bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scientific research output in orthopaedics from China and other top-ranking countries: a 10-year survey of the literature
Authors: Zou Yuming , Li Quan , Xu Weidong 
Published: September 2016

ObjectivesOrthopaedics-related diseases and conditions are a significant burden worldwide. In this study, we aimed to compare the quantity and quality of research output in the field of orthopaedics from Mainland China (MC), USA, UK, Japan and Germany.SettingThe USA, UK, Japan, Germany and MC.ParticipantsWe selected orthopaedics journals from the subject category ‘orthopedics’ from the Science Citation Index Expanded (SCIE).Outcome measuresThe number of publications, the number of publications in the surveyed publication types, impact factor (IF) and citations from the corresponding country from 2005 to 2014 were collected for quantity and quality comparisons.ResultsA total of 128 895 articles were published worldwide in orthopaedics-related journals from 2005 to 2014. The USA contributed the largest proportion (31 190 (24.20%)), followed by the UK (6703 (5.20%)), Japan (5718 (4.41%)), Germany (4701 (3.66%)) and MC (3389 (2.63%)). Publications from MC represented the fewest, but this quantity is rapidly increasing. The quantity of annual publications from MC has exceeded that of Germany since 2012. The USA plays a predominant role in all kinds of publication types under investigation in the study, except in the category of meta-analysis. MC was in the last place for cumulative IFs, and the average IF actually decreased from the beginning of the study. For total and average citations, MC still lags behind the other countries in the study.ConclusionsThe USA has occupied the dominant place in orthopaedics-related research for the last 10 years. Although MC has made great progress in the number of published works in the field of orthopaedics over the last 10 years, the quality of these publishing efforts needs further improvement.
Dual-process cognitive interventions to enhance diagnostic reasoning: a systematic review
Authors: Lambe Kathryn Ann , O'Reilly Gary , Kelly Brendan D , Curristan Sarah 
Published: September 2016

BackgroundDiagnostic error incurs enormous human and economic costs. The dual-process model reasoning provides a framework for understanding the diagnostic process and attributes certain errors to faulty cognitive shortcuts (heuristics). The literature contains many suggestions to counteract these and to enhance analytical and non-analytical modes of reasoning.AimsTo identify, describe and appraise studies that have empirically investigated interventions to enhance analytical and non-analytical reasoning among medical trainees and doctors, and to assess their effectiveness.MethodsSystematic searches of five databases were carried out (Medline, PsycInfo, Embase, Education Resource Information Centre (ERIC) and Cochrane Database of Controlled Trials), supplemented with searches of bibliographies and relevant journals. Included studies evaluated an intervention to enhance analytical and/or non-analytical reasoning among medical trainees or doctors.FindingsTwenty-eight studies were included under five categories: educational interventions, checklists, cognitive forcing strategies, guided reflection, instructions at test and other interventions. While many of the studies found some effect of interventions, guided reflection interventions emerged as the most consistently successful across five studies, and cognitive forcing strategies improved accuracy and confidence judgements. Significant heterogeneity of measurement approaches was observed, and existing studies are largely limited to early-career doctors.ConclusionsResults to date are promising and this relatively young field is now close to a point where these kinds of cognitive interventions can be recommended to educators. Further research with refined methodology and more diverse samples is required before firm recommendations may be made for medical education and policy; however, these results suggest that such interventions hold promise, with much current enthusiasm for new research.
Structural style in a Messinian (intra-Pontian) gravity-driven deformation system, western Black Sea, offshore Romania
Authors: Schleder Z. , Krezsek C. , Lapadat A. , Bega Z. , Ionescu G. , Tari G. 
Published: September 2016

