bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Dysphagia Pre- and Postoperatively in a Case of Eagle’s Syndrome
Authors: Lewis Vicki , Hoffman Ruddy Bari , Lehman Jeffrey , Silverman Erin , Spector Brian
Published: March 2015

Eagle’s syndrome (ES) is rare condition, most frequently described within the context of case study presentation. ES results from elongation of the styloid process, contributing to symptoms such as globus sensation in the throat, as well as pain localized to the ear, neck, face, or tongue. Additional symptoms can include hypersalivation, change in vocal quality, submandibular swelling, and dysphagia. This report discusses evaluation, diagnosis, and surgical intervention with respect to Eagle’s Syndrome in a patient presenting with moderate-severe dysphagia.
Internet of Vehicles for E-Health Applications in View of EMI on Medical Sensors
Authors: Lin Di , Wu Xuanli , Labeau Fabrice , Vasilakos Athanasios
Published: March 2015

Wireless technologies are pervasive to support ubiquitous healthcare applications. However, RF transmission in wireless technologies can lead to electromagnetic interference (EMI) on medical sensors under a healthcare scenario, and a high level of EMI may lead to a critical malfunction of medical sensors. In view of EMI to medical sensors, we propose a joint power and rate control algorithm under game theoretic framework to schedule data transmission at each of wireless sensors. The objective of such a game is to maximize the utility of each wireless user subject to the EMI constraints for medical sensors. We show that the proposed game has a unique Nash equilibrium and our joint power and rate control algorithm would converge to the Nash equilibrium. Numerical results illustrate that the proposed algorithm can achieve robust performance against the variations of mobile hospital environments.
Towards Patient-Oriented Diabetes Care: Results from Two KORA Surveys in Southern Germany
Authors: Schunk Michaela , Stark Renée , Reitmeir Peter , Meisinger Christa , Holle Rolf
Published: March 2015

Objective. This study aims to examine the relationship of diabetes care processes and patient outcomes with an expanded set of indicators regarding patient-oriented care delivery, such as treatment satisfaction, the quality of patient-physician relationship, and a wider range of patient outcomes such as self-management, health behaviour, disease-related burden, and health-related quality of life (HRQL).Methods. The study population consisted of 486 participants with type 2 diabetes in two population-based follow-up surveys, conducted in 2003 to 2005 and 2006 to 2008 in Southern Germany. Data were self-reported and questionnaire-based, including the SF-12 for HRQL. Multiple regression models were used to identify associations between care processes and outcomes with adjustment for confounders.Results. Frequent medical examinations increased the likelihood of self-monitoring activities, such as foot care. A positive patient experienced relationship with their physician is associated with higher adherence to medical recommendations, such as medication intake, and the score of the SF-12 mental component. Participants with diabetes-related complications reported higher levels of medical examinations and multiprofessional care.Conclusions. Indicators of patient-oriented care should become an indispensable part of diabetes clinical practice guidelines with the aim of striving for more effective support of patients.
Efficacy and Interindividual Variability in Motor-Cortex Plasticity following Anodal tDCS and Paired-Associative Stimulation
Authors: Strube Wolfgang , Bunse Tilmann , Malchow Berend , Hasan Alkomiet
Published: March 2015

Interindividual response variability to various motor-cortex stimulation protocols has been recently reported. Comparative data of stimulation protocols with different modes of action is lacking. We aimed to compare the efficacy and response variability of two LTP-inducing stimulation protocols in the human motor cortex: anodal transcranial direct current stimulation (a-tDCS) and paired-associative stimulation (PAS25). In two experiments 30 subjects received 1mA a-tDCS and PAS25. Data analysis focused on motor-cortex excitability change and response defined as increase in MEP applying different cut-offs. Furthermore, the predictive pattern of baseline characteristics was explored. Both protocols induced a significant increase in motor-cortical excitability. In the PAS25 experiments the likelihood to develop a MEP response was higher compared to a-tDCS, whereas for intracortical facilitation (ICF) the likelihood for a response was higher in the a-tDCS experiments. Baseline ICF (12 ms) correlated positively with an increase in MEPs only following a-tDCS and responders had significantly higher ICF baseline values. Contrary to recent studies, we showed significant group-level efficacy following both stimulation protocols confirming older studies. However, we also observed a remarkable amount of nonresponders. Our findings highlight the need to define sufficient physiological read-outs for a given plasticity protocol and to develop predictive markers for targeted stimulation.
A Modification Artificial Bee Colony Algorithm for Optimization Problems
Authors: Liang Jun-Hao , Lee Ching-Hung
Published: March 2015

