bluuebunny/crossref_metadata_2025 huggingface dataset:
How Many Is Enough? Effect of Sample Size in Inter-Subject Correlation Analysis of fMRI
Authors: Pajula Juha , Tohka Jussi
Published: January 2016

Inter-subject correlation (ISC) is a widely used method for analyzing functional magnetic resonance imaging (fMRI) data acquired during naturalistic stimuli. A challenge in ISC analysis is to define the required sample size in the way that the results are reliable. We studied the effect of the sample size on the reliability of ISC analysis and additionally addressed the following question: How many subjects are needed for the ISC statistics to converge to the ISC statistics obtained using a large sample? The study was realized using a large block design data set of 130 subjects. We performed a split-half resampling based analysis repeatedly sampling two nonoverlapping subsets of 10–65 subjects and comparing the ISC maps between the independent subject sets. Our findings suggested that with 20 subjects, on average, the ISC statistics had converged close to a large sample ISC statistic with 130 subjects. However, the split-half reliability of unthresholded and thresholded ISC maps improved notably when the number of subjects was increased from 20 to 30 or more.
Restoration of Partial Blurred Image Based on Blur Detection and Classification
Authors: Yang Dong , Qin Shiyin
Published: January 2016

A new restoration algorithm for partial blurred image which is based on blur detection and classification is proposed in this paper. Firstly, a new blur detection algorithm is proposed to detect the blurred regions in the partial blurred image. Then, a new blur classification algorithm is proposed to classify the blurred regions. Once the blur class of the blurred regions is confirmed, the structure of the blur kernels of the blurred regions is confirmed. Then, the blur kernel estimation methods are adopted to estimate the blur kernels. In the end, the blurred regions are restored using nonblind image deblurring algorithm and replace the blurred regions in the partial blurred image with the restored regions. The simulated experiment shows that the proposed algorithm performs well.
Obesity Reduces Cognitive and Motor Functions across the Lifespan
Authors: Wang Chuanming , Chan John S. Y. , Ren Lijie , Yan Jin H.
Published: January 2016

Due to a sedentary lifestyle, more and more people are becoming obese nowadays. In addition to health-related problems, obesity can also impair cognition and motor performance. Previous results have shown that obesity mainly affects cognition and motor behaviors through altering brain functions and musculoskeletal system, respectively. Many factors, such as insulin/leptin dysregulation and inflammation, mediate the effect of obesity and cognition and motor behaviors. Substantial evidence has suggested exercise to be an effective way to improve obesity and related cognitive and motor dysfunctions. This paper aims to discuss the association of obesity with cognition and motor behaviors and its underlying mechanisms. Following this, mechanisms of exercise to improve obesity-related dysfunctions are described. Finally, implications and future research direction are raised.
An Inverse Robust Optimisation Approach for a Class of Vehicle Routing Problems under Uncertainty
Authors: Sun Liang , Wang Bing
Published: January 2016

There is a trade-off between the total penalty paid to customers (TPC) and the total transportation cost (TTC) in depot for vehicle routing problems under uncertainty (VRPU). The trade-off refers to the fact that the TTC in depot inevitably increases when the TPC decreases andvice versa. With respect to this issue, the vehicle routing problem (VRP) with uncertain customer demand and travel time was studied to optimise the TPC and the TTC in depot. In addition, an inverse robust optimisation approach was proposed to solve this kind of VRPU by combining the ideas of inverse optimisation and robust optimisation so as to improve both the TPC and the TTC in depot. The method aimed to improve the corresponding TTC of the robust optimisation solution under the minimum TPC through minimising the adjustment of benchmark road transportation cost. According to the characteristics of the inverse robust optimisation model, a genetic algorithm (GA) and column generation algorithm are combined to solve the problem. Moreover, 39 test problems are solved by using an inverse robust optimisation approach: the results show that both the TPC and TTC obtained by using the inverse robust optimisation approach are less than those calculated using a robust optimisation approach.
N100 Repetition Suppression Indexes Neuroplastic Defects in Clinical High Risk and Psychotic Youth
Authors: Gonzalez-Heydrich Joseph , Bosquet Enlow Michelle , D’Angelo Eugene , Seidman Larry J. , Gumlak Sarah , Kim April , Woodberry Kristen A. , Rober Ashley , Tembulkar Sahil , O’Donnell Kyle , Hamoda Hesham M. , Kimball Kara , Rotenberg Alexander , Oberman Lindsay M. , Pascual-Leone Alvaro , Keshavan Matcheri S. , Duffy Frank H.
Published: January 2016

Highly penetrant mutations leading to schizophrenia are enriched for genes coding for N-methyl-D-aspartate receptor signaling complex (NMDAR-SC), implicating plasticity defects in the disease’s pathogenesis. The importance of plasticity in neurodevelopment implies a role for therapies that target these mechanisms in early life to prevent schizophrenia. Testing such therapies requires noninvasive methods that can assess engagement of target mechanisms. The auditory N100 is an obligatory cortical response whose amplitude decreases with tone repetition. This adaptation may index the health of plasticity mechanisms required for normal development. We exposed participants aged 5 to 17 years with psychosisn=22, at clinical high risk (CHR) for psychosisn=29, and healthy controlsn=17to an auditory tone repeated 450 times and measured N100 adaptation (mean amplitude during first 150 tones − mean amplitude during last 150 tones). N100 adaptation was reduced in CHR and psychosis, particularly among participants <13 years old. Initial N100 blunting partially accounted for differences. Decreased change in the N100 amplitude with tone repetition may be a useful marker of defects in neuroplastic mechanisms measurable early in life.
Temperature Dependence of Sensors Based on Silver-Decorated Nitrogen-Doped Multiwalled Carbon Nanotubes
Authors: Gracia-Espino Eduardo , Rebollo-Plata Bernabé , Martínez-Gutiérrez Hugo , Muñoz-Sandoval Emilio , López-Urías Florentino , Endo Morinobu , Terrones Humberto , Terrones Mauricio
Published: January 2016

