bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of Pim Kinases Is Sufficient to Promote Resistance to MET Small-Molecule Inhibitors
Authors: An Ningfei , Xiong Ying , LaRue Amanda C. , Kraft Andrew S. , Cen Bo 
Published: December 2015

Abstract
Mesenchymal-epithelial transition (MET) blockade offers a new targeted therapy particularly in those cancers with MET amplification. However, the efficacy and the duration of the response to MET inhibitors are limited by the emergence of drug resistance. Here, we report that resistance to small-molecule inhibitors of MET can arise from increased expression of the prosurvival Pim protein kinases. This resistance mechanism was documented in non–small cell lung cancer and gastric cancer cells with MET amplification. Inhibition of Pim kinases enhanced cell death triggered by short-term treatment with MET inhibitors. Pim kinases control the translation of antiapoptotic protein Bcl-2 at an internal ribosome entry site and this mechanism was identified as the basis for Pim-mediated resistance to MET inhibitors. Protein synthesis was increased in drug-resistant cells, secondary to a Pim-mediated increase in cap-independent translation. In cells rendered drug resistant by chronic treatment with MET inhibitors, genetic or pharmacologic inhibition of Pim kinases was sufficient to restore sensitivity in vitro and in vivo. Taken together, our results rationalize Pim inhibition as a strategy to augment responses and blunt acquired resistance to MET inhibitors in cancer. Cancer Res; 75(24); 5318–28. ©2015 AACR.
Global Cancer Incidence and Mortality Rates and Trends—An Update
Authors: Torre Lindsey A. , Siegel Rebecca L. , Ward Elizabeth M. , Jemal Ahmedin 
Published: December 2015

Abstract
There are limited published data on recent cancer incidence and mortality trends worldwide. We used the International Agency for Research on Cancer's CANCERMondial clearinghouse to present age-standardized cancer incidence and death rates for 2003–2007. We also present trends in incidence through 2007 and mortality through 2012 for select countries from five continents. High-income countries (HIC) continue to have the highest incidence rates for all sites, as well as for lung, colorectal, breast, and prostate cancer, although some low- and middle-income countries (LMIC) now count among those with the highest rates. Mortality rates from these cancers are declining in many HICs while they are increasing in LMICs. LMICs have the highest rates of stomach, liver, esophageal, and cervical cancer. Although rates remain high in HICs, they are plateauing or decreasing for the most common cancers due to decreases in known risk factors, screening and early detection, and improved treatment (mortality only). In contrast, rates in several LMICs are increasing for these cancers due to increases in smoking, excess body weight, and physical inactivity. LMICs also have a disproportionate burden of infection-related cancers. Applied cancer control measures are needed to reduce rates in HICs and arrest the growing burden in LMICs.Cancer Epidemiol Biomarkers Prev; 25(1); 16–27. ©2015 AACR.
See related commentary by Bray, p. 3
ICAM-1–Related Noncoding RNA in Cancer Stem Cells Maintains ICAM-1 Expression in Hepatocellular Carcinoma
Authors: Guo Weixing , Liu Shupeng , Cheng Yuqiang , Lu Lei , Shi Jie , Xu Guixia , Li Nan , Cheng Kai , Wu Mengchao , Cheng Shuqun , Liu Shanrong 
Published: December 2015