This paper presents a modified artificial bee colony algorithm (MABC) for solving function optimization problems and control of mobile robot system. Several strategies are adopted to enhance the performance and reduce the computational effort of traditional artificial bee colony algorithm, such as elite, solution sharing, instant update, cooperative strategy, and population manager. The elite individuals are selected as onlooker bees for preserving good evolution, and, then, onlooker bees, employed bees, and scout bees are operated. The solution sharing strategy provides a proper direction for searching, and the instant update strategy provides the newest information for other individuals; the cooperative strategy improves the performance for high-dimensional problems. In addition, the population manager is proposed to adjust population size adaptively according to the evolution situation. Finally, simulation results for optimization of test functions and tracking control of mobile robot system are introduced to show the effectiveness and performance of the proposed approach.
Voltage Gain Derivation Based on Energy-Balanced Criterion for a Novel Hybrid-Input PV-Wind Power Conversion System
Authors: Shen Chih-Lung , Liang Tsair-Chun , Zhou Siou-Hong , Wang Su-Wen
Published: March 2015

This paper applies energy-balanced criterion to a novel hybrid-input PV-wind power conversion system (HPWPCS) for voltage gain derivation. With the energy-balanced concept, complicated mathematical problems related to voltage gain derivation can be readily resolved. Based on the derived results, it is proven that the proposed HPWPCS is able to process two different kinds of renewable energy resources simultaneously. Even though the HPWPCS includes seven capacitors and three magnetic components, its voltage gain still can be found by the mathematical analysis. In the theoretical derivation, only the energy status of output inductor is dealt with such that complicated derivation procedure is avoided. This analysis method can also be applied to other hybrid green-energy conversion systems. In this paper, a 200 W 50 kHz prototype of HPWPCS is built and examined to verify the mathematical results.
Sentiment Analysis Using Common-Sense and Context Information
Authors: Agarwal Basant , Mittal Namita , Bansal Pooja , Garg Sonal
Published: March 2015

Sentiment analysis research has been increasing tremendously in recent times due to the wide range of business and social applications. Sentiment analysis from unstructured natural language text has recently received considerable attention from the research community. In this paper, we propose a novel sentiment analysis model based on common-sense knowledge extracted from ConceptNet based ontology and context information. ConceptNet based ontology is used to determine the domain specific concepts which in turn produced the domain specific important features. Further, the polarities of the extracted concepts are determined using the contextual polarity lexicon which we developed by considering the context information of a word. Finally, semantic orientations of domain specific features of the review document are aggregated based on the importance of a feature with respect to the domain. The importance of the feature is determined by the depth of the feature in the ontology. Experimental results show the effectiveness of the proposed methods.
An Ovarian Pregnancy in a Patient with a History of Bilateral Salpingectomies: A Rare Case
Authors: Khandaker Sadia , Chitkara Pranav , Cochran Eric , Cutler Jed
Published: March 2015

Background. 1 in 200 ectopic pregnancies are true ovarian pregnancies that fulfill the Spiegelberg criteria. Despite being rare, multiple case reports and series have been reported. Few cases have been published in which the event was preceded by salpingectomy.Case. The patient is a 32-year-old female who presented to the emergency room with abdominal pain. She was found to be pregnant, despite a history of two previous ectopic pregnancies treated with salpingectomies. Sonography confirmed a left adnexal mass and free fluid. Surgery revealed a ruptured ovarian pregnancy which was also confirmed by pathology.Conclusion. This is a case of an ovarian pregnancy in a patient with two previous salpingectomies. It underscores the importance of searching for an ectopic pregnancy in patients with abdominal pain after fertility impairing surgery.
The Efficiency of Barley (Hordeum vulgare) Bran in Ameliorating Blood and Treating Fatty Heart and Liver of Male Rats
Authors: Abulnaja Khalid O. , El Rabey Haddad A.
Published: March 2015

The current study focused on testing the hypolipidemic activity of two doses of barley bran on hypercholesterolemic male rats. Twenty-four male albino rats weighing 180–200 gm were divided into four groups. The first group (G1) was the negative control, the second group (G2) was the positive control group fed 2% cholesterol in the diet, and rats of the third and the fourth groups were fed 2% cholesterol and were cosupplemented with 5% and 10% barley bran, respectively, for 8 weeks. The hypercholesterolemic rats of (G2) showed an increase in lipid profile, liver enzymes, lactate dehydrogenase, creatine kinase-MB, and lipid peroxide and a decrease in antioxidant enzymes, whereas kidney function, fasting blood sugar, glycated hemoglobin total protein, and total bilirubin were not significantly affected compared with the negative control group in G1. Moreover, histology of heart, liver, and kidney of G2 rats showed histopathological changes compared with the negative control. Administration of the two doses of barley bran in G3 and G4 to the hypercholesterolemic rats ameliorated the level of lipids, liver enzymes, lactate dehydrogenase, and creatine kinase-MB. In addition, the histology of heart, liver, and kidney tissues nearly restored the normal state as in G1.
Acute on Chronic Pancreatitis Causing a Highway to the Colon with Subsequent Road Closure: Pancreatic Colonic Fistula Presenting as a Large Bowel Obstruction Treated with Pancreatic Duct Stenting
Authors: Cochrane Justin , Schlepp Greg
Published: March 2015

