bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL17 Promotes Mammary Tumor Progression by Changing the Behavior of Tumor Cells and Eliciting Tumorigenic Neutrophils Recruitment
Authors: Benevides Luciana , da Fonseca Denise Morais , Donate Paula Barbim , Tiezzi Daniel Guimarães , De Carvalho Daniel D. , de Andrade Jurandyr M. , Martins Gislaine A. , Silva João S. 
Published: July 2015

Abstract
The aggressiveness of invasive ductal carcinoma (IDC) of the breast is associated with increased IL17 levels. Studying the role of IL17 in invasive breast tumor pathogenesis, we found that metastatic primary tumor-infiltrating T lymphocytes produced elevated levels of IL17, whereas IL17 neutralization inhibited tumor growth and prevented the migration of neutrophils and tumor cells to secondary disease sites. Tumorigenic neutrophils promote disease progression, producing CXCL1, MMP9, VEGF, and TNFα, and their depletion suppressed tumor growth. IL17A also induced IL6 and CCL20 production in metastatic tumor cells, favoring the recruitment and differentiation of Th17. In addition, IL17A changed the gene-expression profile and the behavior of nonmetastatic tumor cells, causing tumor growth in vivo, confirming the protumor role of IL17. Furthermore, high IL17 expression was associated with lower disease-free survival and worse prognosis in IDC patients. Thus, IL17 blockade represents an attractive approach for the control of invasive breast tumors. Cancer Res; 75(18); 3788–99. ©2015 AACR.
Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity
Authors: Bernardo M. Margarida , Kaplun Alexander , Dzinic Sijana H. , Li Xiaohua , Irish Jonathan , Mujagic Adelina , Jakupovic Benjamin , Back Jessica B. , Van Buren Eric , Han Xiang , Dean Ivory , Chen Yong Q. , Heath Elisabeth , Sakr Wael , Sheng Shijie 
Published: July 2015

Abstract
Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of two-dimensional (2D), three-dimensional (3D), and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro, and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro, and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, docetaxel, MS275, and salinomycin were all cytotoxic. In suspension, while MS275 and salinomycin were toxic, docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension and to salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity and enhances tumor sensitivity to salinomycin, which may hold promise in overcoming tumor cell heterogeneity and plasticity. Cancer Res; 75(18); 3970–9. ©2015 AACR.
TANRIC: An Interactive Open Platform to Explore the Function of lncRNAs in Cancer
Authors: Li Jun , Han Leng , Roebuck Paul , Diao Lixia , Liu Lingxiang , Yuan Yuan , Weinstein John N. , Liang Han 
Published: July 2015

Abstract
Long noncoding RNAs (lncRNA) have emerged as essential players in cancer biology. Using recent large-scale RNA-seq datasets, especially those from The Cancer Genome Atlas (TCGA), we have developed “The Atlas of Noncoding RNAs in Cancer” (TANRIC; http://bioinformatics.mdanderson.org/main/TANRIC:Overview), a user-friendly, open-access web resource for interactive exploration of lncRNAs in cancer. It characterizes the expression profiles of lncRNAs in large patient cohorts of 20 cancer types, including TCGA and independent datasets (&gt;8,000 samples overall). TANRIC enables researchers to rapidly and intuitively analyze lncRNAs of interest (annotated lncRNAs or any user-defined ones) in the context of clinical and other molecular data, both within and across tumor types. Using TANRIC, we have identified a large number of lncRNAs with potential biomedical significance, many of which show strong correlations with established therapeutic targets and biomarkers across tumor types or with drug sensitivity across cell lines. TANRIC represents a valuable tool for investigating the function and clinical relevance of lncRNAs in cancer, greatly facilitating lncRNA-related biologic discoveries and clinical applications. Cancer Res; 75(18); 3728–37. ©2015 AACR.
Metastatic Competence Can Emerge with Selection of Preexisting Oncogenic Alleles without a Need of New Mutations
Authors: Jacob Leni S. , Vanharanta Sakari , Obenauf Anna C. , Pirun Mono , Viale Agnes , Socci Nicholas D. , Massagué Joan 
Published: July 2015

