptional targets of TAZ that modulate immune cell function in the tumor microenvironment are poorly understood. Here, we perform a comprehensive screen for immune-related genes regulated by TAZ and its paralog YAP using NanoString gene expression profiling. We identify the immune checkpoint molecule PD-L1 as a target of Hippo signaling. The upstream kinases of the Hippo pathway, mammalian STE20-like kinase 1 and 2 (MST1/2), and large tumor suppressor 1 and 2 (LATS1/2), suppress PD-L1 expression while TAZ and YAP enhance PD-L1 levels in breast and lung cancer cell lines. PD-L1 expression in cancer cell lines is determined by TAZ activity and TAZ/YAP/TEAD increase PD-L1 promoter activity. Critically, TAZ-induced PD-L1 upregulation in human cancer cells is sufficient to inhibit T-cell function. The relationship between TAZ and PD-L1 is not conserved in multiple mouse cell lines, likely due to differences between the human and mouse PD-L1 promoters. To explore the extent of divergence in TAZ immune-related targets between human and mouse cells, we performed a second NanoString screen using mouse cell lines. We show that many targets of TAZ may be differentially regulated between these species. These findings highlight the role of Hippo signaling in modifying human/murine physiologic/pathologic immune responses and provide evidence implicating TAZ in human cancer immune evasion.Significance: Human-specific activation of PD-L1 by a novel Hippo signaling pathway in cancer immune evasion may have a significant impact on research in immunotherapy. Cancer Res; 78(6); 1457–70. ©2018 AACR.
Genetic Variants in Immune-Related Pathways and Breast Cancer Risk in African American Women in the AMBER Consortium
Authors: Hong Chi-Chen , Sucheston-Campbell Lara E. , Liu Song , Hu Qiang , Yao Song , Lunetta Kathryn L. , Haddad Stephen A. , Ruiz-Narváez Edward A. , Bensen Jeannette T. , Cheng Ting-Yuan David , Bandera Elisa V. , Rosenberg Lynn A. , Haiman Christopher A. , Lee Kelvin , Evans Sharon S. , Abrams Scott I. , Repasky Elizabeth A. , Olshan Andrew F. , Palmer Julie R. , Ambrosone Christine B. 
Published: January 2018

Abstract
Background: Constitutional immunity shaped by exposure to endemic infectious diseases and parasitic worms in Sub-Saharan Africa may play a role in the etiology of breast cancer among African American (AA) women.
Methods: A total of 149,514 gene variants in 433 genes across 45 immune pathways were analyzed in the AMBER consortium among 3,663 breast cancer cases and 4,687 controls. Gene-based pathway analyses were conducted using the adaptive rank truncated product statistic for overall breast cancer risk, and risk by estrogen receptor (ER) status. Unconditional logistic regression analysis was used to estimate ORs and 95% confidence intervals (CIs) for single variants.
Results: The top pathways were Interleukin binding (P = 0.01), Biocarta TNFR2 (P = 0.005), and positive regulation of cytokine production (P = 0.024) for overall, ER+, and ER− cancers, respectively. The most significant gene was IL2RB (P = 0.001) for overall cancer, with rs228952 being the top variant identified (OR = 0.85; 95% CI, 0.79–0.92). Only BCL3 contained a significant variant for ER+ breast cancer. Variants in IL2RB, TLR6, IL8, PRKDC, and MAP3K1 were associated with ER− disease. The only genes showing heterogeneity between ER− and ER+ cancers were TRAF1, MAP3K1, and MAPK3 (P ≤ 0.02). We also noted genes associated with autoimmune and atopic disorders.
Conclusions: Findings from this study suggest that genetic variants in immune pathways are relevant to breast cancer susceptibility among AA women, both for ER+ and ER− breast cancers.
Impact: Results from this study extend our understanding of how inherited genetic variation in immune pathways is relevant to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 27(3); 321–30. ©2018 AACR.
Family History and Risk of Second Primary Breast Cancer after In Situ Breast Carcinoma
Authors: Baglia Michelle L. , Tang Mei-Tzu C. , Malone Kathleen E. , Porter Peggy , Li Christopher I. 
Published: January 2018

