bluuebunny/crossref_metadata_2025 huggingface dataset:
The nuclear retinoid-related orphan receptor-α regulates adipose tissue glyceroneogenesis in addition to hepatic gluconeogenesis
Authors: Kadiri Sarah , Monnier Chloé , Ganbold Munkhzul , Ledent Tatiana , Capeau Jacqueline , Antoine Bénédicte
Published: May 2015

Circadian rhythms have an essential role in feeding behavior and metabolism. RORα is a nuclear receptor involved in the interface of the circadian system and metabolism. The adipocyte glyceroneogenesis pathway derives free fatty acids (FFA) liberated by lipolysis to reesterification into triglycerides, thus regulating FFA homeostasis and fat mass. Glyceroneogenesis shares with hepatic gluconeogenesis the key enzyme phospho enolpyruvate carboxykinase c (PEPCKc), whose gene is a RORα target in the liver. RORα-deficient mice (staggerer, RORsg/sg ) have been shown to exhibit a lean phenotype and fasting hypoglycemia for unsolved reasons. In the present study, we investigated whether adipocyte glyceroneogenesis might also be a target pathway of RORα, and we further evaluated the role of RORα in hepatocyte gluconeogenesis. In vivo investigations comparing RORsg/sg mice with their wild-type (WT) littermates under fasting conditions demonstrated that, in the absence of RORα, the release of FFA into the bloodstream was altered and the rise in glycemia in response to pyruvate reduced. The functional analysis of each pathway, performed in adipose tissue or liver explants, confirmed the impairment of adipocyte glyceroneogenesis and liver gluconeogenesis in the RORsg/sg mice; these reductions of FFA reesterification or glucose production were associated with decreases in PEPCKc mRNA and protein levels. Treatment of explants with RORα agonist or antagonist enhanced or inhibited these pathways, respectively, in tissues isolated from WT but not RORsg/sg mice. Our results indicated that both adipocyte glyceroneogenesis and hepatocyte gluconeogenesis were regulated by RORα. This study demonstrates the physiological function of RORα in regulating both glucose and FFA homeostasis.
New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism
Authors: Miyosawa Katsutoshi , Watanabe Yuichiro , Murakami Kentaro , Murakami Takeshi , Shibata Haruki , Iwashita Masaya , Yamazaki Hiroyuki , Yamazaki Koichi , Ohgiya Tadaaki , Shibuya Kimiyuki , Mizuno Ken , Tanabe Sohei , Singh Sasha A. , Aikawa Masanori
Published: May 2015

Despite significant reduction of cardiovascular events by statin treatment, substantial residual risk persists, driving emerging needs for the development of new therapies. We identified a novel cholesteryl ester transfer protein (CETP) inhibitor, K-312, that raises HDL and lowers LDL cholesterol levels in animals. K-312 also suppresses hepatocyte expression of proprotein convertase subtilisin/kexin 9 (PCSK9), a molecule that increases LDL cholesterol. We explored the underlying mechanism for the reduction of PCSK9 expression by K-312. K-312 inhibited in vitro human plasma CETP activity (IC50; 0.06 μM). Administration of K-312 to cholesterol-fed New Zealand White rabbits for 18 wk raised HDL cholesterol, decreased LDL cholesterol, and attenuated aortic atherosclerosis. Our search for additional beneficial characteristics of this compound revealed that K-312 decreases PCSK9 expression in human primary hepatocytes and in the human hepatoma cell line HepG2. siRNA silencing of CETP in HepG2 did not compromise the suppression of PCSK9 by K-312, suggesting a mechanism independent of CETP. In HepG2 cells, K-312 treatment decreased the active forms of sterol regulatory element-binding proteins (SREBP-1 and -2) that regulate promoter activity of PCSK9. Chromatin immunoprecipitation assays demonstrated that K-312 decreased the occupancy of SREBP-1 and SREBP-2 on the sterol regulatory element of the PCSK9 promoter. PCSK9 protein levels decreased by K-312 treatment in the circulating blood of cholesterol-fed rabbits, as determined by two independent mass spectrometry approaches, including the recently developed, highly sensitive parallel reaction monitoring method. New CETP inhibitor K-312 decreases LDL cholesterol and PCSK9 levels, serving as a new therapy for dyslipidemia and cardiovascular disease.
The Clinical Status of Stem Cell Therapy for Ischemic Cardiomyopathy
Authors: Wang Xianyun , Zhang Jun , Zhang Fan , Li Jing , Li Yaqi , Tan Zirui , Hu Jie , Qi Yixin , Li Quanhai , Yan Baoyong
Published: May 2015

Ischemic cardiomyopathy (ICM) is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ICM. Several stem cell types including cardiac-derived stem cells (CSCs), bone marrow-derived stem cells, mesenchymal stem cells (MSCs), skeletal myoblasts (SMs), and CD34+and CD 133+stem cells have been applied in clinical researches. The clinical effect produced by stem cell administration in ICM mainly depends on the transdifferentiation and paracrine effect. One important issue is that low survival and residential rate of transferred stem cells in the infracted myocardium blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ICM mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient’s physical condition, the particular microenvironment onto which the cells are delivered, and clinical condition remain to be addressed. Here we provide an overview of the pros and cons of these transferred cells and discuss the current state of their therapeutic potential. We believe that stem cell translation will be an ideal option for patients following ischemic heart disease in the future.
Distributed Transmission Probability Control in Fading Channel with State Information
Authors: Xie S. , Low K.S. , Gunawan E.
Published: May 2015

