bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statin-Induced Cancer Cell Death Can Be Mechanistically Uncoupled from Prenylation of RAS Family Proteins
Authors: Yu Rosemary , Longo Joseph , van Leeuwen Jenna E. , Mullen Peter J. , Ba-Alawi Wail , Haibe-Kains Benjamin , Penn Linda Z. 
Published: December 2017

Abstract
The statin family of drugs preferentially triggers tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for protein prenylation cannot explain increased statin sensitivity. Although ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the antiproliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity data indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anticancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.
Significance: The use of statins to target cancer cell EMT may be useful as a therapy to block cancer progression. Cancer Res; 78(5); 1347–57. ©2017 AACR.
Downregulating Neuropilin-2 Triggers a Novel Mechanism Enabling EGFR-Dependent Resistance to Oncogene-Targeted Therapies
Authors: Rizzolio Sabrina , Battistini Chiara , Cagnoni Gabriella , Apicella Maria , Vella Viviana , Giordano Silvia , Tamagnone Luca 
Published: December 2017

Abstract
Neuropilins are a class of cell surface proteins implicated in cell migration and angiogenesis, with aberrant expression in human tumors. Here, we show that the expression of Neuropilin-2 (NRP2) controls EGFR protein levels, thereby impinging on intracellular signaling, viability, and response to targeted therapies of oncogene-addicted cells. Notably, increased NRP2 expression in EGFR-addicted tumor cells led to downregulation of EGFR protein and tumor cell growth inhibition. NRP2 also blunted upregulation of an EGFR "rescue" pathway induced by targeted therapy in Met-addicted carcinoma cells. Cancer cells acquiring resistance to MET oncogene-targeted drugs invariably underwent NRP2 loss, a step required for EGFR upregulation. Mechanistic investigations revealed that NRP2 loss activated NFkB and upregulated the EGFR-associated protein KIAA1199/CEMIP, which is known to oppose the degradation of activated EGFR kinase. Notably, KIAA1199 silencing in oncogene-addicted tumor cells improved therapeutic responses and counteracted acquired drug resistance. Our findings define NRP2 as the pivotal switch of a novel broad-acting and actionable pathway controlling EGFR signaling, and driving resistance to therapies targeting oncogene-addiction.
Significance: These important findings identify the cell surface molecule Nrp2 as the pivotal switch of a novel, actionable pathway driving EGFR upregulation and resistance to oncogene- targeted therapies. Cancer Res; 78(4); 1058–68. ©2017 AACR.
CDKN2A/p16Deletion in Head and Neck Cancer Cells Is Associated with CDK2 Activation, Replication Stress, and Vulnerability to CHK1 Inhibition
Authors: Gadhikar Mayur A. , Zhang Jiexin , Shen Li , Rao Xiayu , Wang Jing , Zhao Mei , Kalu Nene N. , Johnson Faye M. , Byers Lauren A. , Heymach John , Hittelman Walter N. , Udayakumar Durga , Pandita Raj K. , Pandita Tej K. , Pickering Curtis R. , Redwood Abena B. , Piwnica-Worms Helen , Schlacher Katharina , Frederick Mitchell J. , Myers Jeffrey N. 
Published: December 2017