Miocene sediments of the western Black Sea failed gravitationally during the intra-Pontian (Messinian) sea-level fall. In the region of the Histria Trough, this generated two independent collapse systems detaching on the upper part of Oligocene–Lower Miocene shale. This contribution focuses on the eastern system. The eastern linked system is approximately 60 km long in the dip direction, containing about 10 major extensional faults in the updip domain, with a cumulative extension (heave) of 11.4 km. This extension is accommodated downdip partially by 6 – 7 km of lateral compaction and on a single toe thrust with 4.8 km of shortening.
The thin-skinned extension generated both basinwards-dipping faults and counter-regional faults (dip towards the basin margin), with associated rollovers, tilted fault blocks and keystone graben. Broad shale pillow (3 km across) and cuspate shale upwelling developed due to reactive shale diapirism. The collapse of the rollover anticlines into the half-graben suggests a high deformation rate. Downdip, the thrust follows the top of the Oligocene–Lower Miocene unit and steps up into the top of Sarmatian. The thrust hanging-wall anticline collapsed and triggered a mass transport complex (MTC). The top of the MTC is a rugose surface, and we suggest that it remained under water during the Messinian event due to its lack of visible erosion.
Middle Pleistocene glaciation, alluvial fan development and sea-level changes in the Bay of Kotor, Montenegro
Authors: Adamson K. R. , Woodward J. C. , Hughes P. D. , Giglio F. , Del Bianco F. 
Published: September 2016

Abstract

A coarse-grained alluvial fan at Lipci in the Bay of Kotor, western Montenegro, was deposited in the Middle Pleistocene by a high-energy, steep gradient proglacial stream draining an outlet glacier on the Orjen massif. The fan apex is currently about 50 m above sea-level, but the majority (
c.
60%) of this landform now lies offshore. Field mapping, sedimentological analysis and uranium-series dating were combined with a marine bathymetric survey and seismic profiling to explore the morphology and history of the entire fan complex. The Lipci fan was deposited on the margin of a large polje downstream of moraines that formed during the Middle Pleistocene (Marine Isotope Stage 12). The sea-level may have been more than 120 m lower than present during the glacial stages of the Middle Pleistocene. The sediments on the terrestrial portion of the fan are strongly cemented by secondary calcite and the oldest uranium-series ages show that the fan was deposited before 320 ka. These ages are consistent with a larger uranium-series dataset (
n
=39) from other glacial and glacio-fluvial formations surrounding Mount Orjen. Seismic profiling of the submerged portion of the fan in the Bay of Kotor shows well-preserved palaeochannels with inset terraces. The Lipci fan is unusual because even its distal segments are well preserved after exposure to multiple post-Marine Isotope Stage 12 regression–transgression cycles. This is probably due to the strong cementation of the fan sediments and its sheltered location in the Bay of Kotor.
ATM Expression Predicts Veliparib and Irinotecan Sensitivity in Gastric Cancer by Mediating P53-Independent Regulation of Cell Cycle and Apoptosis
Authors: Subhash Vinod Vijay , Tan Shi Hui , Yeo Mei Shi , Yan Fui Leng , Peethala Praveen C. , Liem Natalia , Krishnan Vaidehi , Yong Wei Peng 
Published: September 2016