A wireless system consisting of a finite number of heterogeneous users transmitting packets over a slotted ALOHA Rayleigh-fading channel is investigated in this paper. In this system, each user tries to minimize its number of transmission attempts while meeting the throughput demand. The user interaction in such an ALOHA network is modeled as a random access game. A novel technique to better exploit the channel state information (CSI) named adaptive CSI transmission method is proposed. Benchmarking with the no-CSI method and threshold-based CSI method, it is revealed that the proposed adaptive CSI method can yield up to 9.9% more throughput and 12.3% power reduction. Two simple yet effective guidelines on selecting among these CSI-related methods are formulated for systems with different SNRs and capture ratios. A distributed algorithm is proposed to find the optimal transmission probability. Both analytical and simulation results show that the algorithm exhibits fast convergence speed and is robustness against changes on the number of active nodes in the network.
Cumulative Small Effect Genetic Markers and the Risk of Colorectal Cancer in Poland, Estonia, Lithuania, and Latvia
Authors: Serrano-Fernandez Pablo , Dymerska Dagmara , Kurzawski Grzegorz , Derkacz Róża , Sobieszczańska Tatiana , Banaszkiewicz Zbigniew , Roomere Hanno , Oitmaa Eneli , Metspalu Andres , Janavičius Ramūnas , Elsakov Pavel , Razumas Mindaugas , Petrulis Kestutis , Irmejs Arvīds , Miklaševičs Edvīns , Scott Rodney J. , Lubiński Jan
Published: May 2015

The continued identification of new low-penetrance genetic variants for colorectal cancer (CRC) raises the question of their potential cumulative effect among compound carriers. We focused on 6 SNPs (rs380284, rs4464148, rs4779584, rs4939827, rs6983267, and rs10795668), already described as risk markers, and tested their possible independent and combined contribution to CRC predisposition.Material and Methods.DNA was collected and genotyped from 2330 unselected consecutive CRC cases and controls from Estonia (166 cases and controls), Latvia (81 cases and controls), Lithuania (123 cases and controls), and Poland (795 cases and controls).Results.Beyond individual effects, the analysis revealed statistically significant linear cumulative effects for these 6 markers for all samples except of the Latvian one (correctedPvalue = 0.018 for the Estonian, correctedPvalue = 0.0034 for the Lithuanian, and correctedPvalue = 0.0076 for the Polish sample).Conclusions.The significant linear cumulative effects demonstrated here support the idea of using sets of low-risk markers for delimiting new groups with high-risk of CRC in clinical practice that are not carriers of the usual CRC high-risk markers.
PreliminaryIn VitroEvaluation of Genistein Chemopreventive Capacity as a Result of Esterification and Cyclodextrin Encapsulation
Authors: Danciu Corina , Soica Codruta , Dehelean Cristina , Zupko Istvan , Csanyi Erzsebet , Pinzaru Iulia
Published: May 2015

The present study focuses on the synthesis and analysis of a genistein ester derivative with myristic acid followed by beta cyclodextrin encapsulation; physicochemical analysis using consecrated techniques such as FTIR, MS, DSC, and SEM revealed both a successful esterification and inclusion inside the cyclodextrin cavity. Cytotoxic effects were measuredin vitroon three human cell lines: HeLa (cervix adenocarcinoma), A2780 (ovary carcinoma), and A431 (skin epidermoid carcinoma). Thein vitrobiological analysis exhibited rather poor antiproliferative results on all three tested cancer cell lines, behavior that may be due to the high stability of the complex within thein vitroenvironment.
Incidence and Predictors of Tuberculosis among HIV Positive Children at University of Gondar Referral Hospital, Northwest Ethiopia: A Retrospective Follow-Up Study
Authors: Ayalaw Sualiha Gebeyaw , Alene Kefyalew Addis , Adane Akilew Awoke
Published: May 2015

Background. The aim of this study was to determine the incidence of tuberculosis and its predictors among HIV positive children. Methods. A six-year retrospective follow-up study was conducted among HIV infected children aged less than 15 years. Life table was used to estimate the cumulative probability of tuberculosis free survival. Cox proportional hazards model was used to identify predictors of tuberculosis. Results. A total of 271 HIV positive children were followed for six years and produced 1100.50 person-years of observation. During the follow-up period 52 new TB cases occurred. The overall incidence density of TB was 4.9 per 100 PY. Inappropriate vaccination [AHR: 8.03 (95% CI; 4.61–13.97)], ambulatory functional status [AHR: 1.99 (95% CI; 1.04–3.81)], and having baseline anemia [AHR: 2.23 (95% CI; 1.19–4.15)] were important predictors of time to TB occurrence. Conclusion. TB incidence rate was high. Early diagnosis and treatment of anemia and strengthening immunization program would reduce the risk of TB occurrence.
Modulation of Acid Sphingomyelinase in Melanoma Reprogrammes the Tumour Immune Microenvironment
Authors: Assi Emma , Cervia Davide , Bizzozero Laura , Capobianco Annalisa , Pambianco Sarah , Morisi Federica , De Palma Clara , Moscheni Claudia , Pellegrino Paolo , Clementi Emilio , Perrotta Cristiana
Published: May 2015

