bluuebunny/crossref_metadata_2025 huggingface dataset:
The efficacy of anti‐PD‐1 agents in acral and mucosal melanoma
Authors: Shoushtari Alexander N. , Munhoz Rodrigo R. , Kuk Deborah , Ott Patrick A. , Johnson Douglas B. , Tsai Katy K. , Rapisuwon Suthee , Eroglu Zeynep , Sullivan Ryan J. , Luke Jason J. , Gangadhar Tara C. , Salama April K. S. , Clark Varina , Burias Clare , Puzanov Igor , Atkins Michael B. , Algazi Alain P. , Ribas Antoni , Wolchok Jedd D. , Postow Michael A.
Published: August 2016

BACKGROUND

Therapeutic antibodies against programmed cell death receptor 1 (PD‐1) are considered front‐line therapy in metastatic melanoma. The efficacy of PD‐1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described.

METHODS

A multi‐institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator‐assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression‐free survival and overall survival were assessed using the Kaplan‐Meier method.

RESULTS

Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty‐one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%‐54%) in patients with acral melanoma and 23% (95% confidence interval, 10%‐40%) in those with mucosal melanoma. After a median follow‐up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression‐free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity.

CONCLUSIONS

Response rates to PD‐1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD‐1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354–3362. © 2016 American Cancer Society.
Semiotic open complex systems: Processes and behaviors
Authors: Usó‐Doménech Josep Lluis , Nescolarde‐Selva Josué Antonio , Lloret‐Climent Miguel , Fan Meng
Published: August 2016

An H‐system is a conceptual or semiotic model of reality formed in the mind of the subject. Understanding the behavior of the system means being able to infer causal relationships that explain this system to the Observer‐subject, and therefore having access to mechanisms to construct a mental or ontological mathematical model of the system under study. A process is a mechanism involving a series of successive operations between stimuli and responses. © 2016 Wiley Periodicals, Inc. Complexity 21: 388–396, 2016
Measuring logic complexity can guide pattern discovery in empirical systems
Authors: Gherardi Marco , Rotondo Pietro
Published: August 2016

A definition of complexity based on logic functions, which are widely used as compact descriptions of rules in diverse fields of contemporary science was explored. Detailed numerical analysis shows that (i) logic complexity is effective in discriminating between classes of functions commonly employed in modeling contexts; (ii) it extends the notion of canalization, used in the study of genetic regulation, to a more general and detailed measure; (iii) it is tightly linked to the resilience of a function's output to noise affecting its inputs. Its utility was demonstrated by measuring it in empirical data on gene regulation. Logic complexity is exceptionally low in these systems, and the asymmetry between “on” and “off” states in the data correlates with the complexity in a non‐null way. A model of random Boolean networks clarifies this trend and indicates a common hierarchical architecture in the three systems. © 2016 Wiley Periodicals, Inc. Complexity 21: 397–408, 2016
Synchronization of memristor‐based delayed BAM neural networks with fractional‐order derivatives
Authors: Rajivganthi Chinnathambi , Rihan Fathalla A. , Lakshmanan Shanmugam , Rakkiyappan Rajan , Muthukumar Palanisamy
Published: August 2016

This article deals with the problem of synchronization of fractional‐order memristor‐based BAM neural networks (FMBNNs) with time‐delay. We investigate the sufficient conditions for adaptive synchronization of FMBNNs with fractional‐order 0 < α < 1. The analysis is based on suitable Lyapunov functional, differential inclusions theory, and master‐slave synchronization setup. We extend the analysis to provide some useful criteria to ensure the finite‐time synchronization of FMBNNs with fractional‐order 1 < α < 2, using Mittag‐Leffler functions, Laplace transform, and linear feedback control techniques. Numerical simulations with two numerical examples are given to validate our theoretical results. Presence of time‐delay and fractional‐order in the model shows interesting dynamics. © 2016 Wiley Periodicals, Inc. Complexity 21: 412–426, 2016
Isolation and Assessment of Single Long‐Term Reconstituting Hematopoietic Stem Cells from Adult Mouse Bone Marrow
Authors: Kent David G. , Dykstra Brad J. , Eaves Connie J.
Published: August 2016

Hematopoietic stem cells with long‐term repopulating activity can now be routinely obtained at purities of 40% to 50% from suspensions of adult mouse bone marrow. Here we describe robust protocols for both their isolation as CD45+EPCR+CD150+CD48− (ESLAM) cells using multiparameter cell sorting and for tracking their clonal growth and differentiation activity in irradiated mice transplanted with single ESLAM cells. The simplicity of these procedures makes them attractive for characterizing the molecular and biological properties of individual hematopoietic stem cells with unprecedented power and precision. © 2016 by John Wiley & Sons, Inc.
Derivation of Transgene‐Free Induced Pluripotent Stem Cells from a Single Drop of Blood
Authors: Chen Hong Yu , Tan Hong‐Kee , Loh Yuin‐Han
Published: August 2016

Human‐induced pluripotent stem cells (hiPSCs) have great potential for future use in therapeutic regenerative medicine. Based on the current protocol for deriving hiPSCs, invasive procedures such as skin biopsies and venipuncture are required for obtaining donor samples. Herein, we present a detailed protocol for deriving hiPSCs from human finger‐prick (FP) blood. In this method, the transgene‐free hiPSCs can be easily generated from only 10 µl of FP blood. The finger‐pricked iPSCs (FPiPSCs) show all the pluripotency markers and can be easily differentiated into various cell lineages. The time required for deriving the FPiPSCs is relatively short—10 to 15 days for FP blood expansion and 20 to 30 days for reprogramming. This method can be easily adapted for setting up a large scale iPSC bank as it requires only 10 µl of the donor FP blood, which can be easily collected. © 2016 by John Wiley & Sons, Inc.
Small‐Molecule‐Directed Hepatocyte‐Like Cell Differentiation of Human Pluripotent Stem Cells
Authors: Mathapati Santosh , Siller Richard , Impellizzeri Agata A.R. , Lycke Max , Vegheim Karianne , Almaas Runar , Sullivan Gareth J.
Published: August 2016