Abstract
Several experimental models faithfully recapitulate many important facets of human metastatic disease. Here, we have performed whole-exome sequencing in five widely used experimental metastasis models that were independently derived through in vivo selection from heterogeneous human cancer cell lines. In addition to providing an important characterization of these model systems, our study examines the genetic evolution of metastatic phenotypes. We found that in vivo selected highly metastatic cell populations showed little genetic divergence from the corresponding parental population. However, selection of genetic variations that preexisted in parental populations, including the well-established oncogenic mutations KRASG13D and BRAFG464V, was associated with increased metastatic capability. Conversely, expression of the wild-type BRAF allele in metastatic cells inhibited metastatic outgrowth as well as tumor initiation in mice. Our findings establish that metastatic competence can arise from heterogeneous cancer cell populations without the need for acquisition of additional mutations and that such competence can benefit from further selection of tumor-initiating mutations that seed primary tumorigenesis. Cancer Res; 75(18); 3713–9. ©2015 AACR.
STAT3 Inhibition Enhances the Therapeutic Efficacy of Immunogenic Chemotherapy by Stimulating Type 1 Interferon Production by Cancer Cells
Authors: Yang Heng , Yamazaki Takahiro , Pietrocola Federico , Zhou Heng , Zitvogel Laurence , Ma Yuting , Kroemer Guido 
Published: July 2015

Abstract
STAT3 is an oncogenic transcription factor with potent immunosuppressive functions. We found that pharmacologic inhibition of STAT3 or its selective knockout in cancer cells improved the tumor growth-inhibitory efficacy of anthracycline-based chemotherapies. This combined effect of STAT3 inhibition/depletion and anthracyclines was only found in tumors growing on immunocompetent (not in immunodeficient) mice. As compared with Stat3-sufficient control tumors, Stat3−/− cancer cells exhibited an increased infiltration by dendritic cells and cytotoxic T lymphocytes after chemotherapy. Anthracyclines are known to induce several stress pathways that enhance the immunogenicity of dying and dead cancer cells, thereby stimulating a dendritic cell–dependent and T lymphocyte–mediated anticancer immune response. Among these therapy-relevant stress pathways, Stat3−/− cancer cells manifested one significant improvement, namely an increase in the expression of multiple type-1 interferon-responsive genes, including that of the chemokines Cxcl9 and Cxcl10. This enhanced type-1 interferon response could be suppressed by reintroducing wild-type Stat3 (but not a transactivation-deficient mutant Stat3Y705F) into the tumor cells. This maneuver also abolished the improved chemotherapeutic response of Stat3−/− cancers. Finally, the neutralization of the common type-1 interferon receptor or that of the chemokine receptor CXCR3 (which binds CXCL9 and CXCL10) abolished the difference in the chemotherapeutic response between Stat3−/− and control tumors. Altogether, these results suggest that STAT3 inhibitors may improve the outcome of chemotherapy by enhancing the type-1 interferon response of cancer cells. Cancer Res; 75(18); 3812–22. ©2015 AACR.
BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers
Authors: Tang Zhiyu , Yuan Xi , Du Rong , Cheung Shing-Hu , Zhang Guoliang , Wei Jing , Zhao Yuan , Feng Yingcai , Peng Hao , Zhang Yi , Du Yunguang , Hu Xiaoxia , Gong Wenfeng , Liu Yong , Gao Yajuan , Liu Ye , Hao Rui , Li Shengjian , Wang Shaohui , Ji Jiafu , Zhang Lianhai , Li Shuangxi , Sutton David , Wei Min , Zhou Changyou , Wang Lai , Luo Lusong 
Published: July 2015

Abstract
Oncogenic BRAF, which drives cell transformation and proliferation, has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAFV600E metastatic melanoma, their clinical efficacy in BRAFV600E colorectal cancer is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors. Here, we report characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigation. In vitro, BGB-283 potently inhibits BRAFV600E-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAFV600E and EGFR mutation/amplification. In BRAFV600E colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAFV600E mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAFV600E mutation. Mol Cancer Ther; 14(10); 2187–97. ©2015 AACR.
Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma
Authors: Kang Chan Woo , Jang Kang Won , Sohn Jinyoung , Kim Sung-Moo , Pyo Kyoung-Ho , Kim Hwan , Yun Mi Ran , Kang Han Na , Kim Hye Ryun , Lim Sun Min , Moon Yong Wha , Paik Soonmyung , Kim Dae Joon , Kim Joo Hang , Cho Byoung Chul 
Published: July 2015

Abstract
RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0–G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src. Mol Cancer Ther; 14(10); 2238–48. ©2015 AACR.
Common familial risk factors for schizophrenia and diabetes mellitus
Authors: Foley Debra L , Mackinnon Andrew , Morgan Vera A , Watts Gerald F , Castle David J , Waterreus Anna , Galletly Cherrie A 
Published: July 2015