Vapor sensors are easily fabricated onto alumina substrates using foils of silver-decorated nitrogen-doped multiwalled carbon nanotubes (CNX-MWNTs-Ag) as active sensing material. The vapor sensors are tested using carbon disulfide, acetone, ethanol, and chloroform vapors. The CNX-MWNTs are produced by chemical vapor deposition process and then decorated with 14 nm Ag nanoparticles (Ag-NPs). The samples are characterized using scanning electron microscopy, transmission electron microscopy, and X-ray diffraction. Our results demonstrate that Ag-decorated CNX-MWNTs exhibit a better response and sensitivity when compared with pristine CNX-MWNTs based sensors, making them promising candidates for air-pollutants environmental monitoring. The temperature effect on the sensor performance is also studied; we found that the detection mechanism could be tuned from physisorption, at room temperature, to chemisorption at higher working temperature. Finally, first-principles density functional calculations are carried out to understand the interactions between the systems involved in the sensors, finding good agreement between experimental results and the theoretical approach.
Body Perception and Action Following Deafness
Authors: Houde M. S. , Landry S. P. , Pagé S. , Maheu M. , Champoux F.
Published: January 2016

The effect of deafness on sensory abilities has been the topic of extensive investigation over the past decades. These investigations have mostly focused on visual capacities. We are only now starting to investigate how the deaf experience their own bodies and body-related abilities. Indeed, a growing corpus of research suggests that auditory input could play an important role in body-related processing. Deafness could therefore disturb such processes. It has also been suggested that many unexplained daily difficulties experienced by the deaf could be related to deficits in this underexplored field. In the present review, we propose an overview of the current state of knowledge on the effects of deafness on body-related processing.
Comparative Study on Various Authentication Protocols in Wireless Sensor Networks
Authors: Rajeswari S. Raja , Seenivasagam V.
Published: January 2016

Wireless sensor networks (WSNs) consist of lightweight devices with low cost, low power, and short-ranged wireless communication. The sensors can communicate with each other to form a network. In WSNs, broadcast transmission is widely used along with the maximum usage of wireless networks and their applications. Hence, it has become crucial to authenticate broadcast messages. Key management is also an active research topic in WSNs. Several key management schemes have been introduced, and their benefits are not recognized in a specific WSN application. Security services are vital for ensuring the integrity, authenticity, and confidentiality of the critical information. Therefore, the authentication mechanisms are required to support these security services and to be resilient to distinct attacks. Various authentication protocols such as key management protocols, lightweight authentication protocols, and broadcast authentication protocols are compared and analyzed for all secure transmission applications. The major goal of this survey is to compare and find out the appropriate protocol for further research. Moreover, the comparisons between various authentication techniques are also illustrated.
Boundary-Layer Characteristics of Persistent Regional Haze Events and Heavy Haze Days in Eastern China
Authors: Huaqing Peng , Duanyang Liu , Bin Zhou , Yan Su , Jiamei Wu , Hao Shen , Jiansu Wei , Lu Cao
Published: January 2016

This paper analyzed the surface conditions and boundary-layer climate of regional haze events and heavy haze in southern Jiangsu Province in China. There are 5 types with the surface conditions which are equalized pressure (EQP), the advancing edge of a cold front (ACF), the base of high pressure (BOH), the backside of high pressure (BAH), the inverted trough of low pressure (INT), and saddle pressure (SAP) with the haze days. At that time, 4 types are divided with the regional haze events and each of which has a different boundary-layer structure. During heavy haze, the surface mainly experiences EQP, ACF, BOH, BAH, and INT which also have different boundary-layer structures.
Potential Role of JAK-STAT Signaling Pathway in the Neurogenic-to-Gliogenic Shift in Down Syndrome Brain
Authors: Lee Han-Chung , Tan Kai-Leng , Cheah Pike-See , Ling King-Hwa
Published: January 2016

Trisomy of human chromosome 21 in Down syndrome (DS) leads to several phenotypes, such as mild-to-severe intellectual disability, hypotonia, and craniofacial dysmorphisms. These are fundamental hallmarks of the disorder that affect the quality of life of most individuals with DS. Proper brain development involves meticulous regulation of various signaling pathways, and dysregulation may result in abnormal neurodevelopment. DS brain is characterized by an increased number of astrocytes with reduced number of neurons. In mouse models for DS, the pool of neural progenitor cells commits to glia rather than neuronal cell fate in the DS brain. However, the mechanism(s) and consequences of this slight neurogenic-to-gliogenic shift in DS brain are still poorly understood. To date, Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling has been proposed to be crucial in various developmental pathways, especially in promoting astrogliogenesis. Since both human and mouse models of DS brain exhibit less neurons and a higher percentage of cells with astrocytic phenotypes, understanding the role of JAK-STAT signaling in DS brain development will provide novel insight into its role in the pathogenesis of DS brain and may serve as a potential target for the development of effective therapy to improve DS cognition.
Visual and Refractive Outcomes of a Toric Presbyopia-Correcting Intraocular Lens
Authors: Epitropoulos Alice T.
Published: January 2016

