bluuebunny/crossref_metadata_2025 huggingface dataset:
CFD Simulations of Splash Losses of a Gearbox
Authors: Gorla Carlo , Concli Franco , Stahl Karsten , Höhn Bernd-Robert , Klaus Michaelis , Schultheiß Hansjörg , Stemplinger Johann-Paul
Published: August 2012

Efficiency is becoming a main concern in the design of power transmissions. It is therefore important, especially during the design phase, to have appropriate models to predict the power losses. For this reason, CFD (computational fluid dynamics) simulations were performed in order to understand the influence of geometrical and operating parameters on the losses in power transmissions. The results of the model were validated with experimental results.
Inhibitory Effects ofChung Hun Wha Dam Tang(CHWDT) on High-Fat Diet-Induced Obesity via AMP-Activated Protein Kinase Activation
Authors: Uddin Md. Jamal , Joe Yeonsoo , Zheng Min , Kim Sena , Lee Hoyoung , Kwon Tae-Oh , Chung Hun Taeg
Published: August 2012

TheChung Hun Wha Dam Tang(CHWDT) herbal combination was reported to cease dizziness and phlegm. However, the effect of CHWDT in obesity has not yet been known mechanically. Therefore, we investigated whether this CHWDT could protect the cells from lipogenesis, gluconeogenesis, and inflammation in both in vivo and in vitro. CHWDT significantly decreased body weight, epididymal and perirenal fat content without affecting feed intake in high-fat diet-induced obese mice model. Additionally, CHWDT inhibited obesity-induced SREBP1, FAS, PGC1α, G6Pase, PEPCK and increased CPT1, ACO, and LCAD genes expression in vivo and in vitro. Proinflammatory cytokines like TNF-αand iNOS expression were reduced by CHWDT in both Raw264.7 macrophages and HepG2 cells. In addition, NO production was also significantly decreased by CHWDT in LPS-stimulated macrophages. Furthermore, AMPKαactivation by CHWDT was involved in inhibition of obesity by reducing triglycerides production and increasing CPT1 expression. Based on all of the results, we suggest that CHWDT has inhibitory effects on obesity-induced lipogenesis, gluconeogenesis, and inflammation via AMPKαactivation.
A Small UWB Antenna with Dual Band-Notched Characteristics
Authors: Xu J. , Shen D.-Y. , Wang G.-T. , Zhang X.-H. , Zhang X.-P. , Wu K.
Published: August 2012

A small novel ultrawideband (UWB) antenna with dual band-notched functions is proposed. The dual band rejection is achieved by etching two C-shaped slots on the radiation patch with limited area. A single band-notched antenna is firstly presented, and then an optimized dual band-notched antenna is presented and analyzed. The measured VSWR shows that the proposed antenna could operate from 3.05 to 10.7 GHz with VSWR less than 2, except two stopbands at 3.38 to 3.82 GHz and 5.3 to 5.8 GHz for filtering the WiMAX and WLAN signals. Radiation patterns are simulated by HFSS and verified by CST, and quasiomnidirectional radiation patterns in the H-plane could be observed. Moreover, the proposed antenna has a very compact size and could be easily integrated into portable UWB devices.
Panels Manufactured from Vegetable Fibers: An Alternative Approach for Controlling Noises in Indoor Environments
Authors: Bastos Leopoldo Pacheco , de Melo Gustavo da Silva Vieira , Soeiro Newton Sure
Published: August 2012

Noise control devices such as panels and barriers, when of high efficiency, generally are of difficult acquisition due to high costs turning in many cases their use impracticable, mainly for limited budget small-sized companies. There is a huge requirement for new acoustic materials that have satisfactory performance, not only under acoustic aspect but also other relevant ones and are of low cost. Vegetable fibers are an alternative solution when used as panels since they promise satisfactory acoustic absorption, according to previous researches, exist in abundance, and derive from renewable sources. This paper, therefore, reports on the development of panels made from vegetable fibers (coconut, palm, sisal, and açaí), assesses their applicability by various experimental (flammability, odor, fungal growth, and ageing) tests, and characterize them acoustically in terms of their sound absorption coefficients on a scale model reverberant chamber. Acoustic results point out that the aforementioned fiber panels play pretty well the role of a noise control device since they have compatible, and in some cases, higher performance when compared to commercially available conventional materials.
Prevalence and Reasons for Tooth Loss in a Sample from a Dental Clinic in Brazil
Authors: Montandon Andréia Affonso Barretto , Zuza Elizangela Partata , de Toledo Benedicto Egbert Corrêa
Published: August 2012

