bluuebunny/crossref_metadata_2025_split huggingface dataset:
LGR4 protects hepatocytes from injury in mouse
Authors: Li Ziru , Liu Shiying , Lou Jianing , Mulholland Michael , Zhang Weizhen 
Published: November 2018

Leucine-rich repeat G protein-coupled receptors (LGRs) and their endogenous ligands R-spondin1–4 (Rspo) are critical in embryonic development and in maintenance of stem cells. The functions of the Rspo-LGR system in differentiated cells remain uncharacterized. In this study, the expression profiles of LGRs and Rspos were characterized in mature hepatocytes. A liver-specific knockout of LGR4 in mouse was generated and used to study hepatic ischemia/reperfusion-induced injury (HIRI) as well as lipopolysaccharide/ D- galactosamine (LPS/D-Gal)-induced liver injury. We have demonstrated that, in adult liver, LGR4 is expressed in hepatocytes and responds to Rspo1 with internalization. Rspo1 is responsive to various nutritional states and to mTOR signaling. Activation of LGR4 by Rspo1 significantly reduced tumor necrosis factor-α (TNFα)-induced cell death, and levels of NF-κB-p65 and caspase-3 in cultured hepatocytes. Knockdown of hepatic LGR4 rendered hepatocytes more vulnerable to TNFα-induced damage in cultured primary cells and in the setting of HIRI and LPS/D-Gal-induced liver injury. Rspo1 potentiated both basal and Wnt3a-induced stabilization of β-catenin. Disruption of β-catenin signaling reversed the protective effects of Rspo1 on TNFα-induced hepatocyte toxicity. LGR4 knockdown increased nuclear translocation of NF-κB-p65 in response to acute injury. Overexpression of IKKβ attenuated the protective effects of Rspo1 on TNFα-induced cell death. In conclusion, the Rspo1-LGR4 system represents a novel pathway for cytoprotection and modulation of stress-induced tissue damage. NEW & NOTEWORTHY Functional LGR4 is present in mature hepatocytes. R-spodin1 protects hepatocytes from tumor necrosis factor-α-induced cell death. Liver-specific knockdown of LGR4 renders liver more susceptible to acute injury. LGR4 protects hepatocytes from injury by inhibition of NF-κB signaling.
Modulation of Mutant KrasG12D-Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function
Authors: Zhou Xiaorong , Padanad Mahesh S. , Evers Bret M. , Smith Bethany , Novaresi Nicole , Suresh Shruthy , Richardson James A. , Stein Emily , Zhu Jingfei , Hammer Robert E. , O'Donnell Kathryn A. 
Published: November 2018

Abstract

PROTOCADHERIN 7 (PCDH7), a transmembrane receptor and member of the Cadherin superfamily, is frequently overexpressed in lung adenocarcinoma and is associated with poor clinical outcome. Although PCDH7 was recently shown to promote transformation and facilitate brain metastasis in lung and breast cancers, decreased PCDH7 expression has also been documented in colorectal, gastric, and invasive bladder cancers. These data suggest context-dependent functions for PCDH7 in distinct tumor types. Given that PCDH7 is a potentially targetable molecule on the surface of cancer cells, further investigation of its role in tumorigenesis in vivo is needed to evaluate the therapeutic potential of its inhibition. Here, we report the analysis of novel PCDH7 gain- and loss-of-function mouse models and provide compelling evidence that this cell-surface protein acts as a potent lung cancer driver. Employing a Cre-inducible transgenic allele, we demonstrated that enforced PCDH7 expression significantly accelerates KrasG12D-driven lung tumorigenesis and potentiates MAPK pathway activation. Furthermore, we performed in vivo somatic genome editing with CRISPR/Cas9 in KrasLSL-G12D; Tp53fl/fl (KP) mice to assess the consequences of PCDH7 loss of function. Inactivation of PCDH7 in KP mice significantly reduced lung tumor development, prolonged survival, and diminished phospho-activation of ERK1/2. Together, these findings establish a critical oncogenic function for PCDH7 in vivo and highlight the therapeutic potential of PCDH7 inhibition for lung cancer. Moreover, given recent reports of elevated or reduced PCDH7 in distinct tumor types, the new inducible transgenic model described here provides a robust experimental system for broadly elucidating the effects of PCDH7 overexpression in vivo.