Hepatocyte‐like cells (HLCs) generated in vitro from human pluripotent stem cells (hPSCs) provide an invaluable resource for basic research, regenerative medicine, drug screening, toxicology, and modeling of liver disease and development. This unit describes a small‐molecule‐driven protocol for in vitro differentiation of hPSCs into HLCs without the use of growth factors. hPSCs are coaxed through a developmentally relevant route via the primitive streak to definitive endoderm (DE) using the small molecule CHIR99021 (a Wnt agonist), replacing the conventional growth factors Wnt3A and activin A. The small‐molecule‐derived DE is then differentiated to hepatoblast‐like cells in the presence of dimethyl sulfoxide. The resulting hepatoblasts are then differentiated to HLCs with N‐hexanoic‐Tyr, Ile‐6 aminohexanoic amide (Dihexa, a hepatocyte growth factor agonist) and dexamethasone. The protocol provides an efficient and reproducible procedure for differentiation of hPSCs into HLCs utilizing small molecules. © 2016 by John Wiley & Sons, Inc.
Health Technology Assessment in the Context of Adaptive Pathways for Medicines in Europe: Challenges and Opportunities
Authors: Bouvy JC , Jonsson P , Longson C , Crabb N , Garner S
Published: August 2016

Adaptive pathways for medicines have gained momentum and, in Europe, adaptive pathways have recently been introduced into the European Medicines Agency (EMA) processes after a successful 2‐year pilot. Although the concept, as initially proposed, contained several elements that would have required regulatory reforms, the adaptive pathways program has developed a more pragmatic scope (Box 1). In this article, we explore the main challenges and opportunities adaptive pathways pose from a European health technology assessment (HTA) perspective.
Multifunctional Single‐Site Catalysts for Alkoxycarbonylation of Terminal Alkynes
Authors: Chen Xingkun , Zhu Hejun , Wang Wenlong , Du Hong , Wang Tao , Yan Li , Hu Xiangping , Ding Yunjie
Published: August 2016

A multifunctional copolymer (PyPPh2–SO3H@porous organic polymers, POPs) was prepared by combining acidic groups and heterogeneous P,N ligands through the copolymerization of vinyl‐functionalized 2‐pyridyldiphenylphosphine (2‐PyPPh2) and p‐styrene sulfonic acid under solvothermal conditions. The morphology and chemical structure of the copolymer were evaluated using a series of characterization techniques. Compared with traditional homogeneous Pd(OAc)2/2‐PyPPh2/ p‐toluenesulfonic acid catalyst, the copolymer supported palladium catalyst (Pd–PyPPh2–SO3H@POPs) exhibited higher activity for alkoxycarbonylation of terminal alkynes under the same conditions. This phenomenon could be attributed to the synergistic effect between the single‐site Pd centers, 2‐PyPPh2 ligands, and SO3H groups, the outstanding swelling properties as well as the high enrichment of the reactant concentration by the porous catalyst. In addition, the catalyst could be reused at least 4 times without any apparent loss of activity. The excellent catalytic reactivity and good recycling properties make it an attractive catalyst for industrial applications. This work paves the way for advanced multifunctional porous organic polymers as a new type of platform for heterogeneous catalysis in the future.
Low‐Pressure Vapor‐Assisted Solution Process for Thiocyanate‐Based Pseudohalide Perovskite Solar Cells
Authors: Chiang Yu‐Hsien , Cheng Hsin‐Min , Li Ming‐Hsien , Guo Tzung‐Fang , Chen Peter
Published: August 2016

In this report, we fabricated thiocyanate‐based perovskite solar cells with low‐pressure vapor‐assisted solution process (LP‐VASP) method. Photovoltaic performances are evaluated with detailed materials characterizations. Scanning electron microscopy images show that SCN‐based perovskite films fabricated using LP‐VASP have long‐range uniform morphology and large grain sizes up to 1 μm. The XRD and Raman spectra were employed to observe the characteristic peaks for both SCN‐based and pure CH3NH3PbI3 perovskite. We observed that the Pb(SCN)2 film transformed to PbI2 before the formation of perovskite film. X‐ray photoemission spectra (XPS) show that only a small amount of S remained in the film. Using LP‐VASP method, we fabricated SCN‐based perovskite solar cells and achieved a power conversion efficiency of 12.72 %. It is worth noting that the price of Pb(SCN)2 is only 4 % of PbI2. These results demonstrate that pseudo‐halide perovskites are promising materials for fabricating low‐cost perovskite solar cells.
Development of an Iridium‐Based Catalyst for High‐Pressure Evolution of Hydrogen from Formic Acid
Authors: Iguchi Masayuki , Himeda Yuichiro , Manaka Yuichi , Kawanami Hajime
Published: August 2016