Abstract
Identification of synthetically lethal cellular targets and synergistic drug combinations is important in cancer chemotherapy as they help to overcome treatment resistance and increase efficacy. The Ataxia Telangiectasia Mutated (ATM) kinase is a nuclear protein that plays a major role in the initiation of DNA repair signaling and cell-cycle check points during DNA damage. Although ATM was shown to be associated with poor prognosis in gastric cancer, its implications as a predictive biomarker for cancer chemotherapy remain unexplored. The present study evaluated ATM-induced synthetic lethality and its role in sensitization of gastric cancer cells to PARP and TOP1 inhibitors, veliparib (ABT-888) and irinotecan (CPT-11), respectively. ATM expression was detected in a panel of gastric cell lines, and the IC50 against each inhibitors was determined. The combinatorial effect of ABT-888 and CPT-11 in gastric cancer cells was also determined both in vitro and in vivo. ATM deficiency was found to be associated with enhanced sensitivity to ABT-888 and CPT-11 monotherapy, hence suggesting a mechanism of synthetic lethality. Cells with high ATM expression showed reduced sensitivity to monotherapy; however, they showed a higher therapeutic effect with ABT-888 and CPT-11 combinatorial therapy. Furthermore, ATM expression was shown to play a major role in cellular homeostasis by regulating cell-cycle progression and apoptosis in a P53-independent manner. The present study highlights the clinical utility of ATM expression as a predictive marker for sensitivity of gastric cancer cells to PARP and TOP1 inhibition and provides a deeper mechanistic insight into ATM-dependent regulation of cellular processes. Mol Cancer Ther; 15(12); 3087–96. ©2016 AACR.
Combining Nonclinical Experiments with Translational PKPD Modeling to Differentiate Erlotinib and Gefitinib
Authors: Eigenmann Miro J. , Frances Nicolas , Hoffmann Gerhard , Lavé Thierry , Walz Antje-Christine 
Published: September 2016

Abstract
We quantitatively compare the efficacy of two approved EGFR tyrosine kinase inhibitors, erlotinib and gefitinib, based on in vivo and in vitro data and show how a modeling approach can be used to scale from animal to humans. Gefitinib shows a higher tumor uptake in cancer patients, and we explored the potential impact on pharmacologic and antitumor activity in in vitro and in xenograft mice. Tumor growth inhibition was monitored, and the pharmacokinetics (PK) in plasma and tumor, as well as temporal changes of phospho-Erk (pErk) signals were examined in patient-derived tumor xenograft mice. These data were integrated in a translational PKPD model, allowing us to project an efficacious human dose, which we retrospectively compared with prescribed doses for cancer patients. In vitro experiments showed that cell-cycle arrest was similar for erlotinib and gefitinib. Similar pERK biomarker responses were obtained despite a 6.6-fold higher total tumor exposure for gefitinib. The PKPD model revealed a 3.7-fold higher in vivo potency for gefitinib, which did not translate into a lower anticipated efficacious dose in humans. The model-based dose prediction matched the recommended clinical doses well. These results suggest that despite having lower total tumor-to-plasma ratios, active drug exposure at target site is higher for erlotinib. Considering the PK properties, this translates in a 50% lower recommended daily dose of erlotinib in cancer patients. In summary, total exposure at target site is not suitable to rank compounds, and an integrated modeling and experimental approach can assess efficacy more accurately. Mol Cancer Ther; 15(12); 3110–9. ©2016 AACR.
CT-707, a Novel FAK Inhibitor, Synergizes with Cabozantinib to Suppress Hepatocellular Carcinoma by Blocking Cabozantinib-Induced FAK Activation
Authors: Wang Dan-Dan , Chen Ying , Chen Zi-Bo , Yan Fang-Jie , Dai Xiao-Yang , Ying Mei-Dan , Cao Ji , Ma Jian , Luo Pei-Hua , Han Yong-Xin , Peng Yong , Sun Ying-Hui , Zhang Hui , He Qiao-Jun , Yang Bo , Zhu Hong 
Published: September 2016