Purpose. To evaluate outcomes in astigmatic patients implanted with the Trulign (Bausch + Lomb) toric presbyopia-correcting intraocular lens (IOL) during cataract surgery in a clinical practice setting.Methods. Retrospective study in 40 eyes (31 patients) that underwent cataract extraction and IOL implantation in a procedure using intraoperative wavefront aberrometry guidance (ORA system). Endpoints included uncorrected visual acuity (VA), reduction in refractive cylinder, accuracy to target, axis orientation, and safety.Results. At postoperative month 1, refractive cylinder was ≤0.50 D in 97.5% of eyes (≤1.00 D in 100%), uncorrected distance VA was 20/25 or better in 95%, uncorrected intermediate VA was 20/25 or better in 95%, and uncorrected near VA was 20/40 (J3 equivalent) or better in 92.5%. Manifest refraction spherical equivalent was within 1.00 D of target in 95% of eyes and within 0.50 D in 82.5%. Lens rotation was <5° and best-corrected VA was 20/25 or better in all eyes.Conclusion.The IOL effectively reduced refractive cylinder and provided excellent uncorrected distance and intermediate vision and functional near vision. Refractive predictability and rotational stability were exceptional. Implantation of this toric presbyopia-correcting IOL using ORA intraoperative aberrometry provides excellent refractive and visual outcomes in a standard of care setting.
Atherosclerosis as Extrahepatic Manifestation of Chronic Infection with Hepatitis C Virus
Authors: Voulgaris Theodoros , Sevastianos Vassilios A.
Published: January 2016

Chronic hepatitis C virus infection is associated with significant morbidity and mortality, as a result of progression towards advanced natural course stages including cirrhosis and hepatocellular carcinoma. On the other hand, the SVR following successful therapy is generally associated with resolution of liver disease in patients without cirrhosis. Patients with cirrhosis remain at risk of life-threatening complications despite the fact that hepatic fibrosis may regress and the risk of complications such as hepatic failure and portal hypertension is reduced. Furthermore, recent data suggest that the risk of HCC and all-cause mortality is significantly reduced, but not eliminated, in cirrhotic patients who clear HCV compared to untreated patients and nonsustained virological responders. Data derived from studies have demonstrated a strong link between HCV infection and the atherogenic process. Subsequently HCV seems to represent a strong, independent risk factor for coronary heart disease, carotid atherosclerosis, stroke, and, ultimately, CVD related mortality. The advent of new direct acting antiviral therapy has dramatically increased the sustained virological response rates of hepatitis C infection. In this scenario, the cardiovascular risk has emerged and represents a major concern after the eradication of the virus which may influence the life expectancy and the quality of patients’ life.
First Pediatric Case of Tularemia after a Coyote Bite
Authors: Chomel Bruno B. , Morton Jane A. , Kasten Rickie W. , Chang Chao-chin
Published: January 2016

Bite-transmitted tularemia is a rare event in humans and most of the cases have been associated with cat bites. We report the first pediatric case of tularemia caused by a coyote (Canis latrans) bite. Coyotes can be healthy carriers ofFrancisella tularensisand transmit this infectious agent through a bite. Pediatricians should be aware of this risk after a carnivore bite and implement appropriate antibiotic therapy, as amoxicillin/clavulanate potassium (Augmentin) may have prolonged the typical two to three days’ incubation period commonly observed for tularemia after an animal bite and was not effective in preventing clinical signs in this child. Finally, it emphasizes again the importance of early and late serum samples for appropriate serodiagnostic.
Gingival Overgrowth Leading to the Diagnosis of Familial Tuberous Sclerosis Complex
Authors: Purwar Parth , Sareen Sagar , Sheel Vaibhav , Gupta Abhishek , Ansari Uzma , Becharbhai Patel Umeshbhai , Dixit Manisha , Bhargava Amitesh , Yadav Rajiv Ratan Singh , Bansal Utkarsh , Dixit Jaya
Published: January 2016

Tuberous sclerosis complex (TSC), a neurocutaneous syndrome, is characterized by the development of benign tumours affecting different body systems. We herein present a report of a 40-year-old female patient presenting with dental enamel pits and localized gingival overgrowth that eventually lead to the diagnosis of a case of familial TSC. Diagnosis of familial TSC by comprehensive oral examination and detection of oral manifestations proved to be inevitable as it resulted in institution of appropriate treatment strategies and genetic counselling of the affected family.
Clival Ectopic Pituitary Adenoma Mimicking a Chordoma: Case Report and Review of the Literature
Authors: Karras Constantine L. , Abecassis Isaac Josh , Abecassis Zachary A. , Adel Joseph G. , Bit-Ivan Esther N. , Chandra Rakesh K. , Bendok Bernard R.
Published: January 2016