AbstractCheckpoint kinase inhibitors (CHKi) exhibit striking single-agent activity in certain tumors, but the mechanisms accounting for hypersensitivity are poorly understood. We screened a panel of 49 established human head and neck squamous cell carcinoma (HNSCC) cell lines and report that nearly 20% are hypersensitive to CHKi monotherapy. Hypersensitive cells underwent early S-phase arrest at drug doses sufficient to inhibit greater than 90% of CHK1 activity. Reduced rate of DNA replication fork progression and chromosomal shattering were also observed, suggesting replication stress as a root causative factor in CHKi hypersensitivity. To explore genomic underpinnings of CHKi hypersensitivity, comparative genomic analysis was performed between hypersensitive cells and cells categorized as least sensitive because they showed drug IC50 value greater than the cell panel median and lacked early S-phase arrest. Novel association between CDKN2A/p16 copy number loss, CDK2 activation, replication stress, and hypersensitivity of HNSCC cells to CHKi monotherapy was found. Restoring p16 in cell lines harboring CDKN2A/p16 genomic deletions alleviated CDK2 activation and replication stress, attenuating CHKi hypersensitivity. Taken together, our results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from CHKi therapy.Significance: These results suggest a biomarker-driven strategy for selecting HNSCC patients who may benefit the most from therapy with CHK inhibitors. Cancer Res; 78(3); 781–97. ©2017 AACR.
A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment
Authors: Young Arabella , Ngiow Shin Foong , Gao Yulong , Patch Ann-Marie , Barkauskas Deborah S. , Messaoudene Meriem , Lin Gene , Coudert Jerome D. , Stannard Kimberley A. , Zitvogel Laurence , Degli-Esposti Mariapia A. , Vivier Eric , Waddell Nicola , Linden Joel , Huntington Nicholas D. , Souza-Fonseca-Guimaraes Fernando , Smyth Mark J. 
Published: December 2017

Abstract
Extracellular adenosine is a key immunosuppressive metabolite that restricts activation of cytotoxic lymphocytes and impairs antitumor immune responses. Here, we show that engagement of A2A adenosine receptor (A2AR) acts as a checkpoint that limits the maturation of natural killer (NK) cells. Both global and NK-cell–specific conditional deletion of A2AR enhanced proportions of terminally mature NK cells at homeostasis, following reconstitution, and in the tumor microenvironment. Notably, A2AR-deficient, terminally mature NK cells retained proliferative capacity and exhibited heightened reconstitution in competitive transfer assays. Moreover, targeting A2AR specifically on NK cells also improved tumor control and delayed tumor initiation. Taken together, our results establish A2AR-mediated adenosine signaling as an intrinsic negative regulator of NK-cell maturation and antitumor immune responses. On the basis of these findings, we propose that administering A2AR antagonists concurrently with NK cell–based therapies may heighten therapeutic benefits by augmenting NK cell–mediated antitumor immunity.
Significance: Ablating adenosine signaling is found to promote natural killer cell maturation and antitumor immunity and reduce tumor growth. Cancer Res; 78(4); 1003–16. ©2017 AACR.
Targeting Transmembrane BAX Inhibitor Motif Containing 1 Alleviates Pathological Cardiac Hypertrophy
Authors: Deng Ke-Qiong , Zhao Guang-Nian , Wang Zhihua , Fang Jing , Jiang Zhou , Gong Jun , Yan Feng-Juan , Zhu Xue-Yong , Zhang Peng , She Zhi-Gang , Li Hongliang 
Published: December 2017

Background:
Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality worldwide. Abnormal protein degradation, especially the impaired lysosomal degradation of large organelles and membrane proteins, is involved in the progression of cardiac hypertrophy. However, the underlying mechanisms have not been fully elucidated.

Methods:

We investigated cardiac transmembrane BAX inhibitor motif containing 1 (TMBIM1) mRNA and protein expression levels in samples from patients with heart failure and mice with aortic banding (AB)–induced cardiac hypertrophy. We generated cardiac-specific
Tmbim1
knockout mice and cardiac-specific
Tmbim1
-overexpressing transgenic mice and then challenged them with AB surgery. We used microarray, confocal image, and coimmunoprecipitation analyses to identify the downstream targets of TMBIM1 in cardiac hypertrophy.
Tmbim1
/
Tlr4
double-knockout mice were generated to investigate whether the effects of TMBIM1 on cardiac hypertrophy were Toll-like receptor 4 (TLR4) dependent. Finally, lentivirus-mediated
TMBIM1
overexpression in a monkey AB model was performed to evaluate the therapeutic potential of TMBIM1.