Implications:
In this study, we establish a critical oncogenic function for PCDH7 in vivo using novel mouse models and CRISPR/Cas9 genome editing, and we validate the therapeutic potential of PCDH7 inhibition for lung cancer.
Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study
Authors: Daver Naval , Garcia-Manero Guillermo , Basu Sreyashi , Boddu Prajwal C. , Alfayez Mansour , Cortes Jorge E. , Konopleva Marina , Ravandi-Kashani Farhad , Jabbour Elias , Kadia Tapan , Nogueras-Gonzalez Graciela M. , Ning Jing , Pemmaraju Naveen , DiNardo Courtney D. , Andreeff Michael , Pierce Sherry A. , Gordon Tauna , Kornblau Steven M. , Flores Wilmer , Alhamal Zainab , Bueso-Ramos Carlos , Jorgensen Jeffrey L. , Patel Keyur P. , Blando Jorge , Allison James P. , Sharma Padmanee , Kantarjian Hagop 
Published: November 2018

Abstract

Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22–90) and the median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained &gt;6 months. Six patients (9%) had stable disease &gt;6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)–naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection.

Significance:
Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials.
This article is highlighted in the In This Issue feature, p. 305
Comparison and Evaluation of Statistical Rainfall Disaggregation and High-Resolution Dynamical Downscaling over Complex Terrain
Authors: Poschlod B. , Hodnebrog Ø. , Wood R. R. , Alterskjær K. , Ludwig R. , Myhre G. , Sillmann J. 
Published: November 2018

Abstract
Representative methods of statistical disaggregation and dynamical downscaling are compared in terms of their ability to disaggregate precipitation data into hourly resolution in an urban area with complex terrain. The nonparametric statistical Method of Fragments (MoF) uses hourly data from rain gauges to split the daily data at the location of interest into hourly fragments. The high-resolution, convection-permitting Weather Research and Forecasting (WRF) regional climate model is driven by reanalysis data. The MoF can reconstruct the variance, dry proportion, wet hours per month, number and length of wet spells per rainy day, timing of the maximum rainfall burst, and intensities of extreme precipitation with errors of less than 10%. However, the MoF cannot capture the spatial coherence and temporal interday connectivity of precipitation events due to the random elements involved in the algorithm. Otherwise, the statistical method is well suited for filling gaps in subdaily historical records. The WRF Model is able to reproduce dry proportion, lag-1 autocorrelation, wet hours per month, number and length of wet spells per rainy day, spatial correlation, and 6- and 12-h intensities of extreme precipitation with errors of 10% or less. The WRF approach tends to underestimate peak rainfall of 1- and 3-h aggregates but can be used where no observations are available or when areal precipitation data are needed.
Examination of Generation Mechanisms for an English Channel Meteotsunami: Combining Observations and Modeling
Authors: Williams David A. , Horsburgh Kevin J. , Schultz David M. , Hughes Chris W. 
Published: November 2018