Background. Purely ectopic pituitary adenomas are exceedingly rare. Here we report on a patient that presented with an incidental clival mass thought to be a chordoma. Endonasal resection, tumor pathology, and endocrinology workup revealed a prolactinoma.Case Presentation. A 41-year-old male presented with an incidental clival lesion presumed to be a chordoma. On MRI it involved the entire clivus, extended laterally to the petroclival junction, and invaded the cavernous sinuses bilaterally, encasing both internal carotid arteries, without direct extension into the sella. Intraoperatively, it was clear that the tumor originated from the clivus and that the sellar dura was completely intact. Frozen-section pathology was consistent with a pituitary adenoma. Immunostaining was positive for synaptophysin and prolactin with a low Ki-67 index, suggestive of a prolactinoma. Additional immunohistochemical stains seen in chordomas (EMA, S100, and Brachyury) and other metastatic tumors were negative. A postoperative endocrine workup revealed an elevated serum prolactin of 881.3 ng/mL (normal < 20).Conclusions. In conclusion, it is crucial to maintain an extensive differential diagnosis when evaluating a patient with a clival lesion. Ectopic clival pituitary adenomas, although rare, may warrant an endocrinological workup preoperatively as the majority may respond to medical treatment.
A Branch and Bound Algorithm for the Exact Solution of the Problem of EMU Circulation Scheduling in Railway Network
Authors: Lu Chao , Zhou Lei-shan , Yue Yi-xiang , Chen Ran
Published: January 2016

This paper is concerned with the scheduling of Electrical Multiple Units (EMUs) under the condition of their utilization on one sector or within several interacting sectors. Based on the introduction of the train connection graph which describes the possible connection relationship between trains, the integer programming model of EMU circulation planning is constructed. In order to analyzing the resolution of the model, a heuristic which shares the characteristics with the existing methods is introduced first. This method consists of two stages: one is a greedy strategy to construct a feasible circulation plan fragment, and another is to apply a stochastic disturbance to it to generate a whole feasible solution or get a new feasible solution. Then, an exact branch and bound method which is based on graph designing is proposed. Due to the complexity, the lower bound is computed through a polynomial approximation algorithm which is a modification from the one solving the degree constraint minimum 1-tree problem. Then, a branching strategy is designed to cope with the maintenance constraints. Finally, we report extensive computational results on a railway corridor in which the sectors possess the basic feature of railway networks.
The Association of Peroxisome Proliferator-Activated Receptorδand Additional Gene-Gene Interaction with C-Reactive Protein in Chinese Population
Authors: Ding Xiao-Ying , Yuan Hao-Zheng , Gu Ru , Gao Yan-Feng , Liu Xiao-Gang , Gao Ya
Published: January 2016

Aims. To examine the association between 4 single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptorsδ(PPARδ) polymorphisms and C-reactive protein (CRP) level and additional gene-gene interaction.Methods. Line regression analysis was performed to verify polymorphism association between SNP and CRP levels. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the interaction.Results. A total of 1028 subjects (538 men, 490 women) were selected. The carriers of the C allele (TC or CC) of rs2016520 were associated with a significant decreased level of CRP, regression coefficients was −0.338, and standard error was 0.104 (p=0.001). The carriers of the G allele (CG or GG) of rs9794 were also significantly associated with decreased level of CRP, regression coefficients was −0.219, and standard error was 0.114 (p=0.012). We also found a potential gene-gene interaction between rs2016520 and rs9794. Subjects with rs2016520-TC or CC, rs9794-CG or GG genotypes have lowest CRP level, difference (95% CI) = −0.50 (−0.69 to −0.21) (p<0.001), compared to subjects with rs2016520-TT and rs9794-CC genotypes.Conclusions. rs2016520 and rs9794 minor allele of PPARδand combined effect between the two SNP were associated with decreased CRP level.
Clinical Pain and Neuropsychological Functioning in Parkinson’s Disease: Are They Related?
Authors: Engels Gwenda , Weeda Wouter D. , Vlaar Annemarie M. M. , Weinstein Henry C. , Scherder Erik J. A.
Published: January 2016

Introduction.Pain is an important nonmotor symptom of Parkinson’s disease (PD). Brain areas such as the hippocampus and the prefrontal cortex play an important role in the processing of pain. Since these brain areas are also involved in cognitive functioning, for example, episodic memory and executive functions, respectively, we examined whether a relationship exists between cognitive functioning and spontaneous pain in PD.Methods. Forty-eight patients with PD and 57 controls participated. Cognitive functioning was measured by a comprehensive battery of neuropsychological tests. Both the sensory-discriminative aspect and the motivational-affective aspect of pain were assessed. Multiple linear regression analyses were performed to assess a relation between cognition and pain.Results. Cognition was related to neither the sensory nor the affective aspect of pain in our sample of PD patients. Variance in pain measures was primarily explained by symptoms of depression and anxiety.Discussion. The difference between the affective and the sensory aspect of pain might be due to the neuropathology of PD, which is mainly present in areas processing the affective aspect of pain. Pain treatment might improve when mood is taken into account. We provide several explanations for the lack of an association between pain and cognition.
Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans
Authors: Palego Lionella , Betti Laura , Rossi Alessandra , Giannaccini Gino
Published: January 2016

