bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic, Epigenetic, and Environmental Contributions to Neural Tube Closure
Authors: Wilde Jonathan J. , Petersen Juliette R. , Niswander Lee
Published: October 2014

The formation of the embryonic brain and spinal cord begins as the neural plate bends to form the neural folds, which meet and adhere to close the neural tube. The neural ectoderm and surrounding tissues also coordinate proliferation, differentiation, and patterning. This highly orchestrated process is susceptible to disruption, leading to neural tube defects (NTDs), a common birth defect. Here, we highlight genetic and epigenetic contributions to neural tube closure. We describe an online database we created as a resource for researchers, geneticists, and clinicians. Neural tube closure is sensitive to environmental influences, and we discuss disruptive causes, preventative measures, and possible mechanisms. New technologies will move beyond candidate genes in small cohort studies toward unbiased discoveries in sporadic NTD cases. This will uncover the genetic complexity of NTDs and critical gene-gene interactions. Animal models can reveal the causative nature of genetic variants, the genetic interrelationships, and the mechanisms underlying environmental influences.
Messenger RNA Degradation in Bacterial Cells
Authors: Hui Monica P. , Foley Patricia L. , Belasco Joel G.
Published: October 2014

mRNA degradation is an important mechanism for controlling gene expression in bacterial cells. This process involves the orderly action of a battery of cellular endonucleases and exonucleases, some universal and others present only in certain species. These ribonucleases function with the assistance of ancillary enzymes that covalently modify the 5′ or 3′ end of RNA or unwind base-paired regions. Triggered by initiating events at either the 5′ terminus or an internal site, mRNA decay occurs at diverse rates that are transcript specific and governed by RNA sequence and structure, translating ribosomes, and bound sRNAs or proteins. In response to environmental cues, bacteria are able to orchestrate widespread changes in mRNA lifetimes by modulating the concentration or specific activity of cellular ribonucleases or by unmasking the mRNA-degrading activity of cellular toxins.
Events and Situations
Authors: Zucchi Sandro
Published: October 2014

If we inspect the role of events or situations in formal semantic theories of natural languages, a general strategy common to several theories emerges: Assume that certain linguistic constructions involve a reference to events or situations and appeal to their metaphysical properties to account for semantic properties of the constructions. I concentrate on some paradigmatic cases that illustrate this way of pursuing explanatory tasks in semantics: perception reports, adverbial modification, telicity, and attitude reports.
Learning by Failing: Ideas and Concepts to Tackle γ-Secretases in Alzheimer's Disease and Beyond
Authors: De Strooper Bart , Chávez Gutiérrez Lucía
Published: October 2014

γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all γ-secretases causes serious toxicity. Evolving insights suggest that selective inhibition of one of these proteases, or more subtle modulation of γ-secretases by stimulating their carboxypeptidase-like activity but sparing their endopeptidase activity, are potentially highly interesting approaches. The rapidly growing knowledge of regulation, assembly, and specificity of these intriguing protein complexes and the potential advent of high-resolution structural information could dramatically change the perspective on safe and efficacious γ-secretase inhibition in various disorders.
Predicting Toxicities of Reactive Metabolite–Positive Drug Candidates
Authors: Kalgutkar Amit S. , Dalvie Deepak
Published: October 2014

Because of the inability to predict and quantify the risk of idiosyncratic adverse drug reactions (IADRs) and because reactive metabolites (RMs) are thought to be responsible for the pathogenesis of some IADRs, the potential for RM formation within new chemical entities is routinely examined with the ultimate goal of eliminating or reducing the liability through iterative design. Likewise, avoidance of structural alerts is almost a standard practice in drug design. However, the perceived safety concerns associated with the use of structural alerts and/or RM screening tools as standalone predictors of toxicity risks may be overexaggerated. Numerous marketed drugs form RMs but do not cause idiosyncratic toxicity. In this review article, we present a critique of the structural alert/RM concept as applied in drug discovery and evaluate the evidence linking structural alerts and RMs to observed toxic effects. Pragmatic risk mitigation strategies to aid the advancement of drug candidates that carry a RM liability are also discussed.
Preemptive Clinical Pharmacogenetics Implementation: Current Programs in Five US Medical Centers
Authors: Dunnenberger Henry M. , Crews Kristine R. , Hoffman James M. , Caudle Kelly E. , Broeckel Ulrich , Howard Scott C. , Hunkler Robert J. , Klein Teri E. , Evans William E. , Relling Mary V.
Published: October 2014