Context. Colonic complications associated with acute pancreatitis have a low incidence but carry an increased risk of mortality with delayed diagnosis and treatment. Pancreatic colonic fistula is most commonly associated with walled off pancreatic necrosis or abscess formation and rarely forms spontaneously. Classic clinical manifestations for pancreatic colonic fistula include diarrhea, hematochezia, and fever. Uncommonly pancreatic colonic fistula presents as large bowel obstruction.Case. We report a case of a woman with a history of recurrent episodes of acute pancreatitis who presented with large bowel obstruction secondary to pancreatic colonic fistula. Resolution of large bowel obstruction and pancreatic colonic fistula was achieved with pancreatic duct stenting.Conclusion. Pancreatic colonic fistula can present as large bowel obstruction. Patients with resolved acute pancreatitis who have radiographic evidence of splenic flexure obstruction, but without evidence of mechanical obstruction on colonoscopy, should be considered for ERCP to evaluate for PCF. PCF not associated with walled off pancreatic necrosis or peritoneal abscess can be treated conservatively with pancreatic duct stenting.
Toxicity Biosensor for Sodium Dodecyl Sulfate Using Immobilized Green Fluorescent Protein ExpressingEscherichia coli
Authors: Ooi Lia , Heng Lee Yook , Ahmad Asmat
Published: March 2015

Green fluorescent protein (GFP) is suitable as a toxicity sensor due to its ability to work alone without cofactors or substrates. Its reaction with toxicants can be determined with fluorometric approaches. GFP mutant gene (C48S/S147C/Q204C/S65T/Q80R) is used because it has higher sensitivity compared to others GFP variants. A novel sodium dodecyl sulfate (SDS) toxicity detection biosensor was built by immobilizing GFP expressingEscherichia coliink-Carrageenan matrix. Cytotoxicity effect took place in the toxicity biosensor which leads to the decrease in the fluorescence intensity. The fabricatedE. coliGFP toxicity biosensor has a wide dynamic range of 4–100 ppm, with LOD of 1.7 ppm. Besides, it possesses short response time (<1 min), high reproducibility (0.76% RSD) and repeatability (0.72% RSD,R2>0.98), and long-term stability (46 days).E. coliGFP toxicity biosensor has been applied to detect toxicity induced by SDS in tap water, river water, and drinking water. High recovery levels of SDS indicated the applicability ofE. coliGFP toxicity biosensor in real water samples toxicity evaluation.
Study of On-Ramp PI Controller Based on Dural Group QPSO with Different Well Centers Algorithm
Authors: Wu Tao , Chen Xi , Yan Yusong
Published: March 2015

A novel quantum-behaved particle swarm optimization (QPSO) algorithm, dual-group QPSO with different well centers (DWC-QPSO) algorithm, is proposed by constructing the master-slave subswarms. The new algorithm was applied in the parameter optimization of on-ramp traffic PI controller combining with nonlinear feedback theory. With the critical information contained in the searching space and results of the basic QPSO algorithm, this algorithm avoids the rapid disappearance of swarm diversity and enhances the global searching ability through collaboration between subswarms. Experiment results on an on-ramp traffic control simulation show that DWC-QPSO can be well applied in the study of on-ramp traffic PI controller and the comparison results illustrate that DWC-QPSO outperforms other evolutionary algorithms with enhancement in both adaptability and stability.
An Adapted Firefly Algorithm for Product Development Project Scheduling with Fuzzy Activity Duration
Authors: Huang Minmei , Yuan Jijun , Xiao Jing
Published: March 2015

Efficient scheduling plays an important role in product development project management, especially for the product development project with fuzzy activity times. In this research a trapezoidal fuzzy number is used to represent fuzzy activity duration, and an improved magnitude of the trapezoidal fuzzy number is adopted for fuzzy time comparison. Firstly, a mathematical model for the scheduling problem with minimizing the project completion time for the product development project is established. Then, an adapted fuzzy firefly algorithm is developed to solve the model. The priority value based coding method is used; the fuzzy parallel schedule generation scheme is adopted to generate feasible solutions, and the brightness comparisons are made before updating fireflies’ locations in the proposed algorithm. Finally, the performance of the proposed algorithm is presented by computational experiments based on PSPLIB benchmarks. An example of resource allocation of an electronic product development project is also used to illustrate the effectiveness and efficiency of the proposed algorithm.
Targeting IL11 Receptor in Leukemia and Lymphoma: A Functional Ligand-Directed Study and Hematopathology Analysis of Patient-Derived Specimens
Authors: Karjalainen Katja , Jaalouk Diana E. , Bueso-Ramos Carlos , Bover Laura , Sun Yan , Kuniyasu Akihiko , Driessen Wouter H.P. , Cardó-Vila Marina , Rietz Cecilia , Zurita Amado J. , O'Brien Susan , Kantarjian Hagop M. , Cortes Jorge E. , Calin George A. , Koivunen Erkki , Arap Wadih , Pasqualini Renata
Published: March 2015

Purpose: The IL11 receptor (IL11R) is an established molecular target in primary tumors of bone, such as osteosarcoma, and in secondary bone metastases from solid tumors, such as prostate cancer. However, its potential role in management of hematopoietic malignancies has not yet been determined. Here, we evaluated the IL11R as a candidate therapeutic target in human leukemia and lymphoma.