The inflammatory microenvironment induces tumours to acquire an aggressive and immunosuppressive behaviour. Since acid sphingomyelinase (A‐SMase) downregulation in melanoma was shown to determine a malignant phenotype, we aimed here to elucidate the role of A‐SMase in the regulation of tumour immunogenic microenvironment using in vivo melanoma models in which A‐SMase was either downregulated or maintained at constitutively high levels. We found high levels of inflammatory factors in low A‐SMase expressing tumours, which also displayed an immunosuppressive/protumoural microenvironment: high levels of myeloid‐derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs), as well as low levels of dendritic cells (DCs). In contrast, the restoration of A‐SMase in melanoma cells not only reduced tumour growth and immunosuppression, but also induced a high recruitment at tumour site of effector immune cells with an antitumoural function. Indeed, we observed a poor homing of MDSCs and Tregs and the increased recruitment of CD8+ and CD4+ T lymphocytes as well as the infiltration of DCs and CD8+/CD44high T lymphocytes. This study demonstrates that change of A‐SMase expression in cancer cells is sufficient per se to tune in vivo melanoma growth and that A‐SMase levels modulate immune cells at tumour site. This may be taken into consideration in the setting of therapeutic strategies.
Heuristics for the Buffer Allocation Problem with Collision Probability Using Computer Simulation
Authors: Chiba Eishi
Published: May 2015

The standard manufacturing system for Flat Panel Displays (FPDs) consists of a number of pieces of equipment in series. Each piece of equipment usually has a number of buffers to prevent collision between glass substrates. However, in reality, very few of these buffers seem to be used. This means that redundant buffers exist. In order to reduce cost and space necessary for manufacturing, the number of buffers should be minimized with consideration of possible collisions. In this paper, we focus on an in-line system in which each piece of equipment can have any number of buffers. In this in-line system, we present a computer simulation method for the computation of the probability of a collision occurring. Based on this method, we try to find a buffer allocation that achieves the smallest total number of buffers under an arbitrarily specified collision probability. We also implement our proposed method and present some computational results.
On Pointwise Approximation of Conjugate Functions by Some Hump Matrix Means of Conjugate Fourier Series
Authors: Łenski W. , Szal B.
Published: May 2015

The results generalizing some theorems onN, pnE, γsummability are shown. The same degrees of pointwise approximation as in earlier papers by weaker assumptions on considered functions and examined summability methods are obtained. From presented pointwise results, the estimation on norm approximation is derived. Some special cases as corollaries are also formulated.
Partially Automated Method for Localizing Standardized Acupuncture Points on the Heads of Digital Human Models
Authors: Kim Jungdae , Kang Dae-In
Published: May 2015

Having modernized imaging tools for precise positioning of acupuncture points over the human body where the traditional therapeutic method is applied is essential. For that reason, we suggest a more systematic positioning method that uses X-ray computer tomographic images to precisely position acupoints. Digital Korean human data were obtained to construct three-dimensional head-skin and skull surface models of six individuals. Depending on the method used to pinpoint the positions of the acupoints, every acupoint was classified into one of three types: anatomical points, proportional points, and morphological points. A computational algorithm and procedure were developed for partial automation of the positioning. The anatomical points were selected by using the structural characteristics of the skin surface and skull. The proportional points were calculated from the positions of the anatomical points. The morphological points were also calculated by using some control points related to the connections between the source and the target models. All the acupoints on the heads of the six individual were displayed on three-dimensional computer graphical image models. This method may be helpful for developing more accurate experimental designs and for providing more quantitative volumetric methods for performing analyses in acupuncture-related research.
Phencyclidine Induced Oculogyric Crisis Responding Well to Conventional Treatment
Authors: Tahir Hassan , Daruwalla Vistasp
Published: May 2015

Background. Oculogyric crisis is a form of acute dystonic reaction characterized by involuntary upward deviation of eye ball. Its causes are broad with antipsychotics and antiemetics as the most common causes.Case Presentation. A 25-year-old man with the past medical history of marijuana use presented to ED with involuntary upward deviation of eye 1 day after using phencyclidine (PCP) for the first time. He did not have any other symptoms and was hemodynamically stable. All laboratory investigations were normal except urine drug screen which was positive for PCP. Patient was treated with IV diphenhydramine which improved his symptoms.Conclusion. Illicit drug abuse is a growing problem in our society with increasingly more patients presenting to ED with its complications. The differential diagnosis of acute dystonic reactions should be extended to include illicit drugs as the potential cause of reversible acute dystonias especially in high risk patients.
Adjuvant Chemoradiation Therapy in Gastric Cancer: Critically Reviewing the Past and Visualizing the Next Step Forward
Authors: Papadimitriou Konstantinos , Antoniou Georgios , Rolfo Christian , Russo Antonio , Bronte Giuseppe , Vassiliou Vassilios , Papamichael Demetris , Peeters Marc , Kountourakis Panteleimon
Published: May 2015