Abstract
Purpose: Portal vein tumor thrombus (PVTT) is a major complication of hepatocellular carcinoma (HCC) and is associated with poor survival. Long noncoding RNAs (lncRNA) contribute to HCC metastasis, but whether and how lncRNAs affect PVTT development remains unclear. In the present study, a novel highly expressed lncRNA (ICAM-1–related, ICR) was identified in ICAM-1+ cancer stem cells (CSC) in HCC. This lncRNA regulated CSC properties and contributed to PVTT development.
Experimental Design: We used microarray and bioinformatics analyses to identify differentially expressed lncRNAs. Real-time PCR and Western blotting were used to assess gene expression in cell lines and tumors. Sphere formation assays were performed to investigate stem cell properties of tumor cells in vitro. Retrospective and prospective studies were used to investigate the relationship between ICR expression and clinical outcomes.
Results: Compared with the corresponding primary tumors, PVTT expressed different lncRNAs and mRNAs, including the upregulated lncRNA ICR and ICAM-1. ICR regulated ICAM-1 expression by increasing the stability of its mRNA through RNA duplex formation, which modulated the CSC properties of ICAM-1+ HCC cells. ICR transcription in ICAM-1+ HCC cells was regulated by Nanog, and inhibition of ICR in situ significantly reduced ICAM-1 expression and ICAM-1+ HCC cells in tumors in vivo. Moreover, elevated ICR and ICAM-1 expression in tumors was correlated with PVTT development and poor clinical outcomes.
Conclusions: Our study demonstrates that ICR specifically regulates CSC properties of ICAM-1+ HCC cells and that ICR contributes to PVTT development. Therefore, ICR may be a promising target for HCC therapy. Clin Cancer Res; 22(8); 2041–50. ©2015 AACR.
Simplified Predictive Instrument to Rule Out Acute Coronary Syndromes in a High‐Risk Population
Authors: Fanaroff Alexander C. , Schulteis Ryan D. , Pieper Karen S. , Rao Sunil V. , Newby L. Kristin 
Published: December 2015

Background
It is unclear whether diagnostic protocols based on cardiac markers to identify low‐risk chest pain patients suitable for early release from the emergency department can be applied to patients older than 65 years or with traditional cardiac risk factors.

Methods and Results

In a single‐center retrospective study of 231 consecutive patients with high‐risk factor burden in which a first cardiac troponin (
cT
n) level was measured in the emergency department and a second
cT
n sample was drawn 4 to 14 hours later, we compared the performance of a modified 2‐Hour Accelerated Diagnostic Protocol to Assess Patients with Chest Pain Using Contemporary Troponins as the Only Biomarker (ADAPT) rule to a new risk classification scheme that identifies patients as low risk if they have no known coronary artery disease, a nonischemic electrocardiogram, and 2
cT
n levels below the assay's limit of detection. Demographic and outcome data were abstracted through chart review. The median age of our population was 64 years, and 75% had Thrombosis In Myocardial Infarction risk score ≥2. Using our risk classification rule, 53 (23%) patients were low risk with a negative predictive value for 30‐day cardiac events of 98%. Applying a modified
ADAPT
rule to our cohort, 18 (8%) patients were identified as low risk with a negative predictive value of 100%. In a sensitivity analysis, the negative predictive value of our risk algorithm did not change when we relied only on undetectable baseline
cT
n and eliminated the second
cT
n assessment.

Conclusions
If confirmed in prospective studies, this less‐restrictive risk classification strategy could be used to safely identify chest pain patients with more traditional cardiac risk factors for early emergency department release.
Comparison of Approaches to Revascularization in Patients With Multivessel Coronary Artery Disease Presenting With ST‐Segment Elevation Myocardial Infarction: Meta‐analyses of Randomized Control Trials
Authors: Bajaj Navkaranbir S. , Kalra Rajat , Aggarwal Himanshu , Ather Sameer , Gaba Saurabh , Arora Garima , McGiffin David C. , Ahmed Mustafa , Aslibekyan Stella , Arora Pankaj 
Published: December 2015

Background
Significant controversy exists regarding the best approach for nonculprit vessel revascularization in patients with multivessel coronary artery disease presenting with ST‐segment elevation myocardial infarction. We conducted a systematic investigation to pool data from current randomized controlled trials (RCTs) to assess optimal treatment strategies in this patient population.

Methods and Results

A comprehensive search of SCOPUS from inception through May 2015 was performed using predefined criteria. We compared efficacy and safety outcomes of different approaches by categorizing the studies into 3 groups: (1) complete revascularization (CR) versus culprit lesion revascularization (CL) at index hospitalization, (2) CR at index hospitalization versus staged revascularization (SR) of nonculprit vessels at a separate hospitalization, and (3) comparison of SR versus CL. Eight eligible RCTs met the inclusion criteria: (1) CR versus CL (6 RCTs, n=1727) (2) CR versus SR (3 RCTs, n=311), and (3) SR versus CL (1 RCT, n=149). We observed significantly lower rates of major adverse cardiovascular events, revascularization, and repeat percutaneous coronary interventions among patients treated with CR and SR compared with a CL approach (
P
<0.05). The rates of all‐cause mortality, cause‐specific mortality, major bleeding, reinfarction, stroke, and contrast‐induced nephropathy did not differ in the CR arm compared with the CL arm. The rates of these outcomes were similar in the CR and SR arms.