Experimental Design and Results: First, we show that the IL11R protein is expressed in a variety of human leukemia– and lymphoma–derived cell lines and in a large panel of bone marrow samples from leukemia and lymphoma patients, whereas expression is absent from nonmalignant control bone marrow. Moreover, a targeted peptidomimetic prototype (termed BMTP-11), specifically bound to leukemia and lymphoma cell membranes, induced ligand–receptor internalization mediated by the IL11R, and resulted in a specific dose-dependent cell death induction in these cells. Finally, a pilot drug lead-optimization program yielded a new myristoylated BMTP-11 analogue with an apparent improved antileukemia cell profile.

Conclusions: These results indicate (i) that the IL11R is a suitable cell surface target for ligand-directed applications in human leukemia and lymphoma and (ii) that BMTP-11 and its derivatives have translational potential against this group of malignant diseases. Clin Cancer Res; 21(13); 3041–51. ©2015 AACR.
The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models
Authors: Schuller Alwin G. , Barry Evan R. , Jones Rhys D.O. , Henry Ryan E. , Frigault Melanie M. , Beran Garry , Linsenmayer David , Hattersley Maureen , Smith Aaron , Wilson Joanne , Cairo Stefano , Déas Olivier , Nicolle Delphine , Adam Ammar , Zinda Michael , Reimer Corinne , Fawell Stephen E. , Clark Edwin A. , D'Cruz Celina M.
Published: March 2015

Purpose: Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.

Experimental Design: Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).

Results: AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose- and time-dependent induction of cleaved PARP, a marker of cell death.

Conclusions: Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication. Clin Cancer Res; 21(12); 2811–9. ©2015 AACR.
Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing
Authors: Parry Marina , Rose-Zerilli Matthew J.J. , Ljungström Viktor , Gibson Jane , Wang Jun , Walewska Renata , Parker Helen , Parker Anton , Davis Zadie , Gardiner Anne , McIver-Brown Neil , Kalpadakis Christina , Xochelli Aliki , Anagnostopoulos Achilles , Fazi Claudia , Gonzalez de Castro David , Dearden Claire , Pratt Guy , Rosenquist Richard , Ashton-Key Margaret , Forconi Francesco , Collins Andrew , Ghia Paolo , Matutes Estella , Pangalis Gerassimos , Stamatopoulos Kostas , Oscier David , Strefford Jonathan C.
Published: March 2015

Purpose: Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies.

Experimental Design: We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL.

Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02–4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05–4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08–5.2; P = 0.03).

Conclusions: We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively. Clin Cancer Res; 21(18); 4174–83. ©2015 AACR.
Immune Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Following Flu-TBI versus TLI-ATG Conditioning
Authors: Hannon Muriel , Beguin Yves , Ehx Grégory , Servais Sophie , Seidel Laurence , Graux Carlos , Maertens Johan , Kerre Tessa , Daulne Coline , de Bock Muriel , Fillet Marianne , Ory Aurélie , Willems Evelyne , Gothot André , Humblet-Baron Stéphanie , Baron Frédéric
Published: March 2015

Purpose: A conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) combining total lymphoid irradiation (TLI) plus anti-thymocyte globulin (ATG) has been developed to induce graft-versus-tumor effects without graft-versus-host disease (GVHD).

Experimental Design: We compared immune recovery in 53 patients included in a phase II randomized study comparing nonmyeloablative HCT following either fludarabine plus 2 Gy total body irradiation (TBI arm, n = 28) or 8 Gy TLI plus ATG (TLI arm, n = 25).

Results: In comparison with TBI patients, TLI patients had a similarly low 6-month incidence of grade II-IV acute GVHD, a lower incidence of moderate/severe chronic GVHD (P = 0.02), a higher incidence of CMV reactivation (P < 0.001), and a higher incidence of relapse (P = 0.01). While recovery of total CD8+ T cells was similar in the two groups, with median CD8+ T-cell counts reaching the normal values 40 to 60 days after allo-HCT, TLI patients had lower percentages of naïve CD8 T cells. Median CD4+ T-cell counts did not reach the lower limit of normal values the first year after allo-HCT in the two groups. Furthermore, CD4+ T-cell counts were significantly lower in TLI than in TBI patients the first 6 months after transplantation. Interestingly, while median absolute regulatory T-cell (Treg) counts were comparable in TBI and TLI patients, Treg/naïve CD4+ T-cell ratios were significantly higher in TLI than in TBI patients the 2 first years after transplantation.