Gastric cancer remains one of the most common malignancies worldwide. Despite the significant advances in surgical treatment and multimodality strategies, prognosis has modestly improved over the last two decades. Locoregional relapse remains one of the main issues and the combined chemoradiation treatment seems to be one of the preferred approaches. However, more than ten years after the hallmark INT-0116 trial, minimal progress has been made both in terms of effectiveness and toxicity. Moreover, new regimens added to combined therapy failed to prove favourable results. Herein, we attempt a thorough literature review comparing pros and cons of all relative studies and potential bias, targeting well-designed future approaches.
Properties of the Set of Hadamardized Hurwitz Polynomials
Authors: Aguirre-Hernández Baltazar , Díaz-González Edgar-Cristian , Loredo-Villalobos Carlos-Arturo , García-Sosa Faustino-Ricardo
Published: May 2015

We say that a Hurwitz polynomialptis a Hadamardized polynomial if there are two Hurwitz polynomialsftandgtsuch thatf∗g=p, wheref∗gis the Hadamard product offandg. In this paper, we prove that the set of all Hadamardized Hurwitz polynomials is an open, unbounded, nonconvex, and arc-connected set. Furthermore, we give a result so that a fourth-degree Hurwitz interval polynomial is a Hadamardized polynomial family and we discuss an approach of differential topology in the study of the set of Hadamardized Hurwitz polynomials.
Bilinear Form and Two Bäcklund Transformations for the (3+1)-Dimensional Jimbo-Miwa Equation
Authors: Li He , Gao Yi-Tian
Published: May 2015

With Bell polynomials and symbolic computation, this paper investigates the (3+1)-dimensional Jimbo-Miwa equation, which is one of the equations in the Kadomtsev-Petviashvili hierarchy of integrable systems. We derive a bilinear form and construct a bilinear Bäcklund transformation (BT) for the (3+1)-dimensional Jimbo-Miwa equation, by virtue of which the soliton solutions are obtained. Bell-polynomial-typed BT is also constructed and cast into the bilinear BT.
A Tracking System Supporting Large-Scale Users Based on GPS and G-Sensor
Authors: Zeng Jun , Li Minbo , Cai Yuanfeng
Published: May 2015

As the need for tracking objects in our daily life is increasing, how to take advantage of widely used technologies and devices to meet everyone's need is becoming a burning issue. To achieve this aim, a tracking system supporting large-scale users based on GPS and G-sensors (TSSLSU) is designed to track items by obtaining various pieces information of the item's states and analyzing various conditions. In this system, a microprocessor with Global Positioning System (GPS) modules embedded in target sends data in real-time through General Packet Radio Service (GPRS) and Global System for Mobile Communication (GSM), and an inner G-sensor can fetch real-time state information, such as acceleration and vibration signals. The system designed a message protocol to encapsulate and send these data to servers and also adopted distributed architecture, including backend server cluster, cache queue cluster, database cluster, and web server cluster. This specific architecture provides a better performance when large-scale users visit concurrently. In particular, there are alarm mechanisms to inform the user of any illegal cases through smart phone application and power-saving mechanism for embedded terminal by changing the frequency of sending messages. At any time, user can locate it and query the carrier's previous path by web page or phone application.
The Hepatoprotective Effect of Haoqin Qingdan Decoction against Liver Injury Induced by a Chemotherapeutic Drug Cyclophosphamide
Authors: Li Xiaojiang , Li Baole , Jia Yingjie
Published: May 2015

Haoqin Qingdan decoction (HQQD), a modern Chinese formula, has been widely used in Eastern Asia. Our study focuses on the hepatoprotective effect of HQQD against cyclophosphamide-induced hepatotoxicity. S180, a kind of ascites tumor cells, was used to establish S180-bearing mice, followed by the injection of cyclophosphamide (CP, 80 mg/kg) every other day for 5 times. HQQD was used intragastrically at the dose of 80 g/kg, 40 g/kg, and 20 g/kg twice a day for 12 days. HL-7702 hepatic cell line was incubated with HQQD-medicated serum. Then we detected the effects of HQQD on (i) tumor suppression; (ii) morphological examination; (iii) SOD, MDA, GSH, ALT, and AST; (iv) cleaved caspase-3 expression and (v) cellular viability. CP caused dramatic elevations of AST, ALT, and MDA, while HQQD notably attenuated these elevations. SOD and GSH were notably increased, which were efficiently attenuated by HQQD. CP injection significantly increased apoptosis by increasing cleaved caspase-3 expression, which was obviously inhibited by HQQD, accompanied by the improvement of cells viability. Histopathological examinations supported the above findings. Therefore, HQQD may protect liver tissue through attenuating oxidative stress and the caspase-3-dependent intrinsic apoptosis induced by CP, which suggests the potentially therapeutic effect of HQQD in the use of alkylating agent for cancer chemotherapy.
Viability of Sea Fan Populations Impacted by Disease: Recruitment versus Incidence
Authors: Sabat Alberto M. , Toledo-Hernández Carlos
Published: May 2015