Abstract
Hepatocellular carcinoma is among the leading causes of cancer-related deaths worldwide, and the development of new treatment regimens is urgently needed to improve therapeutic approach. In our study, we found that the combination of a Met inhibitor, cabozantinib, and a novel FAK inhibitor, CT-707, exerted synergistic antitumor effects against hepatocellular carcinoma in vitro and in vivo. Interestingly, further studies showed that therapeutic concentrations of cabozantinib increased the phosphorylation of FAK, which might attenuate the antitumor activity of cabozantinib. The simultaneous exposure to CT-707 effectively inhibited the activation of FAK that was induced by cabozantinib, which contributes to the synergistic effect of the combination. Furthermore, cabozantinib increased the mRNA and protein levels of integrin α5, which is a canonical upstream of FAK, and the introduction of cilengitide to block integrin function could abrogate FAK activation by cabozantinib, indicating that cabozantinib upregulated the phosphorylation of FAK in an integrin-dependent manner. Similar synergy was also observed on PHA-665752, another selective MET inhibitor, indicating that this observation might be a common characteristic of MET-targeting strategies. Our findings not only favor the development of the novel FAK inhibitor CT-707 as a therapeutic agent against hepatocellular carcinoma but also provide a new strategy of combining MET and FAK inhibitors to potentiate the anticancer activities of these two types of agents for treating hepatocellular carcinoma patients. Mol Cancer Ther; 15(12); 2916–25. ©2016 AACR.
Oncogenic Receptor Tyrosine Kinases Directly Phosphorylate Focal Adhesion Kinase (FAK) as a Resistance Mechanism to FAK-Kinase Inhibitors
Authors: Marlowe Timothy A. , Lenzo Felicia L. , Figel Sheila A. , Grapes Abigail T. , Cance William G. 
Published: September 2016

Abstract
Focal adhesion kinase (FAK) is a major drug target in cancer and current inhibitors targeted to the ATP-binding pocket of the kinase domain have entered clinical trials. However, preliminary results have shown limited single-agent efficacy in patients. Despite these unfavorable data, the molecular mechanisms that drive intrinsic and acquired resistance to FAK-kinase inhibitors are largely unknown. We have demonstrated that receptor tyrosine kinases (RTK) can directly bypass FAK-kinase inhibition in cancer cells through phosphorylation of FAK's critical tyrosine 397 (Y397). We also showed that HER2 forms a direct protein–protein interaction with the FAK-FERM-F1 lobe, promoting direct phosphorylation of Y397. In addition, FAK-kinase inhibition induced two forms of compensatory RTK reprogramming: (i) the rapid phosphorylation and activation of RTK signaling pathways in RTKHigh cells and (ii) the long-term acquisition of RTKs novel to the parental cell line in RTKLow cells. Finally, HER2+ cancer cells displayed resistance to FAK-kinase inhibition in 3D growth assays using a HER2 isogenic system and HER2+ cancer cell lines. Our data indicate a novel drug resistance mechanism to FAK-kinase inhibitors whereby HER2 and other RTKs can rescue and maintain FAK activation (pY397) even in the presence of FAK-kinase inhibition. These data may have important ramifications for existing clinical trials of FAK inhibitors and suggest that individual tumor stratification by RTK expression would be important to predict patient response to FAK-kinase inhibitors. Mol Cancer Ther; 15(12); 3028–39. ©2016 AACR.
AMPKα2 Regulates Bladder Cancer Growth through SKP2-Mediated Degradation of p27
Authors: Kopsiaftis Stavros , Sullivan Katie L. , Garg Isha , Taylor John A. , Claffey Kevin P. 
Published: September 2016