L-Tryptophan is the unique protein amino acid (AA) bearing an indole ring: its biotransformation in living organisms contributes either to keeping this chemical group in cells and tissues or to breaking it, by generating in both cases a variety of bioactive molecules. Investigations on the biology of Trp highlight the pleiotropic effects of its small derivatives on homeostasis processes. In addition to protein turn-over, in humans the pathways of Trp indole derivatives cover the synthesis of the neurotransmitter/hormone serotonin (5-HT), the pineal gland melatonin (MLT), and the trace amine tryptamine. The breakdown of the Trp indole ring defines instead the “kynurenine shunt” which produces cell-response adapters as L-kynurenine, kynurenic and quinolinic acids, or the coenzyme nicotinamide adenine dinucleotide (NAD+). This review aims therefore at tracing a “map” of the main molecular effectors in human tryptophan (Trp) research, starting from the chemistry of this AA, dealing then with its biosphere distribution and nutritional value for humans, also focusing on some proteins responsible for its tissue-dependent uptake and biotransformation. We will thus underscore the role of Trp biochemistry in the pathogenesis of human complex diseases/syndromes primarily involving the gut, neuroimmunoendocrine/stress responses, and the CNS, supporting the use of -Omics approaches in this field.
Coordinating Three-Level Supply Chain under Disruptions Using Revenue-Sharing Contract with Effort Dependent Demand
Authors: Pang Qinghua , Hou Yanli , Lv Yifei
Published: January 2016

Considering that the market demand is stochastic and dependent on effort, this essay shows that the benchmark revenue-sharing contract could not coordinate a three-level supply chain consisting of one manufacturer, one distributor, and one retailer. By assuming that the retailer himself bears the effort cost, coordination is achieved by implementing revenue-sharing contract based on rebate and penalty policy in one transaction or two transactions of three-level supply chain, and the former is a special case of the latter. When the disruptions induce the changes of the market demand, the revenue-sharing contract could not coordinate the supply chain. To deal with the problem, this essay introduces two forms of improved revenue-sharing contracts which have antidisruption ability. The model of improved revenue-sharing contract is optimized when the market demand is in the additive form with effort dependent demand. Formulas are given to calculate the optimal contract parameters. Finally, this essay demonstrates the accuracy of the model of improved revenue-sharing contract with the help of numerical examples.
The Impact of Sperm Metabolism duringIn VitroStorage: The Stallion as a Model
Authors: Gibb Zamira , Aitken Robert J.
Published: January 2016

In vitrosperm storage is a necessary part of many artificial insemination orin vitrofertilization regimes for many species, including the human and the horse. In many situations spermatozoa are chilled to temperatures between 4 and 10°C for the purpose of restricting the metabolic rate during storage, in turn, reducing the depletion of ATP and the production of detrimental by-products such as reactive oxygen species (ROS). Another result of lowering the temperature is that spermatozoa may be “cold shocked” due to lipid membrane phase separation, resulting in reduced fertility. To overcome this, a method of sperm storage must be developed that will preclude the need to chill spermatozoa. If a thermally induced restriction-of-metabolic-rate strategy is not employed, ATP production must be supported while ameliorating the deleterious effects of ROS. To achieve this end, an understanding of the nature of energy production by the spermatozoa of the species of interest is essential. Human spermatozoa depend predominantly on glycolytic ATP production, producing significantly less ROS than oxidative phosphorylation, with the more efficient pathway predominantly employed by stallion spermatozoa. This review provides an overview of the implications of sperm metabolism forin vitrosperm storage, with a focus on ambient temperature storage in the stallion.
Capsule Endoscopy for Ileitis with Potential Involvement of Other Sections of the Small Bowel
Authors: Lee Hyun Seok , Lim Yun Jeong
Published: January 2016

Ileitis is defined as inflammation of the ileum. This condition includes ulcers, aphthous ulcers, erosions, and nodular or erythematous mucosa. Various etiologies are associated with ileitis. Crohn’s disease, ulcerative colitis, medications such as nonsteroidal anti-inflammatory drugs, infectious conditions, neoplasms, infiltrative disorders, vasculitides, spondyloarthritis, endometriosis, and radiation therapy-related conditions involve the ileum. However, the differential diagnosis of terminal ileitis can be difficult in many cases. Video capsule endoscopy (VCE) has become a useful tool for the diagnosis of a variety of small bowel lesions. This review describes each of the various conditions associated with ileitis and the diagnostic value of VCE for ileitis, which may help identify and evaluate these conditions in clinical practice. Based on the information provided by VCE, a definitive diagnosis could be made using the patients’ medical history, clinical course, laboratory and ileocolonoscopic findings, radiologic imaging findings, and histologic findings.
RASSF1A Suppresses the Invasion and Metastatic Potential of Human Non–Small Cell Lung Cancer Cells by Inhibiting YAP Activation through the GEF-H1/RhoB Pathway
Authors: Dubois Fatéméh , Keller Maureen , Calvayrac Olivier , Soncin Fabrice , Hoa Lily , Hergovich Alexander , Parrini Maria-Carla , Mazières Julien , Vaisse-Lesteven Mélissa , Camonis Jacques , Levallet Guénaëlle , Zalcman Gérard
Published: January 2016