Results:

TMBIM1 expression was significantly downregulated on hypertrophic stimuli in both human and mice heart samples. Silencing cardiac
Tmbim1
aggravated AB-induced cardiac hypertrophy. This effect was blunted by
Tmbim1
overexpression. Transcriptome profiling revealed that the TLR4 signaling pathway was disrupted dramatically by manipulation of
Tmbim1
. The effects of TMBIM1 on cardiac hypertrophy were shown to be dependent on TLR4 in double-knockout mice. Fluorescent staining indicated that TMBIM1 promoted the lysosome-mediated degradation of activated TLR4. Coimmunoprecipitation assays confirmed that TMBIM1 directly interacted with tumor susceptibility gene 101 via a PTAP motif and accelerated the formation of multivesicular bodies that delivered TLR4 to the lysosomes. Finally, lentivirus-mediated
TMBIM1
overexpression reversed AB-induced cardiac hypertrophy in monkeys.

Conclusions:
TMBIM1 protects against pathological cardiac hypertrophy through promoting the lysosomal degradation of activated TLR4. Our findings reveal the central role of TMBIM1 as a multivesicular body regulator in the progression of pathological cardiac hypertrophy, as well as the role of vesicle trafficking in signaling regulation during cardiac hypertrophy. Moreover, targeting TMBIM1 could be a novel therapeutic strategy for treating cardiac hypertrophy and heart failure.
One Heavenly Kingdom, Two Governments: Mainland China and Taiwan
Authors: Kuo Cheng-tian 
Published: December 2017

Abstract
Over the past three decades political relationships between mainland China and Taiwan have fluctuated precariously between warm peace and cold war. Instead of playing the role of the biblical peacemaker, Christian theologians on both sides have developed irreconcilable nationalist theologies in order to sanctify their respective nationalist programs: Chinese unification versus Taiwanese independence. For the purpose of constructing peace across the Taiwan Strait, a new political theology needs to be built on the centrality of religious freedom to be found in the Bible, democratic values, and the actual politics of both China and Taiwan. The second section of this article analyzes the biblical sources of a Chinese unification theology and a Taiwanese independence theology. The third and fourth sections introduce the historical development of nationalism and nationalist theology in both societies. The fifth section concludes by proposing a democratic union theology that builds on the centrality of religious freedom in the Bible, democratic values, and actual politics.
The Ethical Presupposition of Historical Understanding
Authors: Elgabsi Natan 
Published: December 2017

Abstract
Discussions on Marc Bloch usually focus on The Annales School, his comparative method, or his defence of a distinct historical science. In contrast, I emphasise his seldom-investigated ideas of what historical understanding should involve. I contend that Bloch distinguishes between three different ethical attitudes in studying people and ways of life from the past: scientific passivity; critical judgements; understanding. The task of the historian amounts to understanding other worlds in their own terms. This essay is an exploration of Bloch’s methodology and what historical understanding is needed to do justice to cultures that belong to the past, both conceptually and practically.
The Arctic System Reanalysis, Version 2
Authors: Bromwich D. H. , Wilson A. B. , Bai L. , Liu Z. , Barlage M. , Shih C.-F. , Maldonado S. , Hines K. M. , Wang S.-H. , Woollen J. , Kuo B. , Lin H.-C. , Wee T.-K. , Serreze M. C. , Walsh J. E. 
Published: December 2017