Abstract
AMP-activated protein kinase (AMPK) is the central metabolic regulator of the cell and controls energy consumption based upon nutrient availability. Due to its role in energy regulation, AMPK has been implicated as a barrier for cancer progression and is suppressed in multiple cancers. To examine whether AMPK regulates bladder cancer cell growth, HTB2 and HT1376 bladder cells were treated with an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). AICAR treatment reduced proliferation and induced the expression of p27Kip1 (CDKN1B), which was mediated through an mTOR-dependent mechanism. Interestingly, AMPKα2 knockdown resulted in reduced p27 levels, whereas AMPKα1 suppression did not. To further determine the exact mechanism by which AMPKa2 regulates p27, HTB2 and HT1376 cells were transduced with an shRNA targeting AMPKα2. Stable knockdown of AMPKα2 resulted in increased proliferation and decreased p27 protein. The reduced p27 protein was determined to be dependent upon SKP2. Additionally, loss of AMPKα2 in a xenograft and a chemical carcinogen model of bladder cancer resulted in larger tumors with less p27 protein and high SKP2 levels. Consistent with the regulation observed in the bladder cancer model systems, a comprehensive survey of human primary bladder cancer clinical specimens revealed low levels of AMPKα2 and p27 and high levels of SKP2.
Implications: These results highlight the contribution of AMPKα2 as a mechanism for controlling bladder cancer growth by regulating proliferation through mTOR suppression and induction of p27 protein levels, thus indicating how AMPKα2 loss may contribute to tumorigenesis. Mol Cancer Res; 14(12); 1182–94. ©2016 AACR.
Clinical Response of a Patient to Anti–PD-1 Immunotherapy and the Immune Landscape of Testicular Germ Cell Tumors
Authors: Shah Shalin , Ward James E. , Bao Riyue , Hall Curtis R. , Brockstein Bruce E. , Luke Jason J. 
Published: September 2016

Abstract
Anti–Programed Death 1 (PD-1) is standard immunotherapy for multiple cancers, and the expression of one of its ligands, PD-L1, has been described in germ cell tumors (GCT). Neither the clinical activity of anti–PD-1 nor the incidence of an immunoresponsive tumor microenvironment has been described for GCTs. A patient initially diagnosed with melanoma via fine needle aspiration was treated with one dose of antibody to PD-1. A core needle biopsy was subsequently performed to acquire sufficient tissue for molecular analysis, which led to a change in diagnosis to metastatic embryonal carcinoma. The testicular GCT cohort of The Cancer Genome Atlas was analyzed using a T-cell gene signature associated with benefit from immunotherapy. Primary tumors (N = 134) were categorized as high (T-cell–inflamed), medium, or low (non–T-cell-inflamed) by their T-cell signature derived from RNAseq data. Anti–PD-1 induced decreases in serum markers and a 33% reduction in tumor volume. Gene expression revealed a T-cell–inflamed tumor microenvironment in 47% of testicular GCTs, including seminoma (83%) and nonseminoma (17%) tumor subtypes. Expression of alpha-fetoprotein (AFP) RNA correlated with lack of the T-cell signature, with increasing AFP RNA inversely correlating with the inflamed signature and expression of IFNγ-associated genes. These data suggest that GCTs can respond to anti–PD-1 and that gene expression profiling supports investigation of immunotherapy for treatment of GCTs. Cancer Immunol Res; 4(11); 903–9. ©2016 AACR.
Hydrogen Sulfide Regulates Krüppel‐Like Factor 5 Transcription Activity via Specificity Protein 1 S‐Sulfhydration at Cys664 to Prevent Myocardial Hypertrophy
Authors: Meng Guoliang , Xiao Yujiao , Ma Yan , Tang Xin , Xie Liping , Liu Jieqiong , Gu Yue , Yu Ying , Park Chung‐Min , Xian Ming , Wang Xin , Ferro Albert , Wang Rui , Moore Philip K. , Zhang Zhiren , Wang Hong , Han Yi , Ji Yong 
Published: September 2016

Background

Hydrogen sulfide (H
2
S) is a gasotransmitter that regulates multiple cardiovascular functions. Krüppel‐like factor 5 (KLF5) exerts diverse functions in the cardiovascular system. Whether and how H
2
S regulates KLF5 in myocardial hypertrophy is unknown.