Conclusions: Immune recovery differs substantially between these two conditioning regimens, possibly explaining the different clinical outcomes observed (NCT00603954). Clin Cancer Res; 21(14); 3131–9. ©2015 AACR.
MGMT Expression Predicts PARP-Mediated Resistance to Temozolomide
Authors: Erice Oihane , Smith Michael P. , White Rachel , Goicoechea Ibai , Barriuso Jorge , Jones Chris , Margison Geoffrey P. , Acosta Juan C. , Wellbrock Claudia , Arozarena Imanol
Published: March 2015

Melanoma and other solid cancers are frequently resistant to chemotherapies based on DNA alkylating agents such as dacarbazine and temozolomide. As a consequence, clinical responses are generally poor. Such resistance is partly due to the ability of cancer cells to use a variety of DNA repair enzymes to maintain cell viability. Particularly, the expression of MGMT has been linked to temozolomide resistance, but cotargeting MGMT has proven difficult due to dose-limiting toxicities. Here, we show that the MGMT-mediated resistance of cancer cells is profoundly dependent on the DNA repair enzyme PARP. Both in vitro and in vivo, we observe that MGMT-positive cancer cells strongly respond to the combination of temozolomide and PARP inhibitors (PARPi), whereas MGMT-deficient cells do not. In melanoma cells, temozolomide induced an antiproliferative senescent response, which was greatly enhanced by PARPi in MGMT-positive cells. In summary, we provide compelling evidence to suggest that the stratification of patients with cancer upon the MGMT status would enhance the success of combination treatments using temozolomide and PARPi. Mol Cancer Ther; 14(5); 1236–46. ©2015 AACR.
Synthetic Lethal Screens Identify Vulnerabilities in GPCR Signaling and Cytoskeletal Organization in E-Cadherin–Deficient Cells
Authors: Telford Bryony J. , Chen Augustine , Beetham Henry , Frick James , Brew Tom P. , Gould Cathryn M. , Single Andrew , Godwin Tanis , Simpson Kaylene J. , Guilford Parry
Published: March 2015

The CDH1 gene, which encodes the cell-to-cell adhesion protein E-cadherin, is frequently mutated in lobular breast cancer (LBC) and diffuse gastric cancer (DGC). However, because E-cadherin is a tumor suppressor protein and lost from the cancer cell, it is not a conventional drug target. To overcome this, we have taken a synthetic lethal approach to determine whether the loss of E-cadherin creates druggable vulnerabilities. We first conducted a genome-wide siRNA screen of isogenic MCF10A cells with and without CDH1 expression. Gene ontology analysis demonstrated that G-protein–coupled receptor (GPCR) signaling proteins were highly enriched among the synthetic lethal candidates. Diverse families of cytoskeletal proteins were also frequently represented. These broad classes of E-cadherin synthetic lethal hits were validated using both lentiviral-mediated shRNA knockdown and specific antagonists, including the JAK inhibitor LY2784544, Pertussis toxin, and the aurora kinase inhibitors alisertib and danusertib. Next, we conducted a 4,057 known drug screen and time course studies on the CDH1 isogenic MCF10A cell lines and identified additional drug classes with linkages to GPCR signaling and cytoskeletal function that showed evidence of E-cadherin synthetic lethality. These included multiple histone deacetylase inhibitors, including vorinostat and entinostat, PI3K inhibitors, and the tyrosine kinase inhibitors crizotinib and saracatinib. Together, these results demonstrate that E-cadherin loss creates druggable vulnerabilities that have the potential to improve the management of both sporadic and familial LBC and DGC. Mol Cancer Ther; 14(5); 1213–23. ©2015 AACR.
First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway
Authors: Hagel Margit , Miduturu Chandra , Sheets Michael , Rubin Nooreen , Weng Weifan , Stransky Nicolas , Bifulco Neil , Kim Joseph L. , Hodous Brian , Brooijmans Natasja , Shutes Adam , Winter Christopher , Lengauer Christoph , Kohl Nancy E. , Guzi Timothy
Published: March 2015

Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β (KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC.

Significance: This article documents the discovery of BLU9931, a novel irreversible kinase inhibitor that specifically targets FGFR4 while sparing all other FGFR paralogs and demonstrates exquisite kinome selectivity. BLU9931 is efficacious in tumors with an intact FGFR4 signaling pathway that includes FGF19, FGFR4, and KLB. BLU9931 is the first FGFR4-selective molecule for the treatment of patients with HCC with aberrant FGFR4 signaling. Cancer Discov; 5(4); 424–37. ©2015 AACR.