Although the field of pharmacogenetics has existed for decades, practioners have been slow to implement pharmacogenetic testing in clinical care. Numerous publications describe the barriers to clinical implementation of pharmacogenetics. Recently, several freely available resources have been developed to help address these barriers. In this review, we discuss current programs that use preemptive genotyping to optimize the pharmacotherapy of patients. Array-based preemptive testing includes a large number of relevant pharmacogenes that impact multiple high-risk drugs. Using a preemptive approach allows genotyping results to be available prior to any prescribing decision so that genomic variation may be considered as an inherent patient characteristic in the planning of therapy. This review describes the common elements among programs that have implemented preemptive genotyping and highlights key processes for implementation, including clinical decision support.
A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant
Authors: Gross Eric R. , Zambelli Vanessa O. , Small Bryce A. , Ferreira Julio C.B. , Chen Che-Hong , Mochly-Rosen Daria
Published: October 2014

Asian Americans are one of the fastest-growing populations in the United States. A relatively large subset of this population carries a unique loss-of-function point mutation in aldehyde dehydrogenase 2 (ALDH2), ALDH2*2. Found in approximately 560 million people of East Asian descent, ALDH2*2 reduces enzymatic activity by approximately 60% to 80% in heterozygotes. Furthermore, this variant is associated with a higher risk for several diseases affecting many organ systems, including a particularly high incidence relative to the general population of esophageal cancer, myocardial infarction, and osteoporosis. In this review, we discuss the pathophysiology associated with the ALDH2*2 variant, describe why this variant needs to be considered when selecting drug treatments, and suggest a personalized medicine approach for Asian American carriers of this variant. We also discuss future clinical and translational perspectives regarding ALDH2*2 research.
Eph Receptors and Ephrins: Therapeutic Opportunities
Authors: Barquilla Antonio , Pasquale Elena B.
Published: October 2014

The erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis, and various diseases. Interaction with Eph receptor-interacting protein (ephrin) ligands on the surface of neighboring cells triggers Eph receptor kinase–dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact–dependent communication. Moreover, Eph receptors and ephrins can function independently of each other through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets, and various strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offer opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.
Molecules in Motion: Chemical Reaction and Allied Dynamics in Solution and Elsewhere
Authors: Hynes James T.
Published: October 2014

After my acceptance of the kind invitation from Todd Martínez and Mark Johnson, Co-Editors of this journal, to write this article, I had to decide just how to actually do this, given the existence of a fairly personal and extended autobiographical account of recent vintage detailing my youth, education, and assorted experiences and activities at the University of Colorado, Boulder, and later also at Ecole Normale Supérieure in Paris ( 1 ). In the end, I settled on a differently styled recounting of the adventures with my students, postdocs, collaborators, and colleagues in trying to unravel, comprehend, describe, and occasionally even predict the manifestations and consequences of the myriad assortment of molecular dances that contribute to and govern the rates and mechanisms of chemical reactions in solution (and elsewhere). The result follows.
Exosomes: Vehicles of Intercellular Signaling, Biomarkers, and Vectors of Cell Therapy
Authors: Kourembanas Stella
Published: October 2014

Mesenchymal stem cells (MSCs), whose mechanism of action is predominantly paracrine, are being widely tested for the treatment of a variety of human diseases. No one factor has been proven sufficient to mediate the therapeutic effects of MSCs. However, exosomes—membrane vesicles secreted by many cells, including MSCs—are appealing candidates as vectors of their efficacy. Exosomes can transport and deliver a large cargo of proteins, lipids, and nucleic acids and can modify cell and organ function. In addition to their key role as vehicles of intercellular communication, exosomes are increasingly recognized as biomarkers and prognosticators of disease. Moreover, they have the potential to be used as vehicles of gene and drug delivery for clinical application. This article reviews the biogenesis of exosomes, their molecular composition, and their role as messengers of intercellular communication, focusing on their potential as therapeutic vectors for stem cell therapy.
Phosphoinositide Control of Membrane Protein Function: A Frontier Led by Studies on Ion Channels
Authors: Logothetis Diomedes E. , Petrou Vasileios I. , Zhang Miao , Mahajan Rahul , Meng Xuan-Yu , Adney Scott K. , Cui Meng , Baki Lia
Published: October 2014

Anionic phospholipids are critical constituents of the inner leaflet of the plasma membrane, ensuring appropriate membrane topology of transmembrane proteins. Additionally, in eukaryotes, the negatively charged phosphoinositides serve as key signals not only through their hydrolysis products but also through direct control of transmembrane protein function. Direct phosphoinositide control of the activity of ion channels and transporters has been the most convincing case of the critical importance of phospholipid-protein interactions in the functional control of membrane proteins. Furthermore, second messengers, such as [Ca2+]i, or posttranslational modifications, such as phosphorylation, can directly or allosterically fine-tune phospholipid-protein interactions and modulate activity. Recent advances in structure determination of membrane proteins have allowed investigators to obtain complexes of ion channels with phosphoinositides and to use computational and experimental approaches to probe the dynamic mechanisms by which lipid-protein interactions control active and inactive protein states.
Hypothalamic-pituitary-adrenal axis in lethal canine Staphylococcus aureus pneumonia
Authors: Cortés-Puch Irene , Hicks Caitlin W. , Sun Junfeng , Solomon Steven B. , Eichacker Peter Q. , Sweeney Daniel A. , Nieman Lynnette K. , Whitley Elizabeth M. , Behrend Ellen N. , Natanson Charles , Danner Robert L.
Published: October 2014