Objective: The co-occurrence of type 2 diabetes and psychosis is an important form of medical comorbidity within individuals, but no large-scale study has evaluated comorbidity within families. The aim of this study was to determine whether there is evidence for familial comorbidity between type 2 diabetes and psychosis. Method: Data were analysed from an observational study of a nationally representative sample of 1642 people with psychosis who were in contact with psychiatric services at the time of survey (The 2010 Australian National Survey of Psychosis). Participants were aged 18–64 years and met World Health Organization’s International Classification of Diseases, 10th Revision diagnostic criteria for a psychotic disorder (857 with schizophrenia, 319 with bipolar disorder with psychotic features, 293 with schizoaffective disorder, 81 with depressive psychosis and 92 with delusional disorder or other non-organic psychoses). Logistic regression was used to estimate the association between a family history of diabetes and a family history of schizophrenia. Results: A positive family history of diabetes was associated with a positive family history of schizophrenia in those with a psychotic disorder (odds ratio = 1.35, p = 0.01, adjusted for age and gender). The association was different in those with an affective versus non-affective psychosis (odds ratio = 0.613, p = 0.019, adjusted for age and gender) and was significant only in those with a non-affective psychosis, specifically schizophrenia (odds ratio = 1.58, p = 0.005, adjusted for age and sex). Adjustment for demographic factors in those with schizophrenia slightly strengthened the association (odds ratio = 1.74, p = 0.001, adjusted for age, gender, diagnosis, ethnicity, education, employment, income and marital status). Conclusion: Elevated risk for type 2 diabetes in people with schizophrenia is not simply a consequence of antipsychotic medication; type 2 diabetes and schizophrenia share familial risk factors.
Personality disorders and the DSM-5: Scientific and extra-scientific factors in the maintenance of the status quo
Authors: Gøtzsche-Astrup Oluf , Moskowitz Andrew 
Published: July 2015

Objective: The aim of this study was to review and discuss the evidence for dimensional classification of personality disorders and the historical and sociological bases of psychiatric nosology and research. Method: Categorical and dimensional conceptualisations of personality disorder are reviewed, with a focus on the Diagnostic and Statistical Manual of Mental Disorders–system’s categorisation and the Five-Factor Model of personality. This frames the events leading up to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, personality disorder debacle, where the implementation of a hybrid model was blocked in a last-minute intervention by the American Psychiatric Association Board of Trustees. Explanations for these events are discussed, including the existence of invisible colleges of researchers and the fear of risking a ‘scientific revolution’ in psychiatry. Results: A failure to recognise extra-scientific factors at work in classification of mental illness can have a profound and long-lasting influence on psychiatric nosology. In the end it was not scientific factors that led to the failure of the hybrid model of personality disorders, but opposing forces within the mental health community in general and the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Task Force in particular. Conclusion: Substantial evidence has accrued over the past decades in support of a dimensional model of personality disorders. The events surrounding the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Personality and Personality Disorders Work Group show the difficulties in reconciling two different worldviews with a hybrid model. They also indicate the future of a psychiatric nosology that will be increasingly concerned with dimensional classification of mental illness. As such, the road is paved for more substantial changes to personality disorder classification in the International Classification of Diseases, 11th Revision, in 2017.
Is estimated intra-operative blood loss a reliable predictor of surgical outcomes in laparoscopic colorectal cancer surgery?
Authors: Saleh A , Ihedioha U , Babu B , Evans J , Kang P 
Published: July 2015

Background Studies have shown that laparoscopic surgery for colorectal cancer is often associated with significantly reduced intra-operative blood loss compared to the corresponding open procedures. Increased intra-operative blood loss can be associated with increased risk of post-operative morbidity and mortality. We sought to determine whether estimated intra-operative blood loss was a reliable predictor of post-operative surgical outcomes. Method Prospective data were collected for patients undergoing elective laparoscopic colorectal cancer resections from July 2011 to November 2013. Weighing swabs and measuring blood volume in suction devices calculated the estimated intra-operative blood loss. The operative outcome data including post-operative 30 day morbidity and mortality, length of hospital stay, re-admission and re-operation within 30 days were collected. The operative blood loss was grouped into Group 1 (less than 50 ml, Group 2 (50–150 ml) and Group 3 (over 150 ml). Patients who underwent open operations and laparoscopic conversions were excluded. Results The median age, length of hospital stay, male to female ratio and body mass index were similar in the three groups. There was no 30-day mortality in any of the groups. The number of re-admissions within 30 days was similar in all groups. The re-operation rates within 30 days were higher in Groups 2 and 3 at 11% and 8.6%, respectively. The post-operative complications were 12.5%, 16.7%, and 26% in groups 1, 2 and 3, respectively. There were no anastomotic leaks requiring re-operation noted in Group 3. Discussion This study has shown that intra-operative blood loss was not associated with increased median length of stay nor did it increase the 30 day re-admission rate. However, increased intra-operative blood loss was associated with increased incidence of post-operative morbidity and risk of reoperation within 30 days.
A before and after study of warfarin monitoring in a single region as part of the Scottish patient safety programme in primary care
Authors: McNab Duncan , McKay John , Bowie Paul 
Published: July 2015