See related commentary by Packer and Pollock, p. 355

This article is highlighted in the In This Issue feature, p. 333
Is There a Role for Active Surveillance in Low-Risk Prostate Cancer?
Authors: Augustin Herbert , Mayerhofer Katrin , Seles Maximilian , Pummer Karl
Published: March 2015

Background: Active surveillance (AS) represents an expectant treatment strategy for clinically localized prostate cancer (PCa) with low-risk features. Objective: The actual management as well as the pros and cons of AS were evaluated. Methods: A systematic review of the recent literature was performed using the Medline databases. Conclusions: Since a substantial number of men die with rather than from PCa, there is a considerable role for AS in carefully selected men. AS may also represent a strategy to reduce the burden of overtreatment rooted in intensified PSA testing. Facing the imprecision of risk stratification based on transrectal ultrasound-guided biopsy, accurate clinical staging represents a major medical challenge. Counseling and care require empathy as well as a profound understanding of the biology and the natural history of PCa.
Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety
Authors: Cohen Joshua L. , Glover Matthew E. , Pugh Phyllis C. , Fant Andrew D. , Simmons Rebecca K. , Akil Huda , Kerman Ilan A. , Clinton Sarah M.
Published: March 2015

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations.
Impact of Airflow Limitation on Carotid Atherosclerosis in Coronary Artery Disease Patients
Authors: Hamrah Mohammad Shoaib , Suzuki Susumu , Ishii Hideki , Shibata Yohei , Tatami Yosuke , Osugi Naohiro , Ota Tomoyuki , Kawamura Yoshihiro , Tanaka Akihito , Aso Hiromichi , Takeshita Kyosuke , Sakamoto Junichi , Hasegawa Yoshinori , Murohara Toyoaki
Published: March 2015

Background: Both airflow limitation and smoking are established cardiovascular risk factors. However, their interaction as risk factors for the development of atherosclerosis in coronary artery disease patients remains unclear. Objectives: To evaluate the effect of the interaction between airflow limitation and smoking status on the severity of carotid atherosclerosis. Methods: We categorized the 234 enrolled patients with coronary artery disease into four groups: never-smokers with normal pulmonary function (group A), never-smokers with airflow limitation (group B), ever-smokers with normal pulmonary function (group C), and ever-smokers with airflow limitation (group D). Results: The prevalence of airflow limitation in the enrolled patients was 23.1% (ever-smokers: 15.8%, never-smokers: 7.3%). The prevalence of severe carotid atherosclerosis was 28.2, 29.4, 41.3, and 45.9%, respectively, in the four groups (group D vs. group A, p = 0.035). Even after multivariate adjusting for confounding factors, ever-smokers with airflow limitation were independently associated with severe carotid atherosclerosis (odds ratio 2.89, 95% confidence interval, 1.19-7.00, p = 0.019). Conclusions: Ever-smokers with airflow limitation were significantly associated with severe carotid atherosclerosis among patients with coronary artery disease. These findings also provide additional insight into the correlation between airflow limitation and poor cardiovascular clinical outcomes.
Are Asthmatics Enrolled in Randomized Trials Representative of Real-Life Outpatients?
Authors: Battaglia Salvatore , Basile Marco , Spatafora Mario , Scichilone Nicola
Published: March 2015

Background/Objective: This study was aimed at exploring to what extent populations enrolled in randomized controlled trials (RCTs) of inhalation combination treatment for mild/moderate asthma in adults are fully representative of ‘real-life' populations. The following is a retrospective analysis of the clinical records of outpatient subjects with an ascertained diagnosis of asthma. Methods: A retrospective analysis was performed. Stable conditions, such as smoking habit and chronic diseases other than asthma, were identified as exclusion criteria for RCTs. The selected criteria were then applied to asthmatic outpatients, yielding a population that was potentially eligible for RCTs. Results: Out of 1,909 subjects, 824 (43.2%) met at least one of the exclusion criteria for RCTs. Cigarette smoking (occurring in 34.3% of the entire population), lung diseases other than asthma (5.0%), anxiety and depression (3.3%), arrhythmias (2.3%), and coronary artery disease (1.2%) would have been the most frequent causes for exclusion from RCTs. The proportion of patients excluded from RCTs appears to increase with age, reaching 57.1% in patients aged >85 years. Conclusions: In a real-life setting, >40% of subjects with mild/moderate asthma are currently treated by protocols based on the results of RCTs for which they would not have been eligible. This proportion increases in elderly patients with comorbidities. These findings limit the generalizability of RCTs and advocate that complementary pragmatic studies be conducted.
Dissociation in the Effects of Induced Neonatal Hypoxia-Ischemia on Rapid Auditory Processing and Spatial Working Memory in Male Rats
Authors: Smith Amanda L. , Alexander Michelle , Chrobak James J. , Rosenkrantz Ted S. , Fitch R. Holly
Published: March 2015