Diseases are a threat to the viability of an increasing number of coral populations. In this study we analyze the effect of infection and recruitment rate on the viability and structure of sea fan (Gorgonia ventalina) populations using a size-based matrix model parameterized with data from field studies. The model predicts that the viability of sea fan populations is strongly influenced by disease incidence and recruitment. Under high recruitment rate, the disease incidence threshold for population viability is 0.12/yr. However, populations with no or low incidence may also go locally extinct given persistent low recruitment. The model also predicts an effect of recruitment on disease prevalence. Everything else being equal, sites with low recruitment will exhibit higher disease prevalence than ones with high recruitment, particularly in medium and large colonies. Elasticity analysis reveals that changes in colony survivorship are likely to have the strongest effect on population growth rate, particularly given low recruitment. We conclude that under current levels of incidence sea fan populations in the Caribbean are not at risk. However, future epizootics are likely to produce local extinctions particularly if coinciding spatially or temporally with low recruitment.
Head-to-Head Comparison and Evaluation of 92 Plasma Protein Biomarkers for Early Detection of Colorectal Cancer in a True Screening Setting
Authors: Chen Hongda , Zucknick Manuela , Werner Simone , Knebel Phillip , Brenner Hermann
Published: May 2015

Purpose: Novel noninvasive blood-based screening tests are strongly desirable for early detection of colorectal cancer. We aimed to conduct a head-to-head comparison of the diagnostic performance of 92 plasma-based tumor-associated protein biomarkers for early detection of colorectal cancer in a true screening setting.

Experimental Design: Among all available 35 carriers of colorectal cancer and a representative sample of 54 men and women free of colorectal neoplasms recruited in a cohort of screening colonoscopy participants in 2005–2012 (N = 5,516), the plasma levels of 92 protein biomarkers were measured. ROC analyses were conducted to evaluate the diagnostic performance. A multimarker algorithm was developed through the Lasso logistic regression model and validated in an independent validation set. The .632+ bootstrap method was used to adjust for the potential overestimation of diagnostic performance.

Results: Seventeen protein markers were identified to show statistically significant differences in plasma levels between colorectal cancer cases and controls. The adjusted area under the ROC curves (AUC) of these 17 individual markers ranged from 0.55 to 0.70. An eight-marker classifier was constructed that increased the adjusted AUC to 0.77 [95% confidence interval (CI), 0.59–0.91]. When validating this algorithm in an independent validation set, the AUC was 0.76 (95% CI, 0.65–0.85), and sensitivities at cutoff levels yielding 80% and 90% specificities were 65% (95% CI, 41–80%) and 44% (95% CI, 24–72%), respectively.

Conclusions: The identified profile of protein biomarkers could contribute to the development of a powerful multimarker blood-based test for early detection of colorectal cancer. Clin Cancer Res; 21(14); 3318–26. ©2015 AACR.
Anti-EFNA4 Calicheamicin Conjugates Effectively Target Triple-Negative Breast and Ovarian Tumor-Initiating Cells to Result in Sustained Tumor Regressions
Authors: Damelin Marc , Bankovich Alexander , Park Albert , Aguilar Jorge , Anderson Wade , Santaguida Marianne , Aujay Monette , Fong Sarah , Khandke Kiran , Pulito Virginia , Ernstoff Elana , Escarpe Paul , Bernstein Jeffrey , Pysz Marybeth , Zhong Wenyan , Upeslacis Erik , Lucas Judy , Lucas Justin , Nichols Timothy , Loving Kathryn , Foord Orit , Hampl Johannes , Stull Robert , Barletta Frank , Falahatpisheh Hadi , Sapra Puja , Gerber Hans-Peter , Dylla Scott J.
Published: May 2015

Purpose: Triple-negative breast cancer (TNBC) and ovarian cancer each comprise heterogeneous tumors, for which current therapies have little clinical benefit. Novel therapies that target and eradicate tumor-initiating cells (TIC) are needed to significantly improve survival.

Experimental Design: A panel of well-annotated patient-derived xenografts (PDX) was established, and surface markers that enriched for TIC in specific tumor subtypes were empirically determined. The TICs were queried for overexpressed antigens, one of which was selected to be the target of an antibody–drug conjugate (ADC). The efficacy of the ADC was evaluated in 15 PDX models to generate hypotheses for patient stratification.

Results: We herein identified E-cadherin (CD324) as a surface antigen able to reproducibly enrich for TIC in well-annotated, low-passage TNBC and ovarian cancer PDXs. Gene expression analysis of TIC led to the identification of Ephrin-A4 (EFNA4) as a prospective therapeutic target. An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieved sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. Non-claudin low TNBC tumors exhibited higher expression and more robust responses than other breast cancer subtypes, suggesting a specific translational application for tumor subclassification.