The clinical significance and even existence of critical illness-related corticosteroid insufficiency is controversial. Here, hypothalamic-pituitary-adrenal (HPA) function was characterized in severe canine Staphylococcus aureus pneumonia. Animals received antibiotics and titrated life-supportive measures. Treatment with dexamethasone, a glucocorticoid, but not desoxycorticosterone, a mineralocorticoid, improves outcome in this model. Total and free cortisol, adrenocorticotropic hormone (ACTH). and aldosterone levels, as well as responses to exogenous ACTH were measured serially. At 10 h after the onset of infection, the acute HPA axis stress response, as measured by cortisol levels, exceeded that seen with high-dose ACTH stimulation but was not predictive of outcome. In contrast to cortisol, aldosterone was largely autonomous from HPA axis control, elevated longer, and more closely associated with survival in early septic shock. Importantly, dexamethasone suppressed cortisol and ACTH levels and restored ACTH responsiveness in survivors. Differing strikingly, nonsurvivors, sepsis-induced hypercortisolemia, and high ACTH levels as well as ACTH hyporesponsiveness were not influenced by dexamethasone. During septic shock, only serial measurements and provocative testing over a well-defined timeline were able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identify a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies.
Early methyl donor deficiency alters cAMP signaling pathway and neurosteroidogenesis in the cerebellum of female rat pups
Authors: El Hajj Chehadeh Sarah , Dreumont Natacha , Willekens Jérèmy , Canabady-Rochelle Laetitia , Jeannesson Elise , Alberto Jean-Marc , Daval Jean-Luc , Guéant Jean-Louis , Leininger-Muller Brigitte
Published: October 2014

Early deficiency of the methyl donors folate and vitamin B12 produces hyperhomocysteinemia and cognitive and motor disorders in 21-day-old rat pups from dams fed a diet deficient in methyl donors during gestation and lactation. These disorders are associated with impaired neurogenesis and altered synaptic plasticity in cerebellum. We aimed to investigate whether these disorders could be related to impaired expression of neurosteroidogenesis-associated proteins, key regulator receptors, and some steroid content in the cerebellum. The methyl donor deficiency produced a decreased concentration of folate and vitamin B12, along with accumulation of homocysteine in Purkinje cells in both sexes, whereas the S-adenosylmethionine/ S-adenosylhomocysteine ratio was reduced only in females. The transcription level and protein expression of StAR, aromatase, ERα, ERβ, and LH receptors were decreased only in females, with a marked effect in Purkinje cells, as shown by immunohistochemistry. Consistently, reduced levels of estradiol and pregnenolone were measured in cerebellar extracts of females only. The decreased expression levels of the transcriptional factors CREB, phospho-CREB, and SF-1, the lesser increase of cAMP concentration, and the lower level of phospho-PKC in the cerebellum of deficient females suggest that the activation of neurosteroidogenesis via cAMP-mediated signaling pathways associated with LHR activation would be altered. In conclusion, a gestational methyl donor deficiency impairs neurosteroidogenesis in cerebellum in a sex-dependent manner.
Type 2 iodothyronine deiodinase is upregulated in rat slow- and fast-twitch skeletal muscle during cold exposure
Authors: Louzada Ruy A. , Santos Maria C. S. , Cavalcanti-de-Albuquerque João Paulo A. , Rangel Igor F. , Ferreira Andrea C. F. , Galina Antonio , Werneck-de-Castro Joao Pedro S. , Carvalho Denise P.
Published: October 2014

During cold acclimation, shivering is progressively replaced by nonshivering thermogenesis. Brown adipose tissue (BAT) and skeletal muscle are relevant for nonshivering thermogenesis, which depends largely on thyroid hormone. Since the skeletal muscle fibers progressively adapt to cold exposure through poorly defined mechanisms, our intent was to determine whether skeletal muscle type 2 deiodinase (D2) induction could be implicated in the long-term skeletal muscle cold acclimation. We demonstrate that in the red oxidative soleus muscle, D2 activity increased 2.3-fold after 3 days at 4°C together with the brown adipose tissue D2 activity, which increased 10-fold. Soleus muscle and BAT D2 activities returned to the control levels after 10 days of cold exposure, when an increase of 2.8-fold in D2 activity was detected in white glycolytic gastrocnemius but not in red oxidative gastrocnemius fibers. Propranolol did not prevent muscle D2 induction, but it impaired the decrease of D2 in BAT and soleus after 10 days at 4°C. Cold exposure is accompanied by increased oxygen consumption, UCP3, and PGC-1α genes expression in skeletal muscles, which were partialy prevented by propranolol in soleus and gastrocnemius. Serum total and free T3is increased during cold exposure in rats, even after 10 days, when BAT D2 is already normalized, suggesting that skeletal muscle D2 activity contributes significantly to circulating T3under this adaptive condition. In conclusion, cold exposure is accompanied by concerted changes in the metabolism of BAT and oxidative and glycolytic skeletal muscles that are paralleled by type 2 deiodinase activation.
Representation of remembered stimuli and task information in the monkey dorsolateral prefrontal and posterior parietal cortex
Authors: Qi Xue-Lian , Elworthy Anthony C. , Lambert Bryce C. , Constantinidis Christos
Published: October 2014