A highly efficient and recyclable Ir catalyst bearing a 4,7‐dihydroxy‐1,10‐phenanthroline ligand was developed for the evolution of high‐pressure H2 gas (>100 MPa), and a large amount of atmospheric pressure H2 gas (>120 L), over a long term (3.5 months). The reaction proceeds through the dehydrogenation of highly concentrated aqueous formic acid (FA, 40 vol %, 10 mol L−1) at 80 °C using 1 μmol of catalyst, and a turnover number (TON) of 5 000 000 was calculated. The Ir catalyst precipitated after the reaction owing to its pH‐dependent solubility in water, and 94 mol % was recovered by filtration. Thus, it can be treated and recycled like a heterogeneous catalyst. The catalyst was successfully recycled over 10 times for highpressure FA dehydrogenation at 22 MPa without any treatment or purification.
Ni Nanoparticles Supported on Cage‐Type Mesoporous Silica for CO2 Hydrogenation with High CH4 Selectivity
Authors: Budi Canggih Setya , Wu Hung‐Chi , Chen Ching‐Shiun , Saikia Diganta , Kao Hsien‐Ming
Published: August 2016

Ni nanoparticles (around 4 nm diameter) were successfully supported on cage‐type mesoporous silica SBA‐16 (denoted as Ni@SBA‐16) via wet impregnation at pH 9, followed by the calcination‐reduction process. The Ni@SBA‐16 catalyst with a very high Ni loading amount (22.9 wt %) exhibited exceptionally high CH4 selectivity for CO2 hydrogenation. At a nearly identical loading amount, the Ni@SBA‐16 catalysts with smaller particle size of Ni NPs surprisingly exhibited a higher catalytic activity of CO2 hydrogenation and also led to a higher selectivity on CH4 formation than the Ni@SiO2 catalysts. This enhanced activity of the Ni@SBA‐16 catalyst is suggested to be an accumulative result of the advantageous structural properties of the support SBA‐16 and the well confined Ni NPs within the support; both induced a favorable reaction pathway for high selectivity of CH4 in CO2 hydrogenation.
ESIM‐OFDM‐based transceiver design of a visible light communication system
Authors: Ahsan M. , Asif H. M.
Published: August 2016

Visible light communication (VLC) system has been becoming a potential technology for short‐range data communication over wireless optical channel. In this paper, a real‐time state‐of‐the‐art VLC system prototype is implemented mainly based on enhanced subcarrier index modulation orthogonal frequency division multiplexing (ESIM‐OFDM) modulation scheme. The prototype has been designed using NI cDAQ hardware equipment programmed in matlab/labview. In other words, the developed VLC transceiver labview model is loaded into cDAQ to perform real‐time transmission of text data. The design mainly comprises VLC transmitter, VLC receiver, interfacing NI cDAQ with labview, and implementation of ESIM‐OFDM. It should be noted that the direct output of ESIM‐OFDM is not suitable to drive VLC transmitter circuit; therefore, the key contribution lies in making use of sigma–delta modulator to modify ESIM‐OFDM output to produce constant current signal which in turn could drive VLC transmitter. The second main contribution of the work targets the luminous properties of the designed transmitter that have experimentally been characterized using a LUX meter. Finally, the last contribution of the work is the simulation carried out to analyze the performance of the proposed system with other existing VLC modulation schemes. Copyright © 2016 John Wiley & Sons, Ltd.
Pou4f2‐GFP knock‐in mouse line: A model for studying retinal ganglion cell development
Authors: Zheng Dongwang , Yang Xiaoyan , Sheng Donglai , Yu Dongliang , Liang Guoqing , Guo Luming , Xu Mei , Hu Xu , He Daqiang , Yang Yang , Wang Yuying
Published: August 2016

Pou4f2 acts as a key node in the comprehensive and step‐wise gene regulatory network (GRN) and regulates the development of retinal ganglion cells (RGCs). Accordingly, deletion of Pou4f2 results in RGC axon defects and apoptosis. To investigate the GRN involved in RGC regeneration, we generated a mouse line with a POU4F2‐green fluorescent protein (GFP) fusion protein expressed in RGCs. Co‐localization of POU4F2 and GFP in the retina and brain of Pou4f2‐GFP/+ heterozygote mice was confirmed using immunofluorescence analysis. Compared with those in wild‐type mice, the expression patterns of POU4F2 and POU4F1 and the co‐expression patterns of ISL1 and POU4F2 were unaffected in Pou4f2‐GFP/GFP homozygote mice. Moreover, the quantification of RGCs showed no significant difference between Pou4f2‐GFP/GFP homozygote and wild‐type mice. These results demonstrated that the development of RGCs in Pou4f2‐GFP/GFP homozygote mice was the same as in wild‐type mice. Thus, the present Pou4f2‐GFP knock‐in mouse line is a useful tool for further studies on the differentiation and regeneration of RGCs.
The mismatch between current statistical practice and doctoral training in ecology
Authors: Touchon Justin C. , McCoy Michael W.
Published: August 2016

Ecologists are studying increasingly complex and important issues such as climate change and ecosystem services. These topics often involve large data sets and the application of complicated quantitative models. We evaluated changes in statistics used by ecologists by searching nearly 20,000 published articles in ecology from 1990 to 2013. We found that there has been a rise in sophisticated and computationally intensive statistical techniques such as mixed effects models and Bayesian statistics and a decline in reliance on approaches such as ANOVA or t tests. Similarly, ecologists have shifted away from software such as SAS and SPSS to the open source program R. We also searched the published curricula and syllabi of 154 doctoral programs in the United States and found that despite obvious changes in the statistical practices of ecologists, more than one‐third of doctoral programs showed no record of required or optional statistics classes. Approximately one‐quarter of programs did require a statistics course, but most of those did not cover contemporary statistical philosophy or advanced techniques. Only one‐third of doctoral programs surveyed even listed an optional course that teaches some aspect of contemporary statistics. We call for graduate programs to lead the charge in improving training of future ecologists with skills needed to address and understand the ecological challenges facing humanity.
Aminochlorination of Alkenes with CFBSA
Authors: Pu Xiao‐Qiu , Zhao Hai‐Yong , Lu Ze‐Hai , He Xiao‐Peng , Yang Xian‐Jin
Published: August 2016