Infants born prematurely are at risk for cardiovascular events causing hypoxia-ischemia (HI; reduced blood and oxygen to the brain). HI in turn can cause neuropathology, though patterns of damage are sometimes diffuse and often highly variable (with clinical heterogeneity further magnified by rapid development). As a result, though HI injury is associated with long-term behavioral and cognitive impairments in general, pathology indices for specific infants can provide only limited insight into individual prognosis. The current paper addresses this important clinical issue using a rat model that simulates unilateral HI in a late preterm infant coupled with long-term behavioral evaluation in two processing domains - auditory discrimination and spatial learning/memory. We examined the following: (1) whether deficits on one task would predict deficits on the other (suggesting that subjects with more severe injury perform worse across all cognitive domains) or (2) whether domain-specific outcomes among HI-injured subjects would be uncorrelated (suggesting differential damage to orthogonal neural systems). All animals (sham and HI) received initial auditory testing and were assigned to additional auditory testing (group A) or spatial maze testing (group B). This allowed within-task (group A) and between-task (group B) correlation. Anatomic measures of cortical, hippocampal and ventricular volume (indexing HI damage) were also obtained and correlated against behavioral measures. Results showed that auditory discrimination in the juvenile period was not correlated with spatial working memory in adulthood (group B) in either sham or HI rats. Conversely, early auditory processing performance for group A HI animals significantly predicted auditory deficits in adulthood (p = 0.05; no correlation in shams). Anatomic data also revealed significant relationships between the volumes of different brain areas within both HI and shams, but anatomic measures did not correlate with any behavioral measure in the HI group (though we saw a hippocampal/spatial correlation in shams, in the expected direction). Overall, current data provide an impetus to enhance tools for characterizing individual HI-related pathology in neonates, which could provide more accurate individual prognoses within specific cognitive/behavioral domains and thus improved patient-specific early interventions.
Nitric Oxide Pathway and Proliferation of Neural Progenitors in the Neonatal Rat
Authors: Phan Duy An , Pham Hoa , Pansiot Julien , Gressens Pierre , Charriaut-Marlangue Christiane , Baud Olivier
Published: March 2015

Several lines of evidence demonstrate that inhaled nitric oxide (iNO) not only acts locally on the pulmonary vasculature but also has remote effects on the mature and developing brain under basal or pathological conditions by modulating cerebral blood flow and microvascularization, white matter maturation, inflammation, and subsequent brain repair. Previously, consistent studies demonstrated that increased levels of guanosine 3′,5′ cyclic monophosphate (cGMP), the main effector of biological effect induced by nitric oxide (NO), significantly augment proliferation and neuronal differentiation of adult neural progenitor cells (NPCs). In the present study, we ask the question whether iNO could promote the proliferation of NPCs in the uninjured developing brain. We first reported that iNO exposure at a concentration of 20 ppm during the first 7 days of life was associated with a significant but transient elevation of brain cGMP concentration 2 h after the onset of iNO exposure and a subsequent increase in myelin content of the developing white matter at postnatal day (P) 10. Using BrDu labelling and colabelling with specific cell-type markers we found that iNO exposure of rat pups results in an increased NPC proliferation in several layers of the subventricular zone (SVZ) at both early (30 h) and late (P7) time points. These proliferating NPCs were found to be sustainably viable and subsequently differentiated into oligodendroglial cells in the developing white matter and cortex. We also found that NG2 immunoreactivity around vessel walls, labeling pericyte cells, was increased in NO-exposed rat pups in the periventricular SVZ. In conclusion, iNO appears to act on oligodendrocyte progenitor cells, leading to increased density of mature oligodendrocytes and myelin content in the immature rat brain.
Is the Geriatric Nutritional Risk Index a Significant Predictor of Postoperative Complications in Patients with Esophageal Cancer Undergoing Esophagectomy?
Authors: Yamana Ippei , Takeno Shinsuke , Shibata Ryosuke , Shiwaku Hironari , Maki Kenji , Hashimoto Tatsuya , Shiraishi Takeshi , Iwasaki Akinori , Yamashita Yuichi
Published: March 2015

Background: The Geriatric Nutritional Risk Index (GNRI) is a new index recently introduced for predicting the risk of nutrition-related complications. The GNRI has mainly been reported as a simple and accurate tool to assess the nutritional status and prognosis of elderly patients. So far, there have been no reports of the GNRI in patients with gastrointestinal cancer. Our objective was to examine the association between the GNRI and short-term outcomes, especially postoperative complications, in patients with esophageal cancer who underwent esophagectomy and gastric tube reconstruction. Materials and Methods: The present study enrolled 122 consecutive patients with esophageal cancer who underwent esophagectomy and gastric tube reconstruction. The GNRI at admission to the hospital was calculated as follows: (1.489 × albumin in g/l) + (41.7 × present/ideal body weight). The characteristics and short-term outcomes were compared between two groups: the high (GNRI ≥90) and the low (GNRI <90) GNRI group. The mortality and morbidity rates, especially the rates regarding respiratory complications and anastomotic leakage, were investigated. Results: The mean age of the 122 patients was 63.9 ± 9.1 years (range 43-83). There were no significant differences in either patient or operative characteristics. The low GNRI group had a significantly higher rate of respiratory complications (p = 0.002). A multivariate analysis demonstrated that the GNRI was the only independent significant factor predicting respiratory complications (hazard ratio 3.41, 95% confidence interval 1.19-9.76; p = 0.022). Conclusion: The GNRI is considered to be a clinically useful marker that can be used to assess the nutritional status and predict the development of postoperative respiratory complications in patients with esophageal cancer undergoing esophagectomy and gastric tube reconstruction.
SOX3 Overdosage Permits Normal Sex Development in Females with Random X Inactivation
Authors: Igarashi Maki , Mikami Hitoshi , Katsumi Momori , Miyado Mami , Izumi Yoko , Ogata Tsutomu , Fukami Maki
Published: March 2015