Methods and Results

In our study, hypertrophic myocardial samples in the clinic were collected and underwent histological and molecular biological analysis. Spontaneously hypertensive rats and neonatal rat cardiomyocytes were studied for functional and signaling responses to GYY4137, an H
2
S‐releasing compound. Expression of cystathionine γ‐lyase, a principal enzyme for H
2
S generation in heart, decreased in human hypertrophic myocardium, whereas KLF5 expression increased. After GYY4137 administration for 4 weeks, myocardial hypertrophy was inhibited in spontaneously hypertensive rats, as demonstrated by improvement in cardiac structural parameters, heart mass, size of cardiac myocytes, and expression of atrial natriuretic peptide. H
2
S diminished expression of KLF5 in myocardium of spontaneously hypertensive rats and in hypertrophic cardiomyocytes. H
2
S also inhibits platelet‐derived growth factor A promoter activity, decreased recruitment of KLF5 to the platelet‐derived growth factor A promoter, and reduced atrial natriuretic peptide expression in angiotensin II–stimulated cardiomyocytes, and these effects are suppressed by KLF5 knockdown. KLF5 promoter activity and KLF5 expression was also reversed by H
2
S. H
2
S increased the S‐sulfhydration on specificity protein 1 in cardiomyocytes. Moreover, H
2
S decreased KLF5 promoter activity; reduced KLF5 mRNA expression; attenuated specificity protein 1 binding activity with KLF5 promoter; and inhibited hypertrophy after specificity protein 1 mutated at Cys659, Cys689, and Cys692 but not Cys664 overexpression.

Conclusions

These findings suggest that H
2
S regulates KLF5 transcription activity via specificity protein 1 S‐sulfhydration at Cys664 to prevent myocardial hypertrophy.
Phoradendron longicaule (Viscaceae): a new species from Michoacán, Mexico
Authors: KUIJT JOB , STEINMANN VICTOR W. 
Published: September 2016

Phoradendron longicaule (Viscaceae), a new, nearly leafless species of mistletoe from the Infiernillo-Zicuirán Biosphere Reserve of southern Michoacán, Mexico, is described and illustrated. It occurs in a tropical deciduous forest at elevations of 400 to 500 m, and all known hosts belong to Fabaceae. The long, straight, pendulous stems and elongated vegetative internodes are distinctive features. It is most similar to P. nudum but differs by having 3 or 4 pistillate flowers per fertile bract, expanded albeit highly reduced leaves, and longer vegetative internodes. It is also similar to P. teretifolium from which it differs by having a pendulous habit, longer vegetative internodes, 3 or 4 pistillate flowers per fertile bract, and fruits on short internodes.
Saharan Dust and the Nonlinear Evolution of the African Easterly Jet–African Easterly Wave System
Authors: Grogan Dustin F. P. , Nathan Terrence R. , Chen Shu-Hua 
Published: September 2016

Abstract
The direct radiative effects of Saharan mineral dust (SMD) aerosols on the nonlinear evolution of the African easterly jet–African easterly wave (AEJ–AEW) system is examined using the Weather Research and Forecasting Model coupled to an online dust model. The SMD-modified AEW life cycles are characterized by four stages: enhanced linear growth, weakened nonlinear stabilization, larger peak amplitude, and smaller long-time amplitude. During the linear growth and nonlinear stabilization stages, the SMD increases the generation of eddy available potential energy (APE); this occurs where the maximum in the mean meridional SMD gradient is coincident with the critical surface. As the AEWs evolve beyond the nonlinear stabilization stage, the discrimination between SMD particle sizes due to sedimentation becomes more pronounced; the finer particles meridionally expand, while the coarser particles settle to the surface. The result is a reduction in the eddy APE at the base and the top of the plume.
The SMD enhances the Eliassen–Palm (EP) flux divergence and residual-mean meridional circulation, which generally oppose each other throughout the AEW life cycle. The SMD-modified residual-mean meridional circulation initially dominates to accelerate the flow but quickly surrenders to the EP flux divergence, which causes an SMD-enhanced deceleration of the AEJ during the linear growth and nonlinear stabilization stages. Throughout the AEW life cycle, the SMD-modified AEJ is elevated and the peak winds are larger than without SMD. During the first (second) half of the AEW life cycle, the SMD-modified wave fluxes shift the AEJ axis farther equatorward (poleward) of its original SMD-free position.