Both dorsolateral prefrontal and posterior parietal cortex have been implicated in spatial working memory and representation of task information. Prior experiments training animals to recall the first of a sequence of stimuli and examining the effect of subsequent distractors have identified increased ability of the prefrontal cortex to represent remembered stimuli and filter distractors. It is unclear, however, if this prefrontal functional specialization extends to stimuli appearing earlier in a sequence, when subjects are cued to remember subsequent ones. It is also not known how task information interacts with persistent activity representing remembered stimuli and distractors in the two areas. To address these questions, we trained monkeys to remember either the first or second of two stimuli presented in sequence and recorded neuronal activity from the posterior parietal and dorsolateral prefrontal cortex. The prefrontal cortex was better able to represent the actively remembered stimulus, whereas the posterior parietal cortex was more modulated by distractors; however, task effects interfered with this representation. As a result, large proportions of neurons with persistent activity and task effects exhibited a preference for a stimulus when it appeared as a distractor in both areas. Additionally, prefrontal neurons were modulated to a greater extent by task factors during the delay period of the task. The results indicate that the prefrontal cortex is better able than the posterior parietal cortex to differentiate between distractors and actively remembered stimuli and is more modulated by the task; however, this relative preference is highly context dependent and depends on the specific requirements of the task.
Three timescales in prism adaptation
Authors: Inoue Masato , Uchimura Motoaki , Karibe Ayaka , O'Shea Jacinta , Rossetti Yves , Kitazawa Shigeru
Published: October 2014

It has been proposed that motor adaptation depends on at least two learning systems, one that learns fast but with poor retention and another that learns slowly but with better retention (Smith MA, Ghazizadeh A, Shadmehr R. PLoS Biol 4: e179, 2006). This two-state model has been shown to account for a range of behavior in the force field adaptation task. In the present study, we examined whether such a two-state model could also account for behavior arising from adaptation to a prismatic displacement of the visual field. We first confirmed that an “adaptation rebound,” a critical prediction of the two-state model, occurred when visual feedback was deprived after an adaptation-extinction episode. We then examined the speed of decay of the prism aftereffect (without any visual feedback) after repetitions of 30, 150, and 500 trials of prism exposure. The speed of decay decreased with the number of exposure trials, a phenomenon that was best explained by assuming an “ultraslow” system, in addition to the fast and slow systems. Finally, we compared retention of aftereffects 24 h after 150 or 500 trials of exposure: retention was significantly greater after 500 than 150 trials. This difference in retention could not be explained by the two-state model but was well explained by the three-state model as arising from the difference in the amount of adaptation of the “ultraslow process.” These results suggest that there are not only fast and slow systems but also an ultraslow learning system in prism adaptation that is activated by prolonged prism exposure of 150–500 trials.
Dietary supplementation with polyunsaturated fatty acid during pregnancy modulates DNA methylation at IGF2/H19 imprinted genes and growth of infants
Authors: Lee Ho-Sun , Barraza-Villarreal Albino , Biessy Carine , Duarte-Salles Talita , Sly Peter D. , Ramakrishnan Usha , Rivera Juan , Herceg Zdenko , Romieu Isabelle
Published: October 2014

Epigenetic regulation of imprinted genes is regarded as a highly plausible explanation for linking dietary exposures in early life with the onset of diseases during childhood and adulthood. We sought to test whether prenatal dietary supplementation with docosahexaenoic acid (DHA) during pregnancy may modulate epigenetic states at birth. This study was based on a randomized intervention trial conducted in Mexican pregnant women supplemented daily with 400 mg of DHA or a placebo from gestation week 18–22 to parturition. We applied quantitative profiling of DNA methylation states at IGF2 promoter 3 ( IGF2 P3), IGF2 differentially methylated region (DMR), and H19 DMR in cord blood mononuclear cells of the DHA-supplemented group ( n = 131) and the control group ( n = 130). In stratified analyses, DNA methylation levels in IGF2 P3 were significantly higher in the DHA group than the control group in preterm infants ( P = 0.04). We also observed a positive association between DNA methylation levels and maternal body mass index; IGF2 DMR methylation was higher in the DHA group than the control group in infants of overweight mothers ( P = 0.03). In addition, at H19 DMR, methylation levels were significantly lower in the DHA group than the control group in infants of normal weight mothers ( P = 0.01). Finally, methylation levels at IGF2/H19 imprinted regions were associated with maternal BMI. These findings suggest that epigenetic mechanisms may be modulated by DHA, with potential impacts on child growth and development.
Cardiovascular and Thermal Response to Dry-Sauna Exposure in Healthy Subjects
Authors: Zalewski Pawel , Zawadka-Kunikowska Monika , Słomko Joanna , Szrajda Justyna , Klawe Jacek J. , Tafil-Klawe Malogorzata , Newton Julia
Published: October 2014