A novel catalyst‐free aminochlorination of alkenes was developed by the direct addition of alkenes to N‐chloro‐N‐fluorobenzenesulfonamide (CFBSA). The reaction produces 2‐chloro‐3‐fluoramino and 3‐chloro‐2‐fluoroamino adducts in 1,2‐dichloroethane under reflux and dichloromethane at room temperature, respectively, in a regioselective manner. The electronic and steric effects of the fluorine atom of CFBSA have proven to be crucial for the reactivity and regioselectivity. A variety of transformations have been achieved to form 2‐chloroenamines, chloroamines, aziridines and N‐phenylbenzenesulfonamides under different conditions. Notably, the N–F bond in the adducts formed could be a useful handle for further transformations to useful compounds in organic synthesis.
Palladium‐Catalysed Carbo‐ and Hydroamination of Allenyl Ethers and Aminoallenes: Available Entry to Nitrogen‐Containing Benzo‐Fused Rings
Authors: Gazzola Silvia , Beccalli Egle M. , Bernasconi Alice , Borelli Tea , Broggini Gianluigi , Mazza Alberto
Published: August 2016

The Pd‐catalysed reactions of allenyl ethers and allenylamines derived from commercially available o‐aminophenols and o‐nitroaniline have been studied. Using a wide variety of aryl‐ and heteroaryl halides, carboamination of the allenes led to sequential C–C and C–N bond formation. Both carbo‐ and hydroamination processes resulted in the formation of nitrogen‐containing benzo‐fused rings. In the case of aminoallenes arising from o‐phenylenediamine, the regioselectivity of the cyclization step was strongly dependent on the protecting group tethered to the nitrogen atoms, allowing the formation of five‐ and seven‐membered rings.
Save time and money by implementing secure electronic transcript requests
Authors: Sutton Halley
Published: August 2016

PHOENIX — Moving transcript requests from paper forms to an electronic format can improve the transcript fulfillment experience for your staff members and your students. With electronic ordering, you can provide quick turnaround and 24‐hour access to transcript ordering. But making the change can seem like a daunting task for any office.
Follow 3 key tips for engaging your direct reports
Authors: Jarvis Kimberly , Munin Art
Published: August 2016

Staff members qualify as the strongest resource for helping enrollment management units to advance their mission and support their students. And that's why supporting, developing, and engaging the individuals we supervise are central components of the work we do.
Seismic analysis of a curved bridge considering deck‐abutment pounding interaction: an analytical investigation on the post‐impact response
Authors: Banerjee Arnab , Chanda Avishek , Das Raj
Published: August 2016

Horizontal curved bridges are very common at intersections and at the changing angle of bridge alignment. Almost in every previous earthquake report, it can be seen that the columns of a curved segment experience torsional damage, and the curved decks are unseated from the abutment support. The main reason behind that phenomenon is the in‐plane deck rotation which results because of the complex dynamic coupling between two longitudinal directional vibrations. The curved decks are susceptible to deck rotation because in a curved segment, the centre of mass and the centre of stiffness generally lie outside the bridge deck and are not located at the same point. The pounding with the abutment often increases the rotational tendency of the deck. In this paper, a classical mechanics‐based approach is adopted to analytically estimate the deck rotation potential of curved bridge considering the deck‐abutment pounding interaction. The deck‐abutment pounding is modelled using non‐smooth techniques considering the Newton's impact law in the normal and Coulomb's friction in the tangential direction. Within the scope of this paper, a parametric study is performed to get the ideal combination of the column and bent arrangement and the gap distance. Copyright © 2016 John Wiley & Sons, Ltd.
A modified Galerkin/finite element method for the numerical solution of the Serre‐Green‐Naghdi system
Authors: Mitsotakis D. , Synolakis C. , McGuinness M.
Published: August 2016

A new modified Galerkin/finite element method is proposed for the numerical solution of the fully nonlinear shallow water wave equations. The new numerical method allows the use of low‐order Lagrange finite element spaces, despite the fact that the system contains third order spatial partial derivatives for the depth averaged velocity of the fluid. After studying the efficacy and the conservation properties of the new numerical method, we proceed with the validation of the new numerical model and boundary conditions by comparing the numerical solutions with laboratory experiments and with available theoretical asymptotic results. Copyright © 2016 John Wiley & Sons, Ltd.
A W‐test collapsing method for rare‐variant association testing in exome sequencing data
Authors: Sun Rui , Weng Haoyi , Hu Inchi , Guo Junfeng , Wu William K. K. , Zee Benny Chung‐Ying , Wang Maggie Haitian
Published: August 2016

Advancement in sequencing technology enables the study of association between complex disorder phenotypes and single‐nucleotide polymorphisms with rare mutations. However, the rare genetic variant has extremely small variance and impairs testing power of traditional statistical methods. We introduce a W‐test collapsing method to evaluate rare‐variant association by measuring the distributional differences between cases and controls through combined log of odds ratio within a genomic region. The method is model‐free and inherits chi‐squared distribution with degrees of freedom estimated from bootstrapped samples of the data, and allows for fast and accurate P‐value calculation without the need of permutations. The proposed method is compared with the Weighted‐Sum Statistic and Sequence Kernel Association Test on simulation datasets, and showed good performances and significantly faster computing speed. In the application of real next‐generation sequencing dataset of hypertensive disorder, it identified genes of interesting biological functions associated to metabolism disorder and inflammation, including the MACROD1, NLRP7, AGK, PAK6, and APBB1. The proposed method offers an efficient and effective way for testing rare genetic variants in whole exome sequencing datasets.
Exposure to human immunodeficiency virus/hepatitis C virus in hepatic and stellate cell lines reveals cooperative profibrotic transcriptional activation between viruses and cell types
Authors: Salloum Shadi , Holmes Jacinta A. , Jindal Rohit , Bale Shyam S. , Brisac Cynthia , Alatrakchi Nadia , Lidofsky Anna , Kruger Annie J. , Fusco Dahlene N. , Luther Jay , Schaefer Esperance A. , Lin Wenyu , Yarmush Martin L. , Chung Raymond T.
Published: August 2016