Inactivation of the tumor suppressor gene RASSF1A by promoter hypermethylation represents a key event underlying the initiation and progression of lung cancer. RASSF1A inactivation is also associated with poor prognosis and may promote metastatic spread. In this study, we investigated how RASSF1A inactivation conferred invasive phenotypes to human bronchial cells. RNAi-mediated silencing of RASSF1A induced epithelial-to-mesenchymal transition (EMT), fomenting a motile and invasive cellular phenotype in vitro and increased metastatic prowess in vivo. Mechanistic investigations revealed that RASSF1A blocked tumor growth by stimulating cofilin/PP2A–mediated dephosphorylation of the guanine nucleotide exchange factor GEF-H1, thereby stimulating its ability to activate the antimetastatic small GTPase RhoB. Furthermore, RASSF1A reduced nuclear accumulation of the Hippo pathway transcriptional cofactor Yes-associated protein (YAP), which was reinforced by RhoB activation. Collectively, our results indicated that RASSF1 acts to restrict EMT and invasion by indirectly controlling YAP nuclear shuttling and activation through a RhoB-regulated cytoskeletal remodeling process, with potential implications to delay the progression of RASSF1-hypermethylated lung tumors. Cancer Res; 76(6); 1627–40. ©2016 AACR.
Radiation-Induced Loss of Salivary Gland Function Is Driven by Cellular Senescence and Prevented by IL6 Modulation
Authors: Marmary Yitzhak , Adar Revital , Gaska Svetlana , Wygoda Annette , Maly Alexander , Cohen Jonathan , Eliashar Ron , Mizrachi Lina , Orfaig-Geva Carmit , Baum Bruce J. , Rose-John Stefan , Galun Eithan , Axelrod Jonathan H.
Published: January 2016

Head and neck cancer patients treated by radiation commonly suffer from a devastating side effect known as dry-mouth syndrome, which results from the irreversible loss of salivary gland function via mechanisms that are not completely understood. In this study, we used a mouse model of radiation-induced salivary hypofunction to investigate the outcomes of DNA damage in the head and neck region. We demonstrate that the loss of salivary function was closely accompanied by cellular senescence, as evidenced by a persistent DNA damage response (γH2AX and 53BP1) and the expression of senescence-associated markers (SA-βgal, p19ARF, and DcR2) and secretory phenotype (SASP) factors (PAI-1 and IL6). Notably, profound apoptosis or necrosis was not observed in irradiated regions. Signs of cellular senescence were also apparent in irradiated salivary glands surgically resected from human patients who underwent radiotherapy. Importantly, using IL6 knockout mice, we found that sustained expression of IL6 in the salivary gland long after initiation of radiation-induced DNA damage was required for both senescence and hypofunction. Additionally, we demonstrate that IL6 pretreatment prevented both senescence and salivary gland hypofunction via a mechanism involving enhanced DNA damage repair. Collectively, these results indicate that cellular senescence is a fundamental mechanism driving radiation-induced damage in the salivary gland and suggest that IL6 pretreatment may represent a promising therapeutic strategy to preserve salivary gland function in head and neck cancer patients undergoing radiotherapy. Cancer Res; 76(5); 1170–80. ©2016 AACR.
AKT1 Inhibits Epithelial-to-Mesenchymal Transition in Breast Cancer through Phosphorylation-Dependent Twist1 Degradation
Authors: Li Chia-Wei , Xia Weiya , Lim Seung-Oe , Hsu Jennifer L. , Huo Longfei , Wu Yun , Li Long-Yuan , Lai Chien-Chen , Chang Shih-Shin , Hsu Yi-Hsin , Sun Hui-Lung , Kim Jongchan , Yamaguchi Hirohito , Lee Dung-Fang , Wang Hongmei , Wang Yan , Chou Chao-Kai , Hsu Jung-Mao , Lai Yun-Ju , LaBaff Adam M. , Ding Qingqing , Ko How-Wen , Tsai Fuu-Jen , Tsai Chang-Hai , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: January 2016

Epithelial-to-mesenchymal transition (EMT) is an essential physiologic process that promotes cancer cell migration, invasion, and metastasis. Several lines of evidence from both cellular and genetic studies suggest that AKT1/PKBα, but not AKT2 or AKT3, serves as a negative regulator of EMT and breast cancer metastasis. However, the underlying mechanism by which AKT1 suppresses EMT remains poorly defined. Here, we demonstrate that phosphorylation of Twist1 by AKT1 is required for β-TrCP–mediated Twist1 ubiquitination and degradation. The clinically used AKT inhibitor MK-2206, which possesses higher specificity toward AKT1, stabilized Twist1 and enhanced EMT in breast cancer cells. However, we discovered that resveratrol, a naturally occurring compound, induced β-TrCP–mediated Twist1 degradation to attenuate MK-2206–induced EMT in breast cancer cells. Taken together, our findings demonstrate that resveratrol counteracts the unexpected metastatic potential induced by anti-AKT therapy and therefore suggest that the addition of resveratrol to an anti-AKT therapeutic regimen may provide extra support for limiting EMT. Cancer Res; 76(6); 1451–62. ©2016 AACR.
Cdx2 Expression and Intestinal Metaplasia Induced by H. pylori Infection of Gastric Cells Is Regulated by NOD1-Mediated Innate Immune Responses
Authors: Asano Naoki , Imatani Akira , Watanabe Tomohiro , Fushiya Jun , Kondo Yutaka , Jin Xiaoyi , Ara Nobuyuki , Uno Kaname , Iijima Katsunori , Koike Tomoyuki , Strober Warren , Shimosegawa Tooru
Published: January 2016