Conclusion
Results suggest that CR and SR compared with CL reduce major adverse cardiovascular event and revascularization rates primarily by lowering repeated percutaneous coronary intervention rates. We did not observe any increase in the rate of adverse events while using a CR or SR strategy compared with a CL approach. Current guidelines discouraging CR need to be reevaluated, and clinical judgment should prevail in treating multivessel coronary artery disease patients with ST‐segment elevation myocardial infarction as data from larger RCTs accumulate.
Momentum Balance and Eliassen–Palm Flux on Moist Isentropic Surfaces
Authors: Yamada Ray , Pauluis Olivier 
Published: December 2015

Abstract
Previous formulations for the zonally averaged momentum budget and Eliassen–Palm (EP) flux diagnostics do not adequately account for moist dynamics, since air parcels are not differentiated by their moisture content when averages are taken. The difficulty in formulating the momentum budget in moist coordinates lies in the fact that they are generally not invertible with height. Here, a conditional-averaging approach is used to derive a weak formulation of the momentum budget and EP flux in terms of a general vertical coordinate that is not assumed to be invertible. The generalized equation reduces to the typical mass-weighted zonal-mean momentum equation for invertible vertical coordinates.
The weak formulation is applied here to study the momentum budget on moist isentropes. Recent studies have shown that the meridional mass transport in the midlatitudes is twice as strong on moist isentropes as on dry isentropes. It is shown here that this implies a similar increase in the EP flux between the dry and moist frameworks. Physically, the increase in momentum exchange is tied to an enhancement of the form drag associated with the horizontal structure of midlatitude eddies, where the poleward flow of moist air is located in regions of strong eastward pressure gradient.
Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD
Authors: Alho Ana C. , Kim Haesook T. , Chammas Marie J. , Reynolds Carol G. , Matos Tiago R. , Forcade Edouard , Whangbo Jennifer , Nikiforow Sarah , Cutler Corey S. , Koreth John , Ho Vincent T. , Armand Philippe , Antin Joseph H. , Alyea Edwin P. , Lacerda Joao F. , Soiffer Robert J. , Ritz Jerome 
Published: December 2015

Key Points
Homeostatic recovery after allogeneic HSCT favors the production, expansion, and survival of effector T cells over CD4Tregs. Unbalanced reconstitution of regulatory and effector T-cell subsets contributes to the development of chronic graft-versus-host disease.
How does this message make you feel? A study of user perspectives on software update/warning message design
Authors: Fagan Michael , Khan Mohammad Maifi Hasan , Nguyen Nhan 
Published: December 2015

AbstractSoftware update messages are commonly used to inform users about software updates, recent bug fixes, and various system vulnerabilities, and to suggest recommended actions (e.g., updating software). While various design features (e.g., update options, message layout, update message presentation) of these messages can influence the actions taken by users, no prior study can be found that investigated users opinions regarding various design alternatives. To address this void, this paper focuses on identifying software update message design features (e.g., layout, color, content) that may affect users positively or negatively. Toward that, we conducted a user study where users are shown 13 software update messages along with 1 virus warning message. We collect responses from 155 users through an online survey. Participants gave a total of 809 positive comments and 866 negative comments along with ranking of each image in terms of perceived importance, noticeability, annoyance and confusion. As many of the comments are repetitive and often contain multiple themes, we manually analyzed and performed a bottom-up, inductive coding to identify and refine the underlying themes. Over multiple iterations, positive comments were grouped into 52 categories which were subsequently grouped under four themes. Similarly, negative comments were first grouped into 38 categories which were subsequently grouped under four themes. Based on our analysis, we present the list of design features that are found to be highly correlated to confusion, annoyance, noticeability, and importance, either positively or negatively.
Pregnancy and the Risk of Relapse in Patients Diagnosed With Hodgkin Lymphoma
Authors: Weibull Caroline E. , Eloranta Sandra , Smedby Karin E. , Björkholm Magnus , Kristinsson Sigurdur Y. , Johansson Anna L.V. , Dickman Paul W. , Glimelius Ingrid 
Published: December 2015