AbstractThe Arctic is a vital component of the global climate, and its rapid environmental evolution is an important element of climate change around the world. To detect and diagnose the changes occurring to the coupled Arctic climate system, a state-of-the-art synthesis for assessment and monitoring is imperative. This paper presents the Arctic System Reanalysis, version 2 (ASRv2), a multiagency, university-led retrospective analysis (reanalysis) of the greater Arctic region using blends of the polar-optimized version of the Weather Research and Forecasting (Polar WRF) Model and WRF three-dimensional variational data assimilated observations for a comprehensive integration of the regional climate of the Arctic for 2000–12. New features in ASRv2 compared to version 1 (ASRv1) include 1) higher-resolution depiction in space (15-km horizontal resolution), 2) updated model physics including subgrid-scale cloud fraction interaction with radiation, and 3) a dual outer-loop routine for more accurate data assimilation. ASRv2 surface and pressure-level products are available at 3-hourly and monthly mean time scales at the National Center for Atmospheric Research (NCAR). Analysis of ASRv2 reveals superior reproduction of near-surface and tropospheric variables. Broadscale analysis of forecast precipitation and site-specific comparisons of downward radiative fluxes demonstrate significant improvement over ASRv1. The high-resolution topography and land surface, including weekly updated vegetation and realistic sea ice fraction, sea ice thickness, and snow-cover depth on sea ice, resolve finescale processes such as topographically forced winds. Thus, ASRv2 permits a reconstruction of the rapid change in the Arctic since the beginning of the twenty-first century–complementing global reanalyses. ASRv2 products will be useful for environmental models, verification of regional processes, or siting of future observation networks.
A Positive Feedback Process Related to the Rapid Development of an Extratropical Cyclone over the Kuroshio/Kuroshio Extension
Authors: Hirata Hidetaka , Kawamura Ryuichi , Kato Masaya , Shinoda Taro 
Published: December 2017

Abstract
The active roles of sensible heat supply from the Kuroshio/Kuroshio Extension in the rapid development of an extratropical cyclone, which occurred in the middle of January 2013, were examined by using a regional cloud-resolving model. In this study, a control experiment and three sensitivity experiments without sensible and latent heat fluxes from the warm currents were conducted. When the cyclone intensified, sensible heat fluxes from these currents become prominent around the cold conveyor belt (CCB) in the control run. Comparisons among the four runs revealed that the sensible heat supply facilitates deepening of the cyclone’s central pressure, CCB development, and enhanced latent heating over the bent-back front. The sensible heat supply enhances convectively unstable conditions within the atmospheric boundary layer along the CCB. The increased convective instability is released by the forced ascent associated with frontogenesis around the bent-back front, eventually promoting updraft and resultant latent heating. Additionally, the sensible heating leads to an increase in the water vapor content of the saturated air related to the CCB through an increase in the saturation mixing ratio. This increased water vapor content reinforces the moisture flux convergence at the bent-back front, contributing to the activation of latent heating. Previous research has proposed a positive feedback process between the CCB and latent heating over the bent-back front in terms of moisture supply from warm currents. Considering the above two effects of the sensible heat supply, this study revises the positive feedback process.
Does a strategic planning process that combines rational and adaptive characteristics pay off ? Evidence from European firms
Authors: Ouakouak Mohamed Laid 
Published: December 2017

Rational strategic planning has long been used as an instrument to improve financial performance. With the increasing complexity of the business environment, this positive impact has decreased. As a result, there have been several calls for more work focusing on investigating and understanding the strategic planning process and how it affects financial performance. Many recent studies suggest that a rational approach to strategic planning should be combined with an adaptive approach to build a hybrid approach that is better suited to the current dynamic and complex environment. The purpose of this research is to examine how a strategic planning process that combines rational characteristics and adaptive characteristics improves financial performance. To this end, this study develops and empirically tests a conceptual model, using a quantitative study of 335 European organizations. A combined strategic planning process has a positive impact on financial performance, through the mediators of employee strategic alignment and organizational capabilities. JEL Classification: L10, L25
Time-Dependent Recovery of Human Synovial Membrane Mesenchymal Stem Cell Function After High-Dose Steroid Therapy: Case Report and Laboratory Study
Authors: Yasui Yukihiko , Hart David A. , Sugita Norihiko , Chijimatsu Ryota , Koizumi Kota , Ando Wataru , Moriguchi Yu , Shimomura Kazunori , Myoui Akira , Yoshikawa Hideki , Nakamura Norimasa 
Published: December 2017