Human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection accelerates progressive liver fibrosis; however, the mechanisms remain poorly understood. HCV and HIV independently induce profibrogenic markers transforming growth factor beta‐1 (TGFβ1) (mediated by reactive oxygen species [ROS]) and nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NFκB) in hepatocytes and hepatic stellate cells in monoculture; however, they do not account for cellular crosstalk that naturally occurs. We created an in vitro coculture model and investigated the contributions of HIV and HCV to hepatic fibrogenesis. Green fluorescent protein reporter cell lines driven by functional ROS (antioxidant response elements), NFκB, and mothers against decapentaplegic homolog 3 (SMAD3) promoters were created in Huh7.5.1 and LX2 cells, using a transwell to generate cocultures. Reporter cell lines were exposed to HIV, HCV, or HIV/HCV. Activation of the 3 pathways was measured and compared according to infection status. Extracellular matrix products (collagen type 1 alpha 1 (CoL1A1) and tissue inhibitor of metalloproteinase 1 (TIMP1)) were also measured. Both HCV and HIV independently activated TGFβ1 signaling through ROS (antioxidant response elements), NFκB, and SMAD3 in both cell lines in coculture. Activation of these profibrotic pathways was additive following HIV/HCV coexposure. This was confirmed when examining CoL1A1 and TIMP1, where messenger RNA and protein levels were significantly higher in LX2 cells in coculture following HIV/HCV coexposure compared with either virus alone. In addition, expression of these profibrotic genes was significantly higher in the coculture model compared to either cell type in monoculture, suggesting an interaction and feedback mechanism between Huh7.5.1 and LX2 cells. Conclusion: HIV accentuates an HCV‐driven profibrogenic program in hepatocyte and hepatic stellate cell lines through ROS, NFκB, and TGFβ1 up‐regulation; coculture of hepatocyte and hepatic stellate cell lines significantly increased expression of CoL1A1 and TIMP1; and our novel coculture reporter cell model represents an efficient and more authentic system for studying transcriptional fibrosis responses and may provide important insights into hepatic fibrosis. (Hepatology 2016;64:1951‐1968).
Broad neutralization of hepatitis C virus‐resistant variants by Civacir hepatitis C immunoglobulin
Authors: Tawar Rajiv G. , Heydmann Laura , Bach Charlotte , Schüttrumpf Jörg , Chavan Shailesh , King Barnabas J. , McClure C. Patrick , Ball Jonathan K. , Pessaux Patrick , Habersetzer François , Bartenschlager Ralf , Zeisel Mirjam B. , Baumert Thomas F.
Published: August 2016

Hepatitis C virus (HCV)‐induced end‐stage liver disease is the major indication for liver transplantation (LT). However, reinfection of the liver graft is still common, especially in patients with detectable viral load at the time of LT. Limited data are available on direct‐acting antivirals in the transplant setting for prevention of graft infection. The human hepatitis C immunoglobulin (HCIG) Civacir is an investigational drug that is currently being developed in an ongoing phase 3 clinical trial assessing its safety and efficacy at preventing HCV recurrence after liver transplantation (LT) in the United States. Using well‐characterized patient‐derived HCV variants selected during LT, we studied the molecular mechanism of action of Civacir. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles (HCVpp) and cell culture‐derived HCV (HCVcc) containing patient‐derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after LT. The human hepatitis C immune globulin Civacir is an investigational drug that is currently being developed in an ongoing phase 3 clinical trial assessing safety and efficacy to prevent HCV recurrence after LT in the United States. Using well‐characterized patient‐derived HCV variants selected during LT, we studied the molecular mechanism of action of Civacir. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles and cell culture‐derived HCV containing patient‐derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after liver transplantation. Additionally, we studied neutralization of different HCV genotypes and of direct‐acting antiviral‐resistant viruses. Our results indicate that Civacir potently, broadly, and dose‐dependently neutralizes all tested patient variants in HCV pseudoparticles and cell culture‐derived HCV assays including variants displaying resistance to host neutralizing antibodies and antiviral monoclonal antibodies. The half‐maximal inhibitory concentrations were independent of the phenotype of the viral variant, indicating that virus neutralization by Civacir is not affected by viral selection. Furthermore, Civacir is equally active against tested direct‐acting antiviral‐resistant HCV isolates in cell culture. Conclusion: Collectively, these results demonstrate broad neutralizing activity of Civacir against resistant viruses, likely due to synergy between anti‐HCV antibodies derived from different plasma donors, and support its further clinical development for prevention of liver graft infection. (Hepatology 2016;64:1495‐1506)
First international external quality assessment for hepatitis delta virus RNA quantification in plasma
Authors: Le Gal Frédéric , Brichler Ségolène , Sahli Roland , Chevret Sylvie , Gordien Emmanuel
Published: August 2016