AbstractOn the morning of 23 June 2016, a 0.70-m meteotsunami was observed in the English Channel between the United Kingdom and France. This wave was measured by several tide gauges and coincided with a heavily precipitating convective system producing 10 m s−1 wind speeds at the 10-m level and 1–2.5-hPa surface pressure anomalies. A combination of precipitation rate cross correlations and NCEP–NCAR Reanalysis 1 data showed that the convective system moved northeastward at 19 ± 2 m s−1. To model the meteotsunami, the finite element model Telemac was forced with an ensemble of prescribed pressure forcings, covering observational uncertainty. Ensembles simulated the observed wave period and arrival times within minutes and wave heights within tens of centimeters. A directly forced wave and a secondary coastal wave were simulated, and these amplified as they propagated. Proudman resonance was responsible for the wave amplification, and the coastal wave resulted from strong refraction of the primary wave. The main generating mechanism was the atmospheric pressure anomaly with wind stress playing a secondary role, increasing the first wave peak by 16% on average. Certain tidal conditions reduced modeled wave heights by up to 56%, by shifting the location where Proudman resonance occurred. This shift was mainly from tidal currents rather than tidal elevation directly affecting shallow-water wave speed. An improved understanding of meteotsunami return periods and generation mechanisms would be aided by tide gauge measurements sampled at less than 15-min intervals.
Reforming a state in formation: from Structural Adjustment Programs to Results-Based Management – lessons from two decades of administrative reform in Cameroon
Authors: Tamekou Raoul 
Published: November 2018

This article sets out to examine, from a socio-historical standpoint, the administrative change process specific to Cameroon. By analyzing the mechanisms and processes driving the administrative reforms put in place since the end of the 1980s, the study pinpoints the regularities characteristic of the national trajectory of administrative reform in Cameroon. The article is divided into three sections. The first presents the analytical approach chosen. The second part presents the various repertoires of the reforms put in place, as well as an overview of the main programs. The third, finally, sets outs the lessons drawn from the study. Points for practitioners The article explores the dynamic relationship between the production of administrative reforms and the impact of reforms on the politico-administrative order in Cameroon. It is thus demonstrated that while reform has become considered over the years as a specialized know-how and an objective framework for the construction of public action, it continues to be plagued by rationales that are foreign to the organizational purpose, and comes across as the “art of doing.”
Comparison of cyanoacrylate closure and radiofrequency ablation for the treatment of incompetent great saphenous veins: 36-Month outcomes of the VeClose randomized controlled trial
Authors: Morrison Nick , Kolluri Raghu , Vasquez Michael , Madsen Monte , Jones Andrew , Gibson Kathleen 
Published: November 2018

Objective To evaluate the 36-month efficacy and safety of cyanoacrylate closure for the treatment of incompetent great saphenous veins in comparison with radiofrequency ablation. Methods In this multicenter, prospective, randomized controlled trial, 222 symptomatic subjects with incompetent great saphenous veins were assigned to either cyanoacrylate closure or radiofrequency ablation. The primary endpoint, complete closure of the target great saphenous vein, was determined using duplex ultrasound examination starting from three-month visit. Results At month 36, the great saphenous vein closure rates were 94.4% for the cyanoacrylate closure group and 91.9% for the radiofrequency ablation group. Stable improvement in symptoms and quality of life was observed in both groups. Adverse event rates between the 24- and 36-month visits were similar between the groups as were serious adverse events which were infrequent and judged unrelated to either the device or the procedure in both groups. Conclusions This trial continues to demonstrate the safety and efficacy of cyanoacrylate closure for the treatment of great saphenous vein incompetence with great saphenous vein closure rate at 36 months similar to that of radiofrequency ablation, indicating non-inferiority of cyanoacrylate closure to radiofrequency ablation. The improvement in quality of life outcomes were also sustained and similar between the two treatment groups.
Biomechanical Comparison of Ulnar Collateral Ligament Reconstruction With the Docking Technique Versus Repair With Internal Bracing
Authors: Bodendorfer Blake M. , Looney Austin M. , Lipkin Sloane L. , Nolton Esther C. , Li Jihui , Najarian Robert G. , Chang Edward S. 
Published: November 2018