Purpose Many patients and clinicians are worried that pregnancy after the diagnosis of Hodgkin lymphoma (HL) may increase the risk of relapse despite a lack of empirical evidence to support such concerns. We investigated if an association exists between pregnancy and relapse in women with a diagnosis of HL. Materials and Methods Using Swedish healthcare registers combined with medical records, we included 449 women who received a diagnosis of HL between 1992 and 2009 and who were age 18 to 40 years at diagnosis. Follow-up started 6 months after diagnosis, when the patients' condition was assumed to be in remission. Pregnancy-associated relapse was defined as a relapse during pregnancy or within 5 years after delivery. Hazard ratios (HRs) with 95% CIs were estimated by using the Cox proportional hazards model. Results Among the 449 women, 144 (32%) became pregnant during follow-up. Overall, 47 relapses were recorded, of which one was a pregnancy-associated relapse. The adjusted HR for the comparison of the pregnancy-associated relapse rate to the non–pregnancy-associated relapse rate was 0.29 (95% CI, 0.04 to 2.18). The expected number of relapses in women with a recent pregnancy, given that they would experience the same relapse rate as that of women without a recent pregnancy, was 3.76; the observed-to-expected ratio was 0.27 (95% exact CI, 0.01 to 1.51). Conclusion We found no evidence that a pregnancy after diagnosis increases the relapse rate among women whose HL is in remission. Survivors of HL need to consider a range of factors when deciding about future reproduction. However, given the results of this study, the risk of pregnancy-associated relapse does not need to be considered.
Multi-Institutional Phase II Study of High-Dose Hypofractionated Proton Beam Therapy in Patients With Localized, Unresectable Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma
Authors: Hong Theodore S. , Wo Jennifer Y. , Yeap Beow Y. , Ben-Josef Edgar , McDonnell Erin I. , Blaszkowsky Lawrence S. , Kwak Eunice L. , Allen Jill N. , Clark Jeffrey W. , Goyal Lipika , Murphy Janet E. , Javle Milind M. , Wolfgang John A. , Drapek Lorraine C. , Arellano Ronald S. , Mamon Harvey J. , Mullen John T. , Yoon Sam S. , Tanabe Kenneth K. , Ferrone Cristina R. , Ryan David P. , DeLaney Thomas F. , Crane Christopher H. , Zhu Andrew X. 
Published: December 2015

Purpose To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Materials and Methods In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC. Results Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC. Conclusion High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC.
Dual-Reporter β-Cell-Specific Male Transgenic Rats for the Analysis of β-Cell Functional Mass and Enrichment by Flow Cytometry
Authors: Ghislain Julien , Fontés Ghislaine , Tremblay Caroline , Kebede Melkam A. , Poitout Vincent 
Published: December 2015

AbstractMouse β-cell-specific reporter lines have played a key role in diabetes research. Although the rat provides several advantages, its use has lagged behind the mouse due to the relative paucity of genetic models. In this report we describe the generation and characterization of transgenic rats expressing a Renilla luciferase (RLuc)-enhanced yellow fluorescent protein (YFP) fusion under control of a 9-kb genomic fragment from the rat ins2 gene (RIP7-RLuc-YFP). Analysis of RLuc luminescence and YFP fluorescence revealed that reporter expression is restricted to β-cells in the adult rat. Physiological characteristics including body weight, fat and lean mass, fasting and fed glucose levels, glucose and insulin tolerance, and β-cell mass were similar between two RIP7-RLuc-YFP lines and wild-type littermates. Glucose-induced insulin secretion in isolated islets was indistinguishable from controls in one of the lines, whereas surprisingly, insulin secretion was defective in the second line. Consequently, subsequent studies were limited to the former line. We asked whether transgene activity was responsive to glucose as shown previously for the ins2 gene. Exposing islets ex vivo to high glucose (16.7 mM) or in vivo infusion of glucose for 24 hours increased luciferase activity in islets, whereas the fraction of YFP-positive β-cells after glucose infusion was unchanged. Finally, we showed that fluorescence-activated cell sorting of YFP-positive islet cells can be used to enrich for β-cells. Overall, this transgenic line will enable for the first time the application of both fluorescence and bioluminescence/luminescence-based approaches for the study of rat β-cells.
Decoding the stem cell quiescence cycle – lessons from yeast for regenerative biology
Authors: Dhawan Jyotsna , Laxman Sunil 
Published: December 2015