Introduction Warfarin is an effective drug for patients at risk of thromboembolic events, but sub-optimal pharmacological management may cause significant harm. As part of the Scottish patient safety programme in primary care, one health board region aimed to determine if the international normalised ratio control for patients taking warfarin in general practice improved over the first 12 months of participation. Methods A before and after study of a multi-intervention improvement strategy was employed that combined financial incentivisation, a regional learning collaborative, clinical care bundle implementation, audit and feedback and clinical ‘safety champions’. The main patient outcome measures were: mean time in therapeutic range; proportion with good control (time in therapeutic range >60%) and excellent control (time in therapeutic range > 75%); and the proportion of very abnormal results (international normalised ratio < 1.5 or >5). Chi-square tests were used to determine statistical differences. Results In total, 49 of 55 general practices participated (89%) with 33/55 providing usable data (60%) on 1480 patients (before) and 1946 patients (after), respectively. Improvements were observed in mean time in therapeutic range ( P < 0.05) as well as in the proportion of patients with good control (time in therapeutic range > 60%, P < 0.01) and excellent control (time in therapeutic range > 75%, P = 0.06). A reduction in the proportion of very abnormal results (international normalised ratio < 1.5 or >5) was also observed ( P < 0.01), while the mean number of patient attendances reduced ( P < 0.05). Conclusions The introduction of a complex safety improvement intervention via a national patient safety programme has resulted in modest improvements in the control of warfarin monitoring in a single region. These improvements may potentially reduce the incidence of serious adverse events. The study method, interventions and findings should be of interest to primary care settings with similar warfarin management arrangements internationally.
A survey of morbidity and mortality review meetings in the general surgical units of the West of Scotland
Authors: Khine Myo , Leung Edward , McGregor John R 
Published: July 2015

Background and aims There is little consensus as to the conduct of surgical morbidity and mortality review meetings. The aim of this survey was to determine how surgical morbidity and mortality meetings in the surgical units in the West of Scotland are carried out and to explore possible areas for improvement. Methods and results Forty six surgical trainees distributed between the 15 general surgery units of the West of Scotland were asked to provide details of their surgical morbidity and mortality meetings for the training year 2012–2013. Twenty-five of 46 (54%) specialty trainees responded with all units being represented. All had designated time for surgical morbidity and mortality review. Meeting frequency varied as follows: weekly (3 units), fortnightly (1 unit), monthly (10 units), three monthly (1 unit). Fewer than half the units (6) included Foundation Trainees, and only one meeting was attended by nursing staff. Five units had clear criteria for morbidity, but only three included morbidity collected from outpatient follow-up. A standardised proforma was used to present the cases in only 2 units. Conclusions All 15 surgical units in the West of Scotland have a regular surgical morbidity and mortality meeting but significant variations were observed as to frequency and participating personnel. A more robust system for reporting morbidities should be considered.
Understanding China’s Relations with the Latin American and Caribbean Countries
Authors: Harris Richard L. 
Published: July 2015

Since the formation of the People’s Republic of China (PRC) in 1949, its political leaders have been concerned with securing the country’s sovereignty, national unification, and territorial integrity as well as creating an international environment favorable to its peaceful development as a socialist society and to the development of a new multipolar world order based on peace and international cooperation rather than hegemony, extreme inequality, and war. In pursuit of these strategic goals, the PRC’s political leaders seek to foster long-term economic and political cooperation with the Latin American and Caribbean countries. Desde la formación de la República Popular China (RPC) en 1949, sus líderes políticos se han ocupado de asegurar la soberanía, unificación nacional, e integridad territorial del país, como también de crear un ambiente internacional favorable a su desarrollo pacífico como sociedad socialista y al desarrollo de un nuevo orden multipolar basado en la paz y la cooperación internacional en vez de la hegemonía, desigualdad extrema, y guerra. En la prosecución de estos objetivos estratégicos, los dirigentes políticos de la RPC buscan fomentar la cooperación económica y política de largo plazo con los países de América Latina y el Caribe.