Background: The modified Jobe technique of ulnar collateral ligament (UCL) reconstruction has previously been biomechanically compared with primary repair augmented with internal bracing. However, the docking technique has not been compared with repair with internal bracing. Hypothesis: Load to failure, gapping, and valgus opening angle are similar under valgus loading at 90° of flexion between repair with internal bracing and the docking technique for the UCL. Study Design: Controlled laboratory study. Methods: Nine matched pairs of fresh-frozen cadaveric elbows were potted with the forearm in neutral rotation. The palmaris longus tendon graft was harvested, and the bone was sectioned 14 cm proximal and distal to the elbow joint. First, native UCL testing was performed at 90° of flexion with 0.5 N·m preload, followed by a 5 N·m valgus moment to the elbow in cycles of 1, 10, 100, and 1000 at 1 Hz. The specimens were then loaded to failure at a rate of 0.2 mm/s. Next, the elbows were randomly divided into matched pairs to undergo either UCL reconstruction with docking technique or UCL repair augmented with internal bracing. Last, these specimens underwent testing as aforementioned. Results: Load to failure, gapping, and valgus opening angle did not differ significantly between native ligaments that underwent reconstruction or repair with internal bracing, paired native ligaments and reconstructions, paired native ligaments and repairs augmented with internal bracing, or reconstructions and repairs augmented with internal bracing. Conclusion: UCL reconstruction with docking technique and repair augmented with internal bracing provides valgus stability to the medial elbow comparable to the native ligament at 90°. No significant differences were noted between docking reconstruction and repair techniques for load to failure, gapping, or valgus opening angle during cyclic loading at time zero. Clinical Relevance: Our results suggest that UCL repair with internal bracing has a similar biomechanical profile at the time of initial fixation compared with the docking technique of UCL reconstruction.
Reviewing the clinical significance of ‘fear of abandonment’ in borderline personality disorder
Authors: Palihawadana Venura , Broadbear Jillian H , Rao Sathya 
Published: November 2018

Objectives: To review and highlight the clinical significance of the symptom ‘fear of abandonment’ in borderline personality disorder (BPD). Methods: A systematic search of the literature was conducted using MEDLINE and PubMed, employing search terms including ‘fear of abandonment’, ‘borderline personality disorder’ and ‘rejection’. The most relevant English-language articles and books were selected for this review. Results: Fear of abandonment is widely recognised as a core symptom in BPD; a biopsychosocial explanation for the occurrence of the symptom is presented. While fear of abandonment may differ in its clinical presentation, it has a significant impact on therapeutic engagement, suicidal behaviour and non-suicidal self-injury, clinical management and prognosis. Most evidence based psychotherapies for BPD address the phenomenon of fear of abandonment; however, the lack of specifically targeted treatment interventions is disproportionate to its prominence and clinical significance. Conclusions: Given its defining role in BPD, we recommend fear of abandonment as an important subject of future research and a specific therapy target.
Healthcare-associated infections in intensive care units in Taiwan, South Korea, and Japan: recent trends based on national surveillance reports
Authors: Chiang Cho-Han , Pan Sung-Ching , Yang Tyan-Shin , Matsuda Keisuke , Kim Hong Bin , Choi Young Hwa , Hori Satoshi , Wang Jann-Tay , Sheng Wang-Huei , Chen Yee-Chun , Chang Feng-Yee , Chang Shan-Chwen 
Published: November 2018

Abstract
Background
Sustainable systematic interventions are important for infection prevention and control (IPC). Data from surveillance of healthcare-associated infections (HAI) provides feedback for implementation of IPC programs. To address the paucity of such data in Asia, we searched for national HAI surveillance and IPC programs in this region.

Methods
Data were analysed from open access national surveillance reports of three Asian countries: Taiwan, South Korea and Japan from 2008 to 2015. National IPC programs were identified.

Results
There were differences among the countries in surveillance protocols, hospital coverage rates, and national IPC policies and programs. Nevertheless, there was a 53.0% reduction in overall HAI over the 8-year period. This consisted of a decrease from 9.34 to 5.03 infections per 1000 patient-days in Taiwan, from 7.56 to 2.76 in Korea, and from 4.41 to 2.74 in Japan (Poisson regression, all p < 0.05). Across the three countries, Escherichia coli and Candida albicans were the major pathogens for urinary tract infection. Staphylococcus aureus, Acinetobacter baumannii and Enterococcus faecium were common bloodstream pathogens. For pneumonia, S. aureus, A. baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the predominant pathogens, with considerable country differences. There was a 64.6% decrease in the number of isolates of methicillin-resistant S. aureus, 38.4% decrease in carbapenem-resistant P. aeruginosa and 49.2% decrease in carbapenem-resistant A. baumannii (CRAB) in Taiwan (all p < 0.05), and similarly in Korea with the exception of CRAB (30.5 and 50.4% reduction, respectively, both p < 0.05).