Abstract
Background: Incidence rates of in situ breast carcinomas have increased due to widespread adoption of mammography. Very little is known about why some women with in situ breast cancer later develop second primary breast cancers.
Methods: In this population-based nested case–control study among in situ breast cancer survivors, including 539 cases with a second primary breast cancer and 994 matched controls, we evaluated the association between first-degree family history of breast cancer and risk of developing a second primary breast cancer.
Results: First-degree family history of breast cancer was associated with an increased risk of developing a second primary breast cancer among women with a previous in situ breast cancer [odds ratio (OR) = 1.33, 95% confidence interval (CI), 1.05–1.69] and those with two or more affected first-degree relatives had an even higher risk (OR = 1.94; 95% CI, 1.15–3.28). Those whose relative was diagnosed at less than 50 years old were more likely to develop a second primary breast cancer (OR = 1.78; 95% CI, 1.24–2.57). No difference in risks associated with number or age of affected relatives was observed by menopausal status.
Conclusions: Results from this study suggest that first-degree family history of breast cancer may be an important risk factor for development of a second primary breast cancer among women with a previous in situ breast cancer.
Impact: Given the growing population of in situ breast cancer survivors, a better understanding of risk factors associated with development of a second primary breast cancer is needed to further understand risk. Cancer Epidemiol Biomarkers Prev; 27(3); 315–20. ©2018 AACR.
Family History of Cancer and Risk of Biliary Tract Cancers: Results from the Biliary Tract Cancers Pooling Project
Authors: Van Dyke Alison L. , Langhamer Margaret S. , Zhu Bin , Pfeiffer Ruth M. , Albanes Demetrius , Andreotti Gabriella , Beane Freeman Laura E. , Chan Andrew T. , Freedman Neal D. , Gapstur Susan M. , Giles Graham G. , Grodstein Francine , Liao Linda M. , Luo Juhua , Milne Roger L. , Monroe Kristine R. , Neuhouser Marian L. , Poynter Jenny N. , Purdue Mark P. , Robien Kim , Schairer Catherine , Sinha Rashmi , Weinstein Stephanie , Zhang Xuehong , Petrick Jessica L. , McGlynn Katherine A. , Campbell Peter T. , Koshiol Jill 
Published: January 2018

Abstract
Background: Although some familial cancer syndromes include biliary tract cancers (BTCs; cancers of the gallbladder, intrahepatic and extrahepatic bile ducts, and ampulla of Vater), the few studies that have examined the relationships between family history of cancer (FHC) and BTCs have reported inconclusive findings. The objective of this study was to investigate the associations of FHC with risk of BTC in the Biliary Tract Cancers Pooling Project (BiTCaPP).
Methods: We used Cox proportional hazards regressions models to estimate HRs and 95% confidence intervals for associations between FHC (any, first-degree, in female relative, in male relative, relative with gastrointestinal cancer, and relative with hormonally related cancer) and BTC risk by anatomic site within the biliary tract, adjusting for sex and race/ethnicity. Sensitivity analyses were conducted that restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy.
Results: Data on FHC were available from 12 prospective studies within BiTCaPP, which collectively contributed 2,246 cases (729 gallbladder, 345 intrahepatic and 615 extrahepatic bile duct, and 385 ampulla of Vater cancers) with 21,706,107 person-years of follow-up. A marginal, inverse association between FHC and gallbladder cancer was driven to the null when analysis was restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. FHC was not associated with risk of BTC at the other anatomic sites.
Conclusions: These findings do not support an association between FHC and BTCs.
Impact: In a study of 1.5 million people, FHC is not a risk factor for BTCs. Cancer Epidemiol Biomarkers Prev; 27(3); 348–51. ©2018 AACR.
IDH1/2 Mutations Sensitize Acute Myeloid Leukemia to PARP Inhibition and This Is Reversed by IDH1/2-Mutant Inhibitors
Authors: Molenaar Remco J. , Radivoyevitch Tomas , Nagata Yasunobu , Khurshed Mohammed , Przychodzen Bartolomiej , Makishima Hideki , Xu Mingjiang , Bleeker Fonnet E. , Wilmink Johanna W. , Carraway Hetty E. , Mukherjee Sudipto , Sekeres Mikkael A. , van Noorden Cornelis J.F. , Maciejewski Jaroslaw P. 
Published: January 2018

Abstract
Purpose: Somatic mutations in IDH1/2 occur in approximately 20% of patients with myeloid neoplasms, including acute myeloid leukemia (AML). IDH1/2MUT enzymes produce D-2-hydroxyglutarate (D2HG), which associates with increased DNA damage and improved responses to chemo/radiotherapy and PARP inhibitors in solid tumor cells. Whether this also holds true for IDH1/2MUT AML is not known.
Experimental Design: Well-characterized primary IDH1MUT, IDH2MUT, and IDH1/2WT AML cells were analyzed for DNA damage and responses to daunorubicin, ionizing radiation, and PARP inhibitors.
Results: IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells. IDH1/2MUT inhibitors protected against these treatments. Combined treatment with a PARP inhibitor and daunorubicin had an additive effect on the killing of IDH1/2MUT AML cells. We provide evidence that the therapy sensitivity of IDH1/2MUT cells was caused by D2HG-mediated downregulation of expression of the DNA damage response gene ATM and not by altered redox responses due to metabolic alterations in IDH1/2MUT cells.
Conclusions: IDH1/2MUT AML cells are sensitive to PARP inhibitors as monotherapy but especially when combined with a DNA-damaging agent, such as daunorubicin, whereas concomitant administration of IDH1/2MUT inhibitors during cytotoxic therapy decrease the efficacy of both agents in IDH1/2MUT AML. These results advocate in favor of clinical trials of PARP inhibitors either or not in combination with daunorubicin in IDH1/2MUT AML. Clin Cancer Res; 24(7); 1705–15. ©2018 AACR.