ABSTRACT
In the past decade, major advances have occurred in the understanding of mammalian stem cell biology, but roadblocks (including gaps in our fundamental understanding) remain in translating this knowledge to regenerative medicine. Interestingly, a close analysis of the Saccharomyces cerevisiae literature leads to an appreciation of how much yeast biology has contributed to the conceptual framework underpinning our understanding of stem cell behavior, to the point where such insights have been internalized into the realm of the known. This Opinion article focuses on one such example, the quiescent adult mammalian stem cell, and examines concepts underlying our understanding of quiescence that can be attributed to studies in yeast. We discuss the metabolic, signaling and gene regulatory events that control entry and exit into quiescence in yeast. These processes and events retain remarkable conservation and conceptual parallels in mammalian systems, and collectively suggest a regulated program beyond the cessation of cell division. We argue that studies in yeast will continue to not only reveal fundamental concepts in quiescence, but also leaven progress in regenerative medicine.
Book Reviews
Authors: Shen Wenjing 
Published: December 2015

In Book Reviews, we review an extensive and diverse range of books. They cover theory and applications in operations research, statistics, management science, econometrics, mathematics, computers, and information systems. In addition, we include books in other fields that emphasize technical applications. The editor will be pleased to receive an email from those willing to review a book, with an indication of specific areas of interest. If you are aware of a specific book that you would like to review, or that you think should be reviewed, please contact the editor. The following books are reviewed in this issue of Interfaces, 45(6), November–December 2015: Stochastic Optimization Methods: Applications in Engineering and Operations Research, Kurt Mardi; The Climate Casino: Risk, Uncertainty, and Economics for a Warming World, William D. Nordhaus.
Evaluation Of Slovak Winter Wheat Quality In Terms Of Puroindoline Genes
Authors: Klčová Lenka , Mikulíková Daniela , Masár Štefan , Žofajová Alžbeta 
Published: December 2015

Abstract
The grain hardness of 100 current and 24 old superior Slovak winter wheat cultivars was studied at molecular level. Using polymerase chain reactions (PCRs), normal and null alleles of both puroindoline Pina and Pinb genes were identified. Three different genotypes were found: 1) normal allele of both genes (dominant wild type with soft endosperm) − Pina-D1a/Pinb-D1a; 2) normal allele of the Pina gene and null allele of the Pinb gene – Pina-D1a/Pinb-D1b; and 3) null allele of the Pina gene and normal allele of the Pinb gene Pina-D1b/Pinb-D1a. No Slovak current as well as old wheat cultivar had together null allele of both puroindoline genes. The frequencies of wild-type Pinb-D1a and null Pinb-D1b allele in current cultivars were 62.0% and 38.0%, respectively, whilst in old cultivars, 8.3% and 91.7%, respectively. Regarding null allele Pina-D1b of puroindoline Pina gene, only in Rheia current cultivar, one was found. All other cultivars had wild-type Pina-D1a allele. Alacris, Alana, Axis, Balada, Blava, Bona Dea, Bruta, Charger, Hana, Ilona, IS Karpatia, Ludwig and Sulamit current cultivars were selected as donors of the null Pinb-D1b allele for molecular breeding in order to improve the grain hardness as important wheat quality trait. Statistically significant correlations between null Pinb-D1b allele and grain size as well as colour were found. In comparison with wild type, cultivars with this null allele have paler and longer grain with higher length-to-width ratio and lighter grain colour.