Dry-sauna is a strong thermal stimulus and is commonly used all over the world. The aim of this experiment was to comprehensively analyse cardiovascular and autonomic changes that result from an increase in core body temperature during sauna bath. The study included 9 healthy men with mean age 26.7 ± 3.0 years and comparable anthropomorphical characteristics. Each subject was exposed to one 15-minute session of dry-sauna treatment at 100°C and 30–40% humidity. The autonomic and baseline cardiovascular (i.e., hemodynamic and contractility) parameters were measured noninvasively with Task Force Monitor. Cardiovascular autonomic functions were assessed using baroreceptor reflex sensitivity (BRS) and spectral analysis of heart rate (HRV) and blood pressure (BPV) variability. Measurements were performed four times, at the following stages “before sauna,” “after sauna,” “sauna + 3 h,” and “sauna + 6 h.” The first recording constituted a baseline for the subsequent three measurements. The changes in core body temperature were determined with the Vital Sense telemetric measurement system. Results show that exposure to the extreme external environmental conditions of dry-sauna does not compromise homeostasis in healthy persons. The hemodynamic changes induced by heating are efficiently compensated by the cardiovascular system and do not exert negative effects upon its short-term regulatory potential.
A Ready-to-Eat Antioxidant Rich Appetizer Based on Coleus
aromaticus: Its Development and Shelf Life Evaluation
Authors: Kumar Pawan , Wadikar Dadasaheb , Patki Prakash
Published: October 2014

Antioxidant rich products are valued due to their health benefits and appetizers are required in several pathological and geographical stress situations such as prolonged exposure to altitude. The paper deals with the development of a shelf stable RTE (ready-to-eat) antioxidant rich herbal appetizer convenient to the consumer. Using ginger and Karpurvalli (Coleus aromaticus) as two independent variables, a central composite design with 13 experimental combinations was obtained. These combinations were processed by concentration and dehydration into the appetizer RTE munches using preprocessed ingredients and evaluated for antioxidant activity, vitamin C, and sensory characteristics. The product optimized using Design Expert Statistical Software had the proximate composition of 11.4% fat, 2.3% protein, and 75.0% carbohydrates, supplying about 82.36 Kcals per munch of 20 g. The munches packed in metalized polyester pouches had a shelf life of 10 months at 28 ± 5°C as well as 37°C storage. The RTE appetizer based on Coleus aromaticus was developed with excellent sensory properties and shelf stability.
Heuristic-Based Firefly Algorithm for Bound Constrained Nonlinear Binary Optimization
Authors: Costa M. Fernanda P. , Rocha Ana Maria A. C. , Francisco Rogério B. , Fernandes Edite M. G. P.
Published: October 2014

Firefly algorithm (FA) is a metaheuristic for global optimization. In this paper, we address the practical testing of a heuristic-based FA (HBFA) for computing optima of discrete nonlinear optimization problems, where the discrete variables are of binary type. An important issue in FA is the formulation of attractiveness of each firefly which in turn affects its movement in the search space. Dynamic updating schemes are proposed for two parameters, one from the attractiveness term and the other from the randomization term. Three simple heuristics capable of transforming real continuous variables into binary ones are analyzed. A new sigmoid “erf” function is proposed. In the context of FA, three different implementations to incorporate the heuristics for binary variables into the algorithm are proposed. Based on a set of benchmark problems, a comparison is carried out with other binary dealing metaheuristics. The results demonstrate that the proposed HBFA is efficient and outperforms binary versions of differential evolution (DE) and particle swarm optimization (PSO). The HBFA also compares very favorably with angle modulated version of DE and PSO. It is shown that the variant of HBFA based on the sigmoid “erf” function with “movements in continuous space” is the best, in terms of both computational requirements and accuracy.
Influence of Upstream and Downstream Compressor Stators on Rotor Exit Flow Field
Authors: Key Nicole L.
Published: October 2014

Measurements acquired at the rotor exit plane illuminate the interaction of the rotor with the upstream vane row and the downstream vane row. The relative phase of the upstream and downstream vane rows is adjusted using vane clocking so that the effect of the upstream propagating potential field from the downstream stator can be distinguished from the effects associated with the wakes shed from the upstream stator. Unsteady absolute flow angle information shows that the downstream potential field causes the absolute flow angle to increase in the vicinity of the downstream stator leading edge. The presence of Stator 1 wake is also detected at this measurement plane using unsteady total pressure data. The rotor wakes are measured at different circumferential locations across the vane passage, and the influence of Stator 1 wake on the suction side of the rotor wake is evident. Also, the influence of the downstream stator is detected on the pressure side of the rotor wake for a particular clocking configuration. Understanding the role of the surrounding vane rows on rotor wake development will lead to improved comparison between experimental data and results from computational models.
Pyoderma Gangrenosum: A Review of Clinical Features and Outcomes of 23 Cases Requiring Inpatient Management
Authors: Ye Mingwei Joel , Ye Joshua Mingsheng
Published: October 2014