Submicroscopic duplications involving SOX3 and/or its flanking regions have been identified in 46,XX individuals both with and without disorders of sex development, raising the question whether SOX3 overdosage is sufficient to induce testicular development in genetically female individuals. Here, we report a mother-daughter pair with female phenotypes and random X inactivation. The individuals carry complex X chromosomal rearrangements leading to a copy number gain of genomic regions involving SOX3 and its upstream region. The amplified DNA fragments were detected at Xq27. These results provide evidence that SOX3 overdosage permits normal sex development in 46,XX individuals with random X inactivation.
Effects of Demographic Factors on Survival Time after a Diagnosis of Amyotrophic Lateral Sclerosis
Authors: Jordan Heather , Fagliano Jerald , Rechtman Lindsay , Lefkowitz Daniel , Kaye Wendy
Published: March 2015

Background: The Agency for Toxic Substances and Disease Registry established surveillance projects to determine the incidence, prevalence, and demographic characteristics of persons with Amyotrophic Lateral Sclerosis (ALS) in defined geographic areas. There is a need to characterize and account for the survival and prognostic factors among a population-based cohort of ALS cases in the United States. Methods: A cohort of incident cases diagnosed from 2009-2011 in New Jersey was followed until death or December 31, 2013, whichever happened first. Survival was assessed using Kaplan-Meier curves and Cox proportional hazards regression was used to identify prognostic factors. Results: Sixty-four percent of incident cases died between 2009 and 2013, 93.7% specifically from ALS. Among the 456 cases studied in the survival analysis, the median survival from diagnosis was 21 months; 46% of cases survived longer than two years from diagnosis. Older age predicted shorter survival. While there is some indication of differences because of sex, race, and ethnicity, these differences were not statistically significant when accounting for age. Conclusions: New Jersey mortality data were queried to determine the vital status of a cohort of incident ALS cases and used to investigate relationships between demographic factors and survival. Results are consistent with other population-based studies. Older age was a strong predictor of shorter survival time. Additional follow-up time is needed to characterize longer-term survival.
Progesterone Receptor Isoforms A and B in Pancreatic Neuroendocrine Tumor
Authors: Yazdani Samaneh , Kasajima Atsuko , Ogata Hiroko , Felizola Saulo J.A. , Nakamura Yasuhiro , Onodera Yoshiaki , Watanabe Mika , Motoi Fuyuhiko , Unno Michiaki , Sasano Hironobu
Published: March 2015

Background: Pancreatic neuroendocrine tumors (PNETs) have been reported to express progesterone receptor (PR), and its expression has been demonstrated to be a favorable prognostic factor in these patients. We examined the status of the PR isoforms PRA and PRB in the human PNET cell line and their association with cell proliferation of the tumor cells, which is closely related to the clinical outcome of PNET patients. Methods: Quantitative RT-PCR and cell proliferation assays were performed following treatment with progesterone and RU-486 as a PR antagonist in nontransfected and PRA-transfected cells of the NET cell line QGP-1, which expresses PRB in its native state. PRA, PRB and cyclin D1 (CCND1) were immunolocalized in 87 PNET cases, and the results were compared with clinicopathological parameters. Results: CCND1, c-Fos and c-Jun mRNA levels were all significantly increased by treatment with progesterone in QGP-1 cells with PRB expression compared with PRA-transfected cells (p = 0.02, p = 0.007 and p = 0.001, respectively). The proliferative activity of QGP-1 cells with PRB expression was also significantly stimulated by the administration of progesterone (p = 0.008). PRA immunoreactivity was significantly decreased in higher-grade PNETs (p = 0.04), whereas CCND1 was significantly elevated in higher-grade PNETs (p = 0.035). Conclusion: The results of the present study demonstrate that PRA could play an inhibitory role in the cell proliferation of PNETs, possibly by inhibiting PRB-mediated signals in the presence of progesterone, which could result in decreased CCND1 expression. In addition, the status of PRA in tumor cells could be a prognostic factor in PNETs.