Infection by the hepatitis delta virus (HDV), a satellite of the hepatitis B virus (HBV), increases viral liver disease severity. Its diagnosis is thus vital for HBV‐infected patients. HDV‐RNA load (HDVL) should be assessed and monitored in plasma using real‐time reverse‐transcriptase polymerase chain reaction assays. Taking advantage of the recently‐developed World Health Organization (WHO) HDV international standard (WHO‐HDV‐IS), the first international external quality control for HDVL quantification was performed. Two panels of samples were sent to 28 laboratories in 17 countries worldwide. Panel A comprised 20 clinical samples of various genotypes (1, 2, and 5‐8) and viral loads, including two negative controls. Panel B, composed of dilutions of the WHO‐HDV‐IS, allowed the conversion of results from copies/mL into IU/mL for HDVL standardization and interlaboratory comparisons. Comprehensive analysis revealed a very high heterogeneity of assay characteristics, including their technical steps and technologies. Thirteen labs (46.3%) properly quantified all 18 positive samples; 16 (57.1%) failed to detect one to up to 10 samples, and several others underestimated (>3 log IU/mL) HDVL of African genotype strains (1 and 5‐8). Discrepancies were mainly attributed to either primers or probe mismatches related to the high genetic variability of HDV and, possibly, to the complex secondary structure of the target genomic RNA. The labs were grouped in four clusters by the statistical analysis of their performances. The best clusters comprised the 17 labs that obtained the expected HDVL values, including five that otherwise failed to quantify one or two samples. Conclusion: The results of this international quality‐control study underline the urgent need to improve methods used to monitor HDV viremia and will be instrumental in achieving that goal. (Hepatology 2016;64:1483‐1494)
Angiopoietin‐like protein 1 antagonizes MET receptor activity to repress sorafenib resistance and cancer stemness in hepatocellular carcinoma
Authors: Chen Hsin‐An , Kuo Tsang‐Chih , Tseng Chi‐Feng , Ma Jui‐Ti , Yang Shu‐Ting , Yen Chia‐Jui , Yang Ching‐Yao , Sung Shian‐Ying , Su Jen‐Liang
Published: August 2016

Angiopoietin‐like protein 1 (ANGPTL1) has been shown to act as a tumor suppressor by inhibiting angiogenesis, cancer invasion, and metastasis. However, little is known about the effects of ANGPTL1 on sorafenib resistance and cancer stem cell properties in hepatocellular carcinoma (HCC) and the mechanism underlying these effects. Here, we show that ANGPTL1 expression positively correlates with sorafenib sensitivity in HCC cells and human HCC tissues. ANGPTL1 significantly decreases epithelial‐mesenchymal transition (EMT)‐driven sorafenib resistance, cancer stemness, and tumor growth of HCC cells by repressing Slug expression. ANGPTL1 directly interacts with and inactivates MET receptor, which contributes to Slug suppression through inhibition of the extracellular receptor kinase/protein kinase B (ERK/AKT)‐dependent early growth response protein 1 (Egr‐1) pathway. ANGPTL1 expression inversely correlates with Slug expression, poor sorafenib responsiveness, and poor clinical outcomes in HCC patients. Conclusion: ANGPTL1 inhibits sorafenib resistance and cancer stemness in HCC cells by repressing EMT through inhibition of the MET receptor−AKT/ERK−Egr‐1−Slug signaling cascade. ANGPTL1 may serve as a novel MET receptor inhibitor for advanced HCC therapy. (Hepatology 2016;64:1637‐1651)
Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice
Authors: Okabe Hirohisa , Yang Jing , Sylakowski Kyle , Yovchev Mladen , Miyagawa Yoshitaka , Nagarajan Shanmugam , Chikina Maria , Thompson Michael , Oertel Michael , Baba Hideo , Monga Satdarshan P , Nejak‐Bowen Kari Nichole
Published: August 2016

Hepatic repair is directed chiefly by the proliferation of resident mature epithelial cells. Furthermore, if predominant injury is to cholangiocytes, the hepatocytes can transdifferentiate to cholangiocytes to assist in the repair and vice versa, as shown by various fate‐tracing studies. However, the molecular bases of reprogramming remain elusive. Using two models of biliary injury where repair occurs through cholangiocyte proliferation and hepatocyte transdifferentiation to cholangiocytes, we identify an important role of Wnt signaling. First we identify up‐regulation of specific Wnt proteins in the cholangiocytes. Next, using conditional knockouts of Wntless and Wnt coreceptors low‐density lipoprotein‐related protein 5/6, transgenic mice expressing stable β‐catenin, and in vitro studies, we show a role of Wnt signaling through β‐catenin in hepatocyte to biliary transdifferentiation. Last, we show that specific Wnts regulate cholangiocyte proliferation, but in a β‐catenin‐independent manner. Conclusion: Wnt signaling regulates hepatobiliary repair after cholestatic injury in both β‐catenin‐dependent and ‐independent manners. (Hepatology 2016;64:1652‐1666)
N‐myc downstream‐regulated gene 2 inhibits human cholangiocarcinoma progression and is regulated by leukemia inhibitory factor/MicroRNA‐181c negative feedback pathway
Authors: Wang Jiabei , Xie Changming , Pan Shangha , Liang Yingjian , Han Jihua , Lan Yaliang , Sun Jing , Li Keyu , Sun Boshi , Yang Guangchao , Shi Huawen , Li Yuejin , Song Ruipeng , Liu Xirui , Zhu Mingxi , Yin Dalong , Wang Huanlai , Song Xuan , Lu Zhaoyang , Jiang Hongchi , Zheng Tongsen , Liu Lianxin
Published: August 2016