Pyoderma gangrenosum (PG) is a rare dermatological disorder characterised by the rapid progression of a painful, necrolytic ulcer. This study retrospectively identified patients who were admitted and treated for PG during a 10-year period (2003–2013). Twenty-three patients were included in this study, 16 women and seven men. The mean age at initial admission was 62.8 years (range 30 to 89 years). Lesions were localised to lower limb in 13 patients, peristomal region in four, breast in three, and upper limb in one, and two patients had PG at multiple sites. The variants of PG noted were ulcerative (18), bullous (2), vegetative (2), and pustular (1). Associated systemic diseases were observed in 11 patients (47.8%). Systemic therapies were initiated in 21 patients while two patients received topical treatments. The mean length of hospital stay was 47 days (range 5 to 243 days) and five patients died during their admissions. Seven patients required readmissions for exacerbations of their PG. Our study showed that patients admitted for treatment of PG had high morbidity and mortality. This study also highlights the importance of early and aggressive treatment of patients admitted with PG as well as treating associated systemic diseases and wound infections.
From Single Atoms to Engineered “Super-Atoms”: Interfacing Photons and Atoms in Free Space
Authors: Miroshnychenko Yevhen
Published: October 2014

During the last decades the development of laser cooling and trapping has revolutionized the field of quantum optics. Now we master techniques to control the quantum properties of atoms and light, even at a single atom and single photon level. Understanding and controlling interactions of atoms and light both on the microscopic single particle and on the macroscopic collective levels, are two of the very active directions of the current research in this field. The goal is to engineer quantum systems with tailored properties designed for specific applications. One of the ambitious applications on this way is interfacing quantum information for quantum communication and quantum computing. We summarize here theoretical ideas and experimental methods for interfacing atom-based quantum memories with single flying photons.
Disseminated Alveolar Hydatid Disease Resembling a Metastatic Malignancy: A Diagnostic Challenge—A Report of Two Cases
Authors: Bulakci Mesut , Yilmaz Erdem , Cengel Ferhat , Gocmez Ahmet , Kartal Merve Gulbiz , Isik Emine Goknur , Celenk Erhan , Yegen Gulcin , Salmaslioglu Artur
Published: October 2014

Alveolar hydatid disease or alveolar echinococcosis is a disease of the parasiteEchinococcus multilocularisthat is potentially fatal if left untreated. It primarily involves the liver but can be disseminated to other organs like the lungs and the brain by hematogenous route. Multiorgan involvement and the aggressive appearance of lesions make alveolar hydatid disease easy to confuse with a metastatic malignancy. For this reason, histopathological confirmation is essential for definite diagnosis. We present the imaging features of this disease in two patients in order to emphasize that these lesions can be easily misdiagnosed as malignancies.
Interobserver Agreement for Single Operator Choledochoscopy Imaging: Can We Do Better?
Authors: Sethi Amrita , Doukides Theodore , Sejpal Divyesh V. , Pleskow Douglas K. , Slivka Adam , Adler Douglas G. , Shah Raj J. , Edmundowicz Steven A. , Itoi Takao , Petersen Bret T. , Gress Frank G. , Gaidhane Monica , Kahaleh Michel
Published: October 2014

Background. The SpyGlass Direct Visualization System (Boston Scientific, Natick, MA) is routinely used during single operator choledochoscopy (SOC) to identify biliary lesions or strictures with a diagnostic accuracy up to 88%. The objective of this study was to determine the interobserver agreement (IOA) of modified scoring criteria for diagnosing biliary lesions/strictures. Methods. 27 SPY SOC video clips were reviewed and scored by 9 interventional endoscopists based on published criteria that included the presence and severity of surface structure, vasculature visualization, lesions, and findings. Results. Overall IOA was “slight” for all variables. The K statistics are as follows: surface (K=0.12, SE = 0.02); vessels (K=0.14, SE = 0.02); lesions (K=0.11, SE = 0.02); findings (K=0.08, SE = 0.03); and final diagnosis (K=0.08, SE = 0.02). The IOA for “findings” and “final diagnosis” was also only “slight.” The final diagnosis was malignant (11), benign (11), and indeterminate (5). Conclusion. IOA using the modified criteria of SOC images was slight to almost poor. The average accuracy was less than 50%. These findings reaffirm that imaging criteria for benign and malignant biliary pathology need to be formally established and validated.
Seasonal Variation and Frequency Distribution of Ectoparasites in Crossbreed Cattle in Southeastern Brazil
Authors: Ferraz da Costa Maria do Socorro , Guimarães Marcos Pezzi , Lima Walter dos Santos , Ferraz da Costa Ana Julia , Facury Filho Elias Jorge , Araujo Ricardo Nascimento
Published: October 2014