Conclusions: These findings demonstrate the potential of PF-06647263 (anti–EFNA4-ADC) as a first-in-class compound designed to eradicate TIC. The use of well-annotated PDX for drug discovery enabled the identification of a novel TIC target, pharmacologic evaluation of the compound, and translational studies to inform clinical development. Clin Cancer Res; 21(18); 4165–73. ©2015 AACR.
When Cancer Fights Back: Multiple Myeloma, Proteasome Inhibition, and the Heat-Shock Response
Authors: Shah Shardule P. , Lonial Sagar , Boise Lawrence H.
Published: May 2015

Multiple myeloma is a plasma cell malignancy with an estimated 26,850 new cases and 11,240 deaths in 2015 in the United States. Two main classes of agents are the mainstays of therapy—proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Other new targets are emerging rapidly, including monoclonal antibodies and histone deacetylase (HDAC) inhibitors. These therapeutic options have greatly improved overall survival, but currently only 15% to 20% of patients experience long-term progression-free survival or are cured. Therefore, improvement in treatment options is needed. One potential means of improving clinical options is to target resistance mechanisms for current agents. For example, eliminating the cytoprotective heat-shock response that protects myeloma cells from proteasome inhibition may enhance PI-based therapies. The transcription factor heat-shock factor 1 (HSF1) is the master regulator of the heat-shock response. HSF1 is vital in the proteotoxic stress response, and its activation is controlled by posttranslational modifications (PTM). This review details the mechanisms of HSF1 regulation and discusses leveraging that regulation to enhance PI activity. Mol Cancer Res; 13(8); 1163–73. ©2015 AACR.
Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation
Authors: Van Allen Eliezer M. , Golay Hadrien G. , Liu Yan , Koyama Shohei , Wong Karrie , Taylor-Weiner Amaro , Giannakis Marios , Harden Maegan , Rojas-Rudilla Vanesa , Chevalier Aaron , Thai Tran , Lydon Christine , Mach Stacy , Avila Ada G. , Wong Joshua A. , Rabin Alexandra R. , Helmkamp Joshua , Sholl Lynette , Carter Scott L. , Oxnard Geoffrey , Janne Pasi , Getz Gad , Lindeman Neal , Hammerman Peter S. , Garraway Levi A. , Hodi F. Stephen , Rodig Scott J. , Dranoff Glenn , Wong Kwok-Kin , Barbie David A.
Published: May 2015

PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti–PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer. Cancer Immunol Res; 3(8); 855–63. ©2015 AACR.
Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells
Authors: Boyerinas Benjamin , Jochems Caroline , Fantini Massimo , Heery Christopher R. , Gulley James L. , Tsang Kwong Yok , Schlom Jeffrey
Published: May 2015

Several anti–PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti–PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti–PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti–PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. Cancer Immunol Res; 3(10); 1148–57. ©2015 AACR.
Low-Dose Mineralocorticoid Receptor Blockade Prevents Western Diet–Induced Arterial Stiffening in Female Mice
Authors: DeMarco Vincent G. , Habibi Javad , Jia Guanghong , Aroor Annayya R. , Ramirez-Perez Francisco I. , Martinez-Lemus Luis A. , Bender Shawn B. , Garro Mona , Hayden Melvin R. , Sun Zhe , Meininger Gerald A. , Manrique Camila , Whaley-Connell Adam , Sowers James R.
Published: May 2015

Women are especially predisposed to development of arterial stiffening secondary to obesity because of consumption of excessive calories. Enhanced activation of vascular mineralocorticoid receptors impairs insulin signaling, induces oxidative stress, inflammation, and maladaptive immune responses. We tested whether a subpressor dose of mineralocorticoid receptor antagonist, spironolactone (1 mg/kg per day) prevents aortic and femoral artery stiffening in female C57BL/6J mice fed a high-fat/high-sugar western diet (WD) for 4 months (ie, from 4–20 weeks of age). Aortic and femoral artery stiffness were assessed using ultrasound, pressurized vessel preparations, and atomic force microscopy. WD induced weight gain and insulin resistance compared with control diet–fed mice and these abnormalities were unaffected by spironolactone. Blood pressures and heart rates were normal and unaffected by diet or spironolactone. Spironolactone prevented WD-induced stiffening of aorta and femoral artery, as well as endothelial and vascular smooth muscle cells, within aortic explants. Spironolactone prevented WD-induced impaired aortic protein kinase B/endothelial nitric oxide synthase signaling, as well as impaired endothelium-dependent and endothelium-independent vasodilation. Spironolactone ameliorated WD-induced aortic medial thickening and fibrosis and the associated activation of the progrowth extracellular receptor kinase 1/2 pathway. Finally, preservation of normal arterial stiffness with spironolactone in WD-fed mice was associated with attenuated systemic and vascular inflammation and an anti-inflammatory shift in vascular immune cell marker genes. Low-dose spironolactone may represent a novel prevention strategy to attenuate vascular inflammation, oxidative stress, and growth pathway signaling and remodeling to prevent development of arterial stiffening secondary to consumption of a WD.
Soluble CD40L Is a Useful Marker to Predict Future Strokes in Patients With Minor Stroke and Transient Ischemic Attack
Authors: Li Jiejie , Wang Yilong , Lin Jinxi , Wang David , Wang Anxin , Zhao Xingquan , Liu Liping , Wang Chunxue , Wang Yongjun
Published: May 2015

Background and Purpose—

Elevated soluble CD40 ligand (sCD40L) was shown to be related to cardiovascular events, but the role of sCD40L in predicting recurrent stroke remains unclear.

Methods—

Baseline sCD40L levels were measured in 3044 consecutive patients with acute minor stroke and transient ischemic attack, who had previously been enrolled in the Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events (CHANCE) trial. Cox proportional-hazards model was used to assess the association of sCD40L with recurrent stroke.