Increasing evidence supports a role for N‐myc downstream‐regulated gene 2 (NDRG2) deregulation in tumorigenesis. We investigated the roles and mechanisms of NDRG2 in human cholangiocarcinoma (CCA) progression. In the present study, expression of NDRG2, microRNA (miR)‐181c and leukemia inhibitory factor (LIF) in human CCA and adjacent nontumor tissues were examined. The effects of NDRG2 on CCA tumor growth and metastasis were determined both in vivo and in vitro. The role of the NDRG2/LIF/miR‐181c signaling pathway in cholangiocarcinogenesis and metastasis were investigated both in vivo and in vitro. The results showed that human CCA tissues exhibited decreased levels of NDRG2 and increased levels of miR‐181c and LIF compared with nontumor tissues. NDRG2 could inhibit CCA cell proliferation, chemoresistance, and metastasis both in vitro and in vivo. We found that NDRG2 is a target gene of miR‐181c, and the down‐regulation of NDRG2 was attributed to miR‐181c overexpression in CCA. Furthermore, miR‐181c can be activated by LIF treatment, whereas NDRG2 could inhibit LIF transcription through disrupting the binding between Smad, small mothers against decapentaplegic complex and LIF promoter. Down‐regulation of NDRG2 and overexpression of miR‐181c or LIF are significantly associated with a poorer overall survival (OS) in CCA patients. Finally, we found that a combination of NDRG2, miR‐181c, and LIF expression is a strong predictor of prognosis in CCA patients. Conclusion: These results establish the counteraction between NDRG2 and LIF/miR‐181c as a key mechanism that regulates cholangiocarcinogenesis and metastasis. Our results elucidated a novel pathway in NDRG2‐mediated inhibition of cholangiocarcinogenesis and metastasis and suggest new therapeutic targets, including NDRG2, LIF, miR‐181c, and transforming growth factor beta, in CCA prevention and treatment. (Hepatology 2016;64:1606‐1622)
Evaluation of proton pump inhibitor use on treatment outcomes with ledipasvir and sofosbuvir in a real‐world cohort study
Authors: Tapper Elliot B. , Bacon Bruce R. , Curry Michael P. , Dieterich Douglas T. , Flamm Steven L. , Guest Lauren E. , Kowdley Kris V. , Lee Yoori , Tsai Naoky C. , Younossi Zobair M. , Afdhal Nezam H.
Published: August 2016

Many patients with chronic hepatitis C virus (HCV) are on prolonged proton‐pump inhibitor (PPI) therapy and wish to remain on PPI therapy once treatment for HCV starts. A preliminary report recently suggested decrease rates of sustained virological response (SVR) for patients taking concomitant PPI and ledipasvir/sofosbuvir (LDV/SOF). We sought to determine the effect of PPI use on the rate of SVR in a real‐world cohort of 1,979 patients with chronic HCV treated with LDV/SOF. We collected clinical data and pharmacy dispensing records on patients taking 8, 12, or 24 weeks of LDV/SOF ± ribavirin (RBV). The primary outcome was sustained virological response at 12 weeks after treatment completion (SVR12) in a per‐protocol analysis in order to determine the effect of PPI use adjusted for confounders. Statistical adjustment was performed in propensity‐matched analysis. Among treatment completers, SVR12 was achieved in 441 (97.1%) of PPI recipients compared with 1,497 (98.2%) in PPI nonrecipients (P = 0.19). Neither low‐ nor high‐dose PPI was associated with decreased SVR, although patients taking twice‐daily PPI achieved a lower SVR12 rate (91.2%; 95% confidence interval [CI], 77.0‐97.0; P = 0.046). After propensity matching for PPI use, there were no significant associations between SVR12 and any dose or frequency of PPI use. However, in a sensitivity analysis focusing on patients with cirrhosis, twice‐daily PPI use was associated with lower odds ratio for SVR12 (0.11; 95% CI, 0.02‐0.59). Conclusion: These data from a cohort of real‐world patients receiving hepatitis C antibody therapy with LDF/SOF ± RBV support the prescription labeling suggesting that patients take no more than low‐dose (20‐mg omeprazole equivalents) PPI daily. (Hepatology 2016;64:1893‐1899).
Winter Turf Growing Season Elongation Characteristics of a Thermosyphon Unit that Uses a Shallow Geothermal Source
Authors: Zhou Feng , Ma Guoyuan , Zhang Xiaolin
Published: August 2016

Low temperature stress is an important factor for turf growth in the northern high‐latitude environment. A thermosyphon temperature controlling unit with a shallow geothermal source was proposed by analyzing present techniques to prolong the turf growing season in winter. Thermosyphon unit prototypes were developed and tested in a water park. The relations between ambient temperature, depth, material, structure, underground temperature, and root temperature were studied experimentally. The thermosyphon unit performance was analyzed. Results indicate that underground and root temperatures remain almost constant with an hourly ambient temperature. The root temperature remains steady due to the thermosyphon unit application. The underground temperature increases with the depth increase, and the increment is at most 1 °C. The root temperature of a copper thermosyphon unit is higher than that of a steel thermosyphon unit, and the temperature difference can reach 2 °C. The root temperature of a type I thermosyphon unit is higher than that of a type II, and the temperature increase is less than 1 °C. The root temperature variation due to the thermosyphon material is smaller with the increase in depth.
Plasmin Prevents Dystrophic Calcification After Muscle Injury
Authors: Mignemi Nicholas A , Yuasa Masato , Baker Courtney E , Moore Stephanie N , Ihejirika Rivka C , Oelsner William K , Wallace Christopher S , Yoshii Toshitaka , Okawa Atsushi , Revenko Alexey S , MacLeod A Robert , Bhattacharjee Gourab , Barnett Joey V , Schwartz Herbert S , Degen Jay L , Flick Matthew J , Cates Justin M , Schoenecker Jonathan G
Published: August 2016