Conclusion
We found a significant decrease in HAI across the three countries in association with sequential multifaceted interventions such as hand hygiene, care bundles, and antimicrobial stewardships. Further regional collaboration could be forged to develop joint strategies to prevent HAI.
Recent updates for biomaterials used in total hip arthroplasty
Authors: Hu Chang Yong , Yoon Taek-Rim 
Published: November 2018

Abstract

Background
Total hip arthroplasty (THA) is probably one of the most successful surgical interventions performed in medicine. Through the revolution of hip arthroplasty by principles of low friction arthroplasty was introduced by Sir John Charnley in 1960s. Thereafter, new bearing materials, fixation methods, and new designs has been improved. The main concern regarding failure of THA has been the biological response to particulate polyethylene debris generated by conventional metal on polyethylene bearing surfaces leading to osteolysis and aseptic loosening of the prosthesis. To resolve these problems, the materials of the modern THA were developed since then.

Methods
A literature search strategy was conducted using various search terms in PUBMED. The highest quality articles that met the inclusion criteria and best answered the topics of focus of this review were selected. Key search terms included ‘total hip arthroplasty’, ‘biomaterials’, ‘stainless steel’, ‘cobalt-chromium’, ‘titanium’, ‘polyethylene’, and ‘ceramic’.

Results
The initial search retrieved 6921 articles. Thirty-two articles were selected and used in the review.

Conclusion
This article introduces biomaterials used in THA and discusses various bearing materials in currentclinical use in THA as well as the newer biomaterials which may even further decrease wear and improve THA survivorship.
PHENOMENON OF A TRANSACTIONAL RENT IN AGRARIAN BUSINESS
Authors: Barkhatov Viktor , Bents Daria , Silova Elena , Kozlova Elena 
Published: November 2018

The phenomenon of a transactional rent in agrarian business in Russian regions is studied in the presented paperwork. The authors have found such phenomenon while they were analyzing contractual relations in regional agrarian branches. The research was supported by the state grant for young scientists in 2015-2016. The authors gathered a set of qualitative and quantitative results exploring the problem of agrarian contractual relations.The article’s purpose is to research the nature and forms of transactional rent, to develop a technique of the quantitative assessment of contractual relations’ efficiency, and to evaluate that level.Transactional rent is understood as the income gained by one subject (contractor) while there are reasons to suppose that this income shall belong to the other subject of a transaction (if the market is perfect). Transactional rent is a result of imperfection in the market mechanism. The authors consider inefficiency of the contractual relations as the main problem of agrarian market functioning. That is shown by the presence of high market barriers, discriminating conditions, multiplicity of subjects of a contractual chain, and lack of regulation of contractual relations in business practice. The high prices of food for customers, monopolization of markets at the level of retail trade, high level of shadow operations in this market and, respectively, imperfection of monitoring over food quality are the consequences of similar inefficiencies of contractual relations. Threat of food security and regional economic stability in general can arise as the result of a high level of transactional rent. The research is based on neoinstitutional methodology. Key methods of research are statistical and econometric as a method of economic modeling. For carrying out empirical research, authors have access to the paid database (FIRA PRO) where a huge number of statistical information on the agrarian market is available. For the analysis of the level of transactional rent in agrarian business, the authors use a technique with such indicators as effectiveness ratio of the contract relations and coefficient of opportunism. In the conducted statistical research, it is established that the greatest transactional rent is formed at the third element of an agrarian contract chain (wholesale trade).