Results—

Patients in the top tertile of sCD40L levels had increased risk of recurrent stroke comparing with those in the bottom tertile, after adjusted for conventional confounding factors (hazard ratio, 1.49; 95% confidence interval, 1.11–2.00;
P
=0.008). The patients with elevated levels of both sCD40L and high-sensitive C-reactive protein also had increased risk of recurrent stroke (hazard ratio, 1.81; 95% confidence interval, 1.23–2.68;
P
=0.003).

Conclusions—

Elevated sCD40L levels independently predict recurrent stroke in patients with minor stroke and transient ischemic attack.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00979589.
The Enduring Value of Christian Realism
Authors: Patterson Eric
Published: May 2015

Christian realism is a “community of discourse” launched by Reinhold Niebuhr and his contemporaries that remains relevant today providing thoughtful perspective on contemporary policy challenges in the foreign policy analysis strand of the formal study of International Relations. The essay lays out some of the basic principles that unite Christian realists, considers whether or not it can be considered a strain of academic “International Relations Theory”, suggests areas for the growth of Christian realist discourse in applied political thinking today, and concludes with some differences between Niebuhrian and Kuyperian approaches.
Reformational Insights for the Study of International Relations
Authors: Chaplin Jonathan
Published: May 2015

This essay presents a brief overview of selected insights deriving from reformational social and political philosophy, especially that of Herman Dooyeweerd, relevant to the study of international relations. Three clusters of potentially fruitful reformational concepts are identified. These relate to, first, the nature of the discipline of International Relations; second, the “structural purpose” of the state and other political entities; third, the plural, non-state actors of global civil society. It is proposed that distinctively reformational insights can offer illuminating orientations towards, or at least pose valuable research questions confronting, the development of a Christianly-informed ir theory today.
Robert Schuman’s Commitment to European Unification
Authors: Krijtenburg Margriet
Published: May 2015

With the eu struggling to maintain itself, it is highly relevant to look into the drive for and original vision on European unification of its principal architect, Robert Schuman, then French Minister of Foreign Affairs. The Schuman Declaration (1950) gave birth to the eu and procured the longest period of peace among its member states since the Treaty of Verdun (843). This article shows how Schuman’s Catholic faith influenced his life and therefore his politics. His drive to be a faithful instrument of Providence, supported by his origins from Alsace-Lorraine, made him strive towards peace on the European continent. He envisaged a European political integration through economic cooperation at the service of man and his transcendence and rooted in the common European spiritual and cultural heritage. This implied reconciliation, effective solidarity, subsidiarity and supra-nationality for European common interests through an integration in small steps.
Introduction
Authors: Buijs Govert , Polinder Simon
Published: May 2015

This introduction proposes that the re-emergence and rediscovery of religion should be seen against the background of globalization on the one hand and localization on the other. These processes require an open dialogue on the architecture and guiding morality of the global order, in which religion is not only a factor to be taken seriously, but also a participant itself. A Christian contribution to this dialogue can draw on an age-old tradition of Jewish and Christian engagement with the political order, manifesting itself in three genres: judgment, expectation, and exhortation. The introduction also explains the aim of the Kuyper seminars and provides a short overview of the articles in this issue.
Revalidation and redescription of Brachymystax tsinlingensis Li, 1966 (Salmoniformes: Salmonidae) from China
Authors: XING YING-CHUN , LV BIN-BIN , YE EN-QI , FAN EN-YUAN , LI SHI-YANG , WANG LI-XIN , ZHANG CHUN-GUANG , ZHAO YA-HUI
Published: May 2015

Brachymystax tsinlingensis Li, 1966 is revalidated and redescribed. It can be distinguished from all congeners by the following combination of characteristics: no spots on operculum; gill rakers 15-20; lateral-line scales 98-116; pyloric caeca 60-71. Unique morphological characters and genetic divergence of this species are discussed. This species has a limited distribution in several streams of the middle part of the Qinling Mountains in China. Methods for management and protection of B. tsinlingensis need to be re-evaluated.
Description of four new species of Hypaeus Simon and redescription of H. taczanowskii Mello-Leitão (Araneae: Salticidae: Amycinae)
Authors: ARAÚJO MAGDA H.S. , RUIZ GUSTAVO R.S.
Published: May 2015

Four new species of Hypaeus Simon are described from the Brazilian Amazon, all based on both sexes: H. tridactylus sp. nov. and H. femoratus sp. nov. from Juruti, Pará, and H. poseidon sp. nov. and H. terraemediae sp. nov. from São Félix do Xingu, Pará. Additionally, Asaracus pauciaculeis Caporiacco, 1947 is transferred from Mago O.P.-Cambridge, resulting in Hypaeus pauciaculeis comb. nov. Both sexes of H. taczanowskii (Mello-Leitão, 1948), the type species of Hypaeus, are redescribed for comparisons.
New Conopid records from the Afrotropical Region (Diptera). Part 1: Paramyopa Kröber, Pseudoconops Camras, Stylogaster Macquart, Thecophora Rondani, and Zodion Latreille
Authors: STUKE JENS-HERMANN
Published: May 2015