Extensive or persistent calcium phosphate deposition within soft tissues after severe traumatic injury or major orthopedic surgery can result in pain and loss of joint function. The pathophysiology of soft tissue calcification, including dystrophic calcification and heterotopic ossification (HO), is poorly understood; consequently, current treatments are suboptimal. Here, we show that plasmin protease activity prevents dystrophic calcification within injured skeletal muscle independent of its canonical fibrinolytic function. After muscle injury, dystrophic calcifications either can be resorbed during the process of tissue healing, persist, or become organized into mature bone (HO). Without sufficient plasmin activity, dystrophic calcifications persist after muscle injury and are sufficient to induce HO. Downregulating the primary inhibitor of plasmin (α2-antiplasmin) or treating with pyrophosphate analogues prevents dystrophic calcification and subsequent HO in vivo. Because plasmin also supports bone homeostasis and fracture repair, increasing plasmin activity represents the first pharmacologic strategy to prevent soft tissue calcification without adversely affecting systemic bone physiology or concurrent muscle and bone regeneration. © 2016 American Society for Bone and Mineral Research.
Global Mental Health: An Introduction
Authors: Verdeli Helen
Published: August 2016

In this introductory paper to the Global Mental Health volume, the inception and development of the filed in the last 15 years is reviewed, placing an emphasis on a series of pivotal turning points. A critical delivery strategy, task‐shifting is briefly described, as well as the fundamental principles of Interpersonal Psychotherapy (IPT), an evidence‐based psychotherapy being adapted and delivered in low‐resource settings. Nine case studies by the trainees, supervisors, or local providers from India, the United States, Haiti, Israel, Colombia, and Kenya, presented in this volume, illustrate the prevention and treatment processes or in‐depth assessment of “psychological distress” as locally defined and expressed.
Population Pharmacokinetics and Pharmacodynamics of Meropenem in Nonobese, Obese, and Morbidly Obese Patients
Authors: Chung Eun Kyoung , Cheatham S. Christian , Fleming Megan R. , Healy Daniel P. , Kays Michael B.
Published: August 2016

The study objective was to evaluate meropenem population pharmacokinetics and pharmacodynamics in nonobese, obese, and morbidly obese patients. Forty adult patients—11 nonobese (body mass index [BMI] < 30 kg/m2), 9 obese (30 kg/m2 ≤ BMI < 40 kg/m2), and 20 morbidly obese (BMI ≥ 40 kg/m2)—received meropenem 500 mg every 6 hours (q6h), q8h, or q12h or 1 g q6h or q8h, infused over 0.5 hour. Population pharmacokinetic modeling was performed using NONMEM, and 5000‐patient Monte‐Carlo simulations were performed to calculate probability of target attainment (PTA) for 5 dosing regimens, infused over 0.5 and 3 hours, using fT>MIC of 40%, 54%, and 100% of the dosing interval. A 2‐compartment linear‐elimination model best described the serum concentration‐time data, and creatinine clearance was significantly associated with systemic clearance. Pharmacokinetic parameters were not significantly different among patient groups. In patients with creatinine clearances ≥50 mL/min, all simulated dosing regimens achieved >90% PTA at 40% fT>MIC in all patient groups at MICs ≤2 mg/L. Only 500 mg q8h, infused over 0.5 hour, did not achieve >90% PTA at 54% fT>MIC in nonobese and morbidly obese patients. At 100% fT>MIC, 1 g q6h and 2 g q8h, infused over 3 hours, reliably achieved >90% PTA in all patient groups. Meropenem pharmacokinetics are comparable among nonobese, obese, and morbidly obese patients. Standard dosing regimens provide adequate pharmacodynamic exposures for susceptible pathogens at 40% and 54% fT>MIC, but prolonged infusions of larger doses are needed for adequate exposures at 100% fT>MIC. Dosage adjustments based solely on body weight are unnecessary.
Simultaneous bisphenol F degradation, heterotrophic nitrification and aerobic denitrification by a bacterial consortium
Authors: Lu Hong , Weng Zihang , Wei Hao , Zhou Jiti , Wang Jing , Liu Guangfei , Guo Wanqian
Published: August 2016

BACKGROUND

Traditional aerobic autotrophic nitrification and anoxic heterotrophic denitrification have many limitations. Recently, the simultaneous heterotrophic nitrification–aerobic denitrification (HN‐AD) process has received increasing attention. Thus, the possibility of the simultaneous removal of bisphenols and NH4+‐N via HN‐AD was investigated.

RESULTS

A bisphenols‐degrading bacterial consortium was enriched and capable of degrading 50 mg L−1 bisphenol A, 300 mg L−1 4,4‐dihydroxybenzophenone, 375 mg L−1 bisphenol F (BPF) and 10 mg L−1 bis(4‐hydroxyphenyl)sulfide under aerobic conditions. Further studies showed that the bacterial consortium could completely degrade 300 mg L−1 BPF and remove NH4+‐N at 35 °C with 150 rpm at the C/N ratio of over 10. Moreover, BPF mineralization and NH4+‐N reduction to N2 were observed. Clone library analysis indicated that Salmonella enterica, Enterobacter,Citrobacter and Pseudomonas could cooperate to degrade BPF and reduce NH4+‐N to N2. Among these species, the isolated Pseudomonas sp. HS‐2 was capable of simultaneous BPF degradation and NH4+‐N removal via HN‐AD.

CONCLUSION

The experimental results demonstrated that the enriched bacterial consortium and the isolated strain HS‐2 could simultaneously remove BPF and NH4+‐N via HN‐AD, indicating that this is a potential way for the treatment of wastewaters containing these compounds. © 2016 Society of Chemical Industry