Background: The use of mesenchymal stem cells from various tissue sources to repair injured tissues has been explored over the past decade in large preclinical models and is now moving into the clinic. Purpose: To report the case of a patient who exhibited compromised mesenchymal stem cell (MSC) function shortly after use of high-dose steroid to treat Bell’s palsy, who recovered 7 weeks after therapy. Study Design: Case report and controlled laboratory study. Methods: A patient enrolled in a first-in-human clinical trial for autologous implantation of a scaffold-free tissue engineered construct (TEC) derived from synovial MSCs for chondral lesion repair had a week of high-dose steroid therapy for Bell’s palsy. Synovial tissue was harvested for MSC preparation after a 3-week recovery period and again at 7 weeks after therapy. Results: The MSC proliferation rates and cell surface marker expression profiles from the 3-week sample met conditions for further processing. However, the cells failed to generate a functional TEC. In contrast, MSCs harvested at 7 weeks after steroid therapy were functional in this regard. Further in vitro studies with MSCs and steroids indicated that the effect of in vivo steroids was likely a direct effect of the drug on the MSCs. Conclusion: This case suggests that MSCs are transiently compromised after high-dose steroid therapy and that careful consideration regarding timing of MSC harvest is critical. Clinical Relevance: The drug profiles of MSC donors and recipients must be carefully monitored to optimize opportunities to successfully repair damaged tissues.
Patient Behaviour on Non‐Accidental Poisoning ‐ A Prospective Study
Authors: Man CY , Cheung WL 
Published: December 2017

Poisoning or drug overdose is a common presentation to the Accident and Emergency Departments (AED) in Hong Kong. This prospective study examined 74 patients with intentional poisoning attending an Accident and Emergency department over a 3 month‐period. A pre‐set questionnaire was designed seeking the following information: demographic characteristics, patient behaviour, the source of ingestants, patient's knowledge about the ingestants, home interventions, medical and psychiatric history, and final outcomes. The incidence of intentional poisoning was 0.16%. Most were female in 21–40 years age group, single, had a job and had secondary level education. They were usually healthy and had no psychiatric illness. Drugs (mostly hypnotic/sedatives) and household products made up most of the ingestants. The ‘Sleep‐On’, ‘Sleep‐Qik’, and ‘Honslin’ were the most common hypnotic/sedative. These ingestants were chosen largely because of their easy accessibility rather than the toxicity. The majority presented within 2 hours of ingestion although with an initial attempt to die, paradoxically they did not believe that they would die from the overdose. Most events occurred at patient's own home. Emotional, family and marital problems constituted the vast majority of the precipitating factors. About 40% of patients ingested more than one substance (alcohol being the most common co‐ingestant) or had an concurrent acting‐out behaviour. Although most patients knew the nature of the ingestant, very few (less than 15%) understood its side‐effects or their contraindications. There was no mortality or significant morbidity. Over 60% did not have any psychiatric disorder after psychiatric assessment. Knowledge of pattern of poisonings and patient behaviour in local setting is important in terms of prevention, public education and the provision of the optimal care to these patients.
The Evolution of Emergency Medicine
Authors: Chung Ch 
Published: December 2017

Objective Emergency Medicine as an independent medical specialty has a history of only about 30 years. However, emergency medical care has been practised ever since human civilization. As emergency physicians, it is necessary to know the evolution of Emergency Medicine throughout the centuries and its development in different parts of the World. Lessons learned in the past may guide our future development. Methods Medical literature on evolution, development and history of Emergency Medicine were searched from the Medline, HealthSTAR and EMBASE. Relevant full text articles were retrieved through hospital library network. Information was also obtained through Internet and books on history of medicine. Results Most of the articles were contained in the International Report Section of the Annals of Emergency Medicine. The historical development, the catalysts for change and the different models of modern emergency care were found to be interesting and enlightening. Conclusion Emergency Medicine is still at its formative stage. Different models exist in different parts of the World. The specialty is rapidly changing and moving in different directions, both locally and internationally.