New records of 38 species of the Conopid genera Paramyopa Kröber, 1916a, Pseudoconops Camras, 1962b, Stylogaster Macquart, 1835, Thecophora Rondani, 1845, and Zodion Latreille, 1797 are presented from the Afrotropical Region. Stylogaster angolensis spec. nov. (Angola), Stylogaster cryptica spec. nov. (Ethiopia), Stylogaster fianarantsoensis spec. nov. (Madagascar), Stylogaster ivindoensis spec. nov. (Gabon), Stylogaster malaisei spec. nov. (Madagascar), Stylogaster occulta spec. nov. (Democratic Republic of Congo, Burundi), Stylogaster rwenzoriensis spec. nov. (Democratic Republic of Congo), Stylogaster tanzaniensis spec. nov. (Tanzania), Thecophora clementsi spec. nov. (Madagascar), Thecophora freidbergi spec. nov. (Kenya), Thecophora nigrifrons spec. nov. (Kenya, Cameroon), Thecophora obsoleta spec. nov. (Madagascar), and Thecophora submetallica spec. nov. (Madagascar) are new to science. A neotype is designated for Thecophora pilosa (Kröber, 1916). Thecophora africana (Brunetti, 1925), Thecophora flavicornis (Kröber, 1936), and Thecophora ruwenzori (Camras, 1962) are new junior synonyms of Thecophora pilosa; Paramyopa schultzei (Bezzi, 1908) is a new junior synonym of Paramyopa oestracea (Loew, 1863) (syn. nov.). Stylogaster nitidula Kröber, 1936 is interpretated as a nomen dubium (stat. rev.).
Digitate and capitate soft corals (Cnidaria: Octocorallia: Alcyoniidae) from Western Australia with reports on new species and new Australian geographical records
Authors: BRYCE MONIKA , POLISENO ANGELO , ALDERSLADE PHILIP , VARGAS SERGIO
Published: May 2015

We report on digitate and capitate Octocorallia within the genera Parasphaerasclera McFadden & Ofwegen, 2013, Eleutherobia Pütter, 1900, Sphaerasclera McFadden & Ofwegen, 2013, and Paraminabea Williams & Alderslade, 1999 from tropical Western Australian waters. Three new species (Parasphaerasclera kimberleyensis, Eleutherobia australiensis, Eleutherobia imaharai) are described, with a discussion of their taxonomic placement in the light of a recent treatment of the genus Eleutherobia and related taxa by McFadden & Ofwegen (2013). In addition, range extensions for three species are reported, Parasphaerasclera grayi (Thomson & Dean, 1931) known from Indonesia and the Pacific Ocean, Eleutherobia somaliensis Verseveldt & Bayer, 1988 from Somalia, and Eleutherobia splendens (Thomson & Dean, 1931) recorded from Indonesia and the Philippines. Additionally, one new Australian geographical record (Sphaerasclera flammicerebra) (Williams, 2003) with a known distribution from Palau to Mauritius, has been included. We complement morphological taxonomy with molecular data (mtMutS, 28S rDNA) to analyse and clarify phylogenetic placement of these species. The mitochondrial mtMutS phylogeny supported Eleutherobia, Paraminabea, Parasphaerasclera and Sphaerasclera as distinct monophyletic genera. Phylogenetic analyses based on 28S rDNA lacked resolution and were largely unresolved. Additionally, the molecular data corroborated our proposed morphological hypothesis of the placement of the new species P. kimberleyensis sp. nov. with no anthocodial armature in the genus Parasphaerasclera, and the assignment of the new species, E. australiensis sp. nov. and E. imaharai sp. nov., with distinct polyps sclerites in the genus Eleutherobia.
Lineage divergence in Odorrana graminea complex (Anura: Ranidae: Odorrana)
Authors: XIONG RONGCHUAN , LI CHENG , JIANG JIANPING
Published: May 2015

The confusing and unstable taxonomy of Odorrana livida (Rana livida) since its first record has made it a focal frog complex for systematics. In China, four species, Odorrana nebulosa, O. graminea, O. sinica, O. leporipes, were described to closely resemble O. livida or O. chloronota based on their morphological similarities, accompanied by much taxonomic confusion because of ambiguities in the wide distribution and morphological variations. Currently O. graminea is being used as the name of a provisional monotypic species group to include all the populations in China that closely resemble O. livida or O. chloronota. Here, we conducted a range-wide molecular phylogeographic analysis of the large green odorous frog (Odorrana graminea) complex across the majority of its range in China, based on 2780 bp DNA sequences of three mitochondrial genes (12S, 16S, ND2) in 107 samples from 20 sites. Our data recognized three distinct phylogeographic lineages of the Odorrana graminea (lato sensu) complex in China, and they together with a Thailand lineage formed a monophyletic group. Among the four lineages within O. graminea complex, the average genetic distances based on the concatenated sequences of 12S, 16S and ND2 were 7.5–8.8% and those based on 16S rRNA alone were 4.2–5.5%. Furthermore, canonical discriminant functions in morphometric analyses showed signiﬁcant separations of all the paired lineage comparisons in China. The aforementioned genetic divergence and mismatched phenotypes among the lineages within the Odorrana graminea complex, in addition to their non-overlapping geographic distributions, imply extensive lineage diversification. However, precise taxonomic status of these lineages needs more studies based on adequate type information and more thorough species delimitation based on analysis of differentiaton in bioacoustic and nuclear genetic characters especially regarding gene flow and admixture in geographical contact zones.