The aims of this study were to evaluate the seasonal variation and frequency distribution of Rhipicephalus (Boophilus) microplus, Haematobia irritans, and Dermatobia hominis on crossbred heifers under field conditions in the northeast of Minas Gerais state, southeastern Brazil. From November 2007 to September 2009 (23 months), 40 heifers aged 16.6±2.4 months were divided into groups A (1/4 Holstein × 3/4 Gir) and B (1/2 Holstein × 1/2 Gir) and had the monthly infestation estimated along with the climatic conditions. The mean maximum and minimum temperatures were 28.5 and 19°C, respectively. The ectoparasites were present on animals in all months of the year. The levels of ticks on the animals were low (3.0±0.2 ticks/animal), with the highest density in midwinter. The temperature was the climatic factor that most influenced the tick levels. The population of H. irritans (13.9±0.3 flies/animal) and D. hominis (1.5±0.2 larvae/animal) on heifers was more influenced by rainfall and exhibited two population peaks during the year. 1/2 Holstein heifers harbored significantly more H. irritans and D. hominis than 1/4 Holstein heifers. The results are discussed considering the most appropriate periods to apply ectoparasiticides and the genetic make-up of the animals.
A Theoretical Study of Bulk Tungsten (W) Based on Momentum Transfer (q-Dependent)
Authors: Rai D. P. , Thapa R. K.
Published: October 2014

The ground state electronic properties of bulk (W) were studied within the density functional theory (DFT). We have also analyzed the momentum- (q-) dependent loss function, dielectric constant, and optical conductivity (OC) within TD-DFT random-phase approximation (RPA). The loss function is plotted in the energy range 0–55 eV. The energy loss function spectrum shows four prominent peaks, two lower peaks below along with two sharp peaks above 30 eV. The different nature of peaks depends on the momentum transfer q. The peak caused by interband transition showed a less pronounced dispersion. From the dielectric function curve we have predicted the plasmon excitation at around 1.75 eV and calculated the corresponding plasma frequency (ωp)=26.585×1014 s−1.
Association between Anxiety Levels and Weight Change in the Multiethnic Study of Atherosclerosis
Authors: Rieke Katherine , Durazo-Arvizu Ramon , Liu Kiang , Michos Erin D. , Luke Amy , Kramer Holly
Published: October 2014

Objective. To examine the association between anxiety and weight change in a multiethnic cohort followed for approximately 10 years.Methods. The study population consisted of participants of the multiethnic study of atherosclerosis who met specified inclusion criteria (n= 5,799). Weight was measured at baseline and four subsequent follow-up exams. Anxiety was analyzed as sex-specific anxiety quartiles (QANX). The relationship between anxiety level and weight change was examined using a mixed-effect model with weight as the dependent variable, anxiety and time as the independent variables, and adjusted for covariates.Results. Average annual weight change (range) was −0.17 kg (−6.04 to 4.38 kg) for QANX 1 (lowest anxiety), −0.16 kg (−10.71 to 4.45 kg) for QANX 2, −0.15 kg (−8.69 to 6.39 kg) for QANX 3, and −0.20 kg (−7.12 to 3.95 kg) for QANX 4 (highest anxiety). No significant association was noted between QANX and weight change. However, the highest QANX was associated with a −2.48 kg (95% CI = −3.65, −1.31) lower baseline weight compared to the lowest QANX after adjustment for all covariates.Conclusions. Among adults, age 45–84, higher levels of anxiety, defined by the STPI trait anxiety scale, are associated with lower average baseline weight but not with weight change.
Mitochondrial DNA Copy Number and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Risk in Two Prospective Studies
Authors: Kim Christopher , Bassig Bryan A. , Seow Wei Jie , Hu Wei , Purdue Mark P. , Huang Wen-Yi , Liu Chin-San , Cheng Wen-Ling , Männistö Satu , Vermeulen Roel , Weinstein Stephanie J. , Lim Unhee , Hosgood H. Dean , Bonner Matthew R. , Caporaso Neil E. , Albanes Demetrius , Lan Qing , Rothman Nathaniel
Published: October 2014

Background: Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study and pooled with published ATBC (Alpha-Tocopherol, Beta-Carotene) data.

Methods: In PLCO, 292 NHL cases (95 CLL/SLL cases) and 301 controls were pooled with 142 NHL cases (47 CLL/SLL cases) and 142 controls from ATBC. Subjects answered a questionnaire and provided blood. DNA was extracted from prediagnostic peripheral white blood, and mtDNA CN assayed by quantitative polymerase chain reaction. Unconditional logistic regression estimated mtDNA CN and NHL risk by odds ratios (OR) and 95% confidence intervals (95% CI).