Chronic infection with the bacterial Helicobacter pylori is a major cause of gastric and duodenal ulcer disease, gastric mucosal atrophy, and cancer. H. pylori–induced expression of the intestinal epithelial–specific transcription factor caudal-related homeobox 2 (Cdx2) contributes to intestinal metaplasia, a precursor event to gastric cancer. Given a role for the bacterial pattern recognition molecule nucleotide-binding oligomerization domain 1 (NOD1) in the innate immune response to bacterial infection, we investigated mechanisms used by NOD1 to regulate H. pylori infection and its propensity towards the development of intestinal metaplasia. We found that Cdx2 was induced by H. pylori infection in both normal and neoplastic gastric epithelial cells in a manner that was inversely related to NOD1 signaling. Mechanistic investigations revealed that Cdx2 induction relied upon activation of NF-κB but was suppressed by NOD1-mediated activation of TRAF3, a negative regulator of NF-κB. In vivo, prolonged infection of NOD1-deficient mice with H. pylori led to increased Cdx2 expression and intestinal metaplasia. Furthermore, gastric epithelial cells from these mice exhibited increased nuclear expression of the NF-κB p65 subunit and decreased expression of TRAF3. Overall, our findings illuminated a role for NOD1 signaling in attenuating H. pylori–induced Cdx2 expression in gastric epithelial cells, suggesting a rationale to augment NOD1 signaling in H. pylori–infected patients to limit their risks of accumulating precancerous gastric lesions. Cancer Res; 76(5); 1135–45. ©2016 AACR.
EGFR Signaling Enhances Aerobic Glycolysis in Triple-Negative Breast Cancer Cells to Promote Tumor Growth and Immune Escape
Authors: Lim Seung-Oe , Li Chia-Wei , Xia Weiya , Lee Heng-Huan , Chang Shih-Shin , Shen Jia , Hsu Jennifer L. , Raftery Daniel , Djukovic Danijel , Gu Haiwei , Chang Wei-Chao , Wang Hung-Ling , Chen Mong-Liang , Huo Longfei , Chen Chung-Hsuan , Wu Yun , Sahin Aysegul , Hanash Samir M. , Hortobagyi Gabriel N. , Hung Mien-Chie
Published: January 2016

Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T-cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. EGF signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGFR, thereby increasing lactate excretion, which leads to inhibition of local cytotoxic T-cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-d-glucose with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC. Cancer Res; 76(5); 1284–96. ©2016 AACR.
Identification of DNA Methylation–Independent Epigenetic Events Underlying Clear Cell Renal Cell Carcinoma
Authors: Becket Elinne , Chopra Sameer , Duymich Christopher E. , Lin Justin J. , You Jueng Soo , Pandiyan Kurinji , Nichols Peter W. , Siegmund Kimberly D. , Charlet Jessica , Weisenberger Daniel J. , Jones Peter A. , Liang Gangning
Published: January 2016

Alterations in chromatin accessibility independent of DNA methylation can affect cancer-related gene expression, but are often overlooked in conventional epigenomic profiling approaches. In this study, we describe a cost-effective and computationally simple assay called AcceSssIble to simultaneously interrogate DNA methylation and chromatin accessibility alterations in primary human clear cell renal cell carcinomas (ccRCC). Our study revealed significant perturbations to the ccRCC epigenome and identified gene expression changes that were specifically attributed to the chromatin accessibility status whether or not DNA methylation was involved. Compared with commonly mutated genes in ccRCC, such as the von Hippel-Lindau (VHL) tumor suppressor, the genes identified by AcceSssIble comprised distinct pathways and more frequently underwent epigenetic changes, suggesting that genetic and epigenetic alterations could be independent events in ccRCC. Specifically, we found unique DNA methylation–independent promoter accessibility alterations in pathways mimicking VHL deficiency. Overall, this study provides a novel approach for identifying new epigenetic-based therapeutic targets, previously undetectable by DNA methylation studies alone, that may complement current genetic-based treatment strategies. Cancer Res; 76(7); 1954–64. ©2016 AACR.
Statin Use and Breast Cancer Risk in the Nurses' Health Study
Authors: Borgquist Signe , Tamimi Rulla M. , Chen Wendy Y. , Garber Judy E. , Eliassen A. Heather , Ahern Thomas P.
Published: January 2016

Preclinical studies support an anticancer effect of statin drugs, yet epidemiologic evidence remains inconsistent regarding their role in breast cancer primary prevention. Here, we report an updated analysis of the association between statin use and breast cancer incidence in the Nurses' Health Study (NHS) cohort. Postmenopausal NHS participants without a cancer history were followed from 2000 until 2012 (n = 79,518). Data on statin use were retrieved from biennial questionnaires. We fit Cox regression models to estimate associations between longitudinal statin use and breast cancer incidence. Over 823,086 person-years of follow-up, 3,055 cases of invasive breast cancer occurred. Compared with never users, both former and current statin users had similar rates of invasive breast cancer incidence [former users: HRadj, 0.96; 95% confidence interval (CI), 0.82–1.1; current users: HRadj, 1.1; 95% CI, 0.92–1.3]. Associations did not differ by estrogen receptor (ER) status or histology (ductal vs. lobular carcinoma). Statin use was not associated with risk of invasive breast cancer, irrespective of histologic subtype and ER status. Statin drugs do not appear to modify processes involved in breast cancer initiation. Cancer Epidemiol Biomarkers Prev; 25(1); 201–6. ©2016 AACR.
Translating Clinical Evidence-Based Medicine into the Real World: Single-Center Experience with Cabazitaxel in Metastatic Prostate Cancer Patients
Authors: Moriceau Guillaume , Guillot Aline , Pacaut Cécile , Méry Benoîte , Falk Alexander Tuan , Trone Jane-Chloé , Collard Olivier , De Laroche Guy , Fournel Pierre , Merrouche Yacine , Magné Nicolas
Published: January 2016