Results: Greater mtDNA CN was associated with increased risk of CLL/SLL among males in PLCO (3rd vs. 1st tertile: OR, 2.21; 95% CI, 1.03–4.72; Ptrend: 0.049) and pooled (T3 vs. T1: OR, 3.12; 95% CI, 1.72–5.68; Ptrend: 0.0002). Association was stronger among male smokers (Ptrend: <0.0001) and essentially identical for cases diagnosed <6, >6–8, and >8 years from blood draw (pooled: Pinteraction: 0.65). mtDNA CN and risk of other NHL subtypes and multiple myeloma showed no association.

Conclusions and Impact: Mitochondrial DNA CN was associated with risk of CLL/SLL in males/male smokers. The risk was observed among cases diagnosed as long as 8 years after blood draw. These results suggest that higher mtDNA CN may reflect a process involved in CLL/SLL development. Cancer Epidemiol Biomarkers Prev; 24(1); 148–53. ©2014 AACR.
A Phase II Study of the Efficacy and Safety of the Combination Therapy of the MEK Inhibitor Refametinib (BAY 86-9766) Plus Sorafenib for Asian Patients with Unresectable Hepatocellular Carcinoma
Authors: Lim Ho Yeong , Heo Jeong , Choi Hye Jin , Lin Cheng-Yao , Yoon Jung-Hwan , Hsu Chiun , Rau Kun-Ming , Poon Ronnie T.P. , Yeo Winnie , Park Joong-Won , Tay Miah Hiang , Hsieh Wen-Son , Kappeler Christian , Rajagopalan Prabhu , Krissel Heiko , Jeffers Michael , Yen Chia-Jui , Tak Won Young
Published: October 2014

Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177).

Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability.

Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients.

Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. Clin Cancer Res; 20(23); 5976–85. ©2014 AACR.
A Tissue Biomarker–Based Model That Identifies Patients with a High Risk of Distant Metastasis and Differential Survival by Length of Androgen Deprivation Therapy in RTOG Protocol 92-02
Authors: Pollack Alan , Dignam James J. , Diaz Dayssy A. , Wu Qian , Stoyanova Radka , Bae Kyounghwa , Dicker Adam P. , Sandler Howard , Hanks Gerald E. , Feng Felix Y.
Published: October 2014

Purpose: To examine the relationship between the expression of 7 promising apoptotic/cell proliferation proteins (Ki-67, p53, MDM2, bcl-2, bax, p16, and Cox-2) and risk of distant metastasis.

Experimental Design: RTOG 92-02 compared external beam radiotherapy (EBRT) to approximately 70 Gy + short-term androgen deprivation therapy (STADT) with EBRT + long-term ADT (LTADT). Immunohistochemical analysis was available for ≥4 biomarkers in 616 of 1,521 assessable cases. Biomarkers were evaluated individually and jointly via multivariable modeling of distant metastasis using competing risks hazards regression, adjusting for age, prostate-specific antigen, Gleason score, T stage, and treatment.

Results: Modeling identified four biomarkers (Ki-67, MDM2, p16 and Cox-2) that were jointly associated with distant metastasis. The c-index was 0.77 for the full model and 0.70 for the model without the biomarkers; a relative improvement of about 10% (likelihood ratio P < 0.001). Subdivision of the patients into quartiles based on predicted distant metastasis risk identified a high-risk group with 10-year distant metastasis risk of 52.5% after EBRT + STADT and 31% with EBRT + LTADT; associated 10-year prostate cancer–specific mortality (PCSM) risks were 45.9% and 14.5% with STADT and LTADT.

Conclusion: Four biomarkers were found to contribute significantly to a model that predicted distant metastasis and identified a subgroup of patients at a particularly high risk of both distant metastasis and PCSM when EBRT + STADT was used. LTADT resulted in significant reductions in distant metastasis and improvements in PCSM, and there was a suggestion of greater importance in the very high risk subgroup. Clin Cancer Res; 20(24); 6379–88. ©2014 AACR.
Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer
Authors: Suryawanshi Swati , Huang Xin , Elishaev Esther , Budiu Raluca A. , Zhang Lixin , Kim SungHwan , Donnellan Nicole , Mantia-Smaldone Gina , Ma Tianzhou , Tseng George , Lee Ted , Mansuria Suketu , Edwards Robert P. , Vlad Anda M.
Published: October 2014

Purpose: Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear-cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC).

Experimental Design: RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n = 32), benign endometriosis (n = 30), atypical endometriosis (n = 15), and EAOC (n = 43). Serous tumors (n = 15) were included as nonendometriosis-associated controls. The immune microenvironment was profiled using Nanostring and the nCounter GX Human Immunology Kit, comprising probes for a total of 511 immune genes.

Results: One third of the patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer-like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation.

Conclusions: These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC. Clin Cancer Res; 20(23); 6163–74. ©2014 AACR.