Background: We studied the efficacy and safety of cabazitaxel in unselected real-life patients. Patients and Methods: We retrospectively investigated all patients with metastatic prostate cancer (mPC) treated with cabazitaxel 25 mg/m2 i.v. every 3 weeks combined with oral prednisolone (10 mg once daily) after first-line docetaxel chemotherapy. Study issues were to report patient characteristics and cabazitaxel data in terms of tolerance and efficacy. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. All data were compared with TROPIC results. Results: From 2011 to 2014, 41 patients received cabazitaxel; 15 patients (37%) had a performance status (PS) ≥2 versus 7% (p < 0.0001) in TROPIC, and 38 patients (93%) presented a Gleason score ≥7 at baseline (vs. 60%; p < 0.0001). All patients had metastatic disease at baseline. Previous therapies were radiotherapy in 17 patients (41 vs. 61%; p = 0.01) and surgery in 24 patients (59 vs. 52%; p = 0.4). The median number of cabazitaxel cycles was 5 (1-10) versus 6 (3-10) in TROPIC. Five patients completed 10 cycles of cabazitaxel (12%) versus 28% in TROPIC (p = 0.03). Toxicities were anemia (12 patients, 29%), diarrhea (9 patients, 22%), nausea (7 patients, 17%), pain (6 patients, 15%), sepsis (4 patients, 10%), neutropenia (3 patients, 7%) and urinary tract infection (1 patient, 2%). The tumor response rate was 19.5 versus 14.4% in TROPIC (nonsignificant). PFS was 4.5 months (95% CI 3.3-6.4) in our analysis and 2.8 months (95% CI 2.4-3.0) in TROPIC. OS was 12.1 months (95% CI 9.2 to not reached) and 15.1 months (95% CI 14.1-16.3), respectively. Conclusion: In our unselected mPC patients with poorer baseline clinical conditions and aggressive disease, cabazitaxel seems efficient and not more toxic than in the TROPIC study.
The Evolution of Critical Care Nephrology in Edmonton
Authors: Bagshaw Sean M. , Gibney R.T. Noel
Published: January 2016

The University of Alberta (UofA) in Edmonton, Canada has a rich and productive history supporting the development of critical care medicine, nephrology and the evolving subspecialty of critical care nephrology. The first hemodialysis program for patients with chronic renal failure in Canada was developed at the University of Alberta Hospital. The UofA is also recognized for its early pioneering work on the diagnosis, etiology and outcomes associated with acute kidney injury (AKI), the development of a diagnostic scheme renal allograft rejection (Banff classification), and contributions to the Renal Disaster Relief Task Force. Edmonton was one of the first centers in Canada to provide continuous renal replacement therapy. This has grown into a comprehensive clinical, educational and research center for critical care nephrology. Critical care medicine in Edmonton now leads and participates in numerous critical care nephrology initiatives dedicated to AKI, renal replacement therapy, renal support in solid organ transplantation, and extracorporeal blood purification. Critical care medicine in Edmonton is recognized across Canada and across the globe as a leading center of excellence in critical care nephrology, as an epicenter for research innovation and for training a new generation of clinicians with critical care nephrology expertise.
Retinal Vein Occlusions: Therapeutic Switch in Macular Oedema Treatment with a 12-Month Follow-Up
Authors: Chiquet Christophe , Bron Alain M. , Straub Morgane , Dupuy Caroline , Isaico Rodica , Aptel Florent , Creuzot-Garcher Catherine
Published: January 2016

Purpose: To compare the visual and anatomical outcomes of patients with macular oedema secondary to retinal vein occlusion (RVO) after a switch from bevacizumab to intravitreal injection of a dexamethasone implant (IVI-DEX) or conversely. Methods: 48 patients - 40 in the antivascular endothelial growth factor (VEGF) DEX sequence (AD group), 8 in the DEX anti-VEGF sequence (DA group) - were included in this multicentre retrospective study and evaluated at baseline, 1, 3, 6 and 12 months after the switch. The outcome measurements were visual acuity (VA) and central macular thickness (CMT) evaluated by spectral domain optical coherence tomography. Patients were defined as ‘good responders' if CMT was ≤ 300 µm after the switch. Results: VA significantly improved at 1 month in the AD group (p = 0.03) but not in the DA group (p = 0.40). CMT decreased significantly in the AD group at 1, 6 and 12 months (p = 0.002, p = 0.005 and p = 0.002, respectively). In the DA group, VA did not change from baseline at any time point, and CMT decreased at 1 month (p = 0.02) but not later on. Conclusions: In patients with macula oedema secondary to RVO, the switch from bevacizumab to IVI-DEX seems more beneficial in terms of short-term VA and long-term reduction of CMT than the DEX anti-VEGF agent sequence.