Purpose.To evaluate the prevalence and reasons for teeth extractions in a sample from a dental clinic in Brazil.Methods.The prevalence of teeth mortality was analyzed by gender, age, tooth type and reasons for extraction on 800 teeth of 439 subjects, whose data was collected in clinical records in a convenience sample.Results.The groups with range from 35 to 44 years, 45 to 54 years and 55 to 64 years revealed significantly greater number of teeth extractions than other age groups (P<0.0001). The anterior teeth loss increased significantly with aging, while the tooth mortality of premolar and molar were higher in younger people. The caries was the more prevalent reason for tooth mortality among young and adults up to 44 years old, while the periodontal disease was the main reason for extractions from 45 years old until range of 81 years (P<0.0001).Conclusions.It can be suggested that some reasons for tooth loss were age-dependent, but the caries and the periodontal diseases were the main reasons for tooth mortality in this Brazilian sample.
Collaborative Exploration with a Micro Aerial Vehicle: A Novel Interaction Method for Controlling a MAV with a Hand-Held Device
Authors: Pitman David , Cummings Mary L.
Published: August 2012

In order to collaboratively explore an environment with a Micro Aerial Vehicle (MAV), an operator needs a mobile interface, which can support the operator’s divided attention. To this end, we developed the Micro Aerial Vehicle Exploration of an Unknown Environment (MAV-VUE) interface, which allows operators with minimal training the ability to remotely explore their environment with a MAV. MAV-VUE employs a concept we term Perceived First-Order (PFO) control, which allows an operator to effectively “fly” a MAV with no risk to the vehicle. PFO control utilizes a position feedback control loop to fly the MAV while presenting rate feedback to the operator. A usability study was conducted to evaluate MAV-VUE. This interface was connected remotely to an actual MAV to explore a GPS-simulated urban environment.
Development and Validation of a Stability Indicating LC Method for the Assay and Related Substances Determination of a Proteasome Inhibitor Bortezomib
Authors: Srinivasulu Kasa , Naidu Mopidevi Narasimha , Rajasekhar Kadaboina , Veerender Murki , Suryanarayana Mulukutla Venkata
Published: August 2012

A novel, simple, sensitive, stability indicating HPLC method was developed and validated for quantification of impurities (process related and degradants) and assay determination of bortezomib. Stability indicating power of the method was established by forced degradation experiments and mass balance study. The chromatographic separation was achieved with Waters SymmetryShield RP18 column using gradient elution using the mobile phase-A consists of a mixture of water-acetonitrile-formic acid (715 : 285 : 1, v/v/v) and the mobile phase-B consists a mixture of methanol-water-formic acid (800 : 200 : 1, v/v/v), respectively. The developed method is validated for parameters like precision, accuracy, linearity, LOD, LOQ, and ruggedness. Central composite experimental design (CCD) was applied to check the robustness of the method. The stability tests were also performed on drug substances as per ICH norms.
Parametric Mapping of Brain Tissues from Diffusion Kurtosis Tensor
Authors: Chen Yuanyuan , Zhao Xin , Ni Hongyan , Feng Jie , Ding Hao , Qi Hongzhi , Wan Baikun , Ming Dong
Published: August 2012

Diffusion kurtosis imaging (DKI) is a new diffusion magnetic resonance imaging (MRI) technique to go beyond the shortages of conventional diffusion tensor imaging (DTI) from the assumption that water diffuse in biological tissue is Gaussian. Kurtosis is used to measure the deviation of water diffusion from Gaussian model, which is called non-Gaussian, in DKI. However, the high-order kurtosis tensor in the model brings great difficulties in feature extraction. In this study, parameters like fractional anisotropy of kurtosis eigenvalues (FAek) and mean values of kurtosis eigenvalues (Mek) were proposed, and regional analysis was performed for 4 different tissues: corpus callosum, crossing fibers, thalamus, and cerebral cortex, compared with other parameters. Scatterplot analysis and Gaussian mixture decomposition of different parametric maps are used for tissues identification. Diffusion kurtosis information extracted from kurtosis tensor presented a more detailed classification of tissues actually as well as clinical significance, and the FAek ofD-eigenvalues showed good sensitivity of tissues complexity which is important for further study of DKI.
Multiple Solutions for Nonlinear Doubly Singular Three-Point Boundary Value Problems with Derivative Dependence
Authors: Pandey R. K. , Barnwal A. K.
Published: August 2012

We study the existence of multiple nonnegative solutions for the doubly singular three-point boundary value problem with derivative dependent data function-(p(t)y′(t))′=q(t)f(t,y(t),p(t)y′(t)),0<t<1,y(0)=0,y(1)=α1y(η). Here,p∈C[0,1]∩C1(0,1]withp(t)>0on(0,1]andq(t)is allowed to be discontinuous att=0. The fixed point theory in a cone is applied to achieve new and more general results for existence of multiple nonnegative solutions of the problem. The results are illustrated through examples.
The Effects of Unripe Grape Juice on Lipid Profile Improvement
Authors: ZibaeeNezhad Mohammad Javad , Mohammadi Esmael , Babaie Beigi Mohammad Ali , Mirzamohammadi Fatemeh , Salehi Oveis
Published: August 2012

Introduction. Consumption of unripe grape juice (verjuice) has been portrayed by the traditional belief, as a means of combating dyslipidemia. We aimed to evaluate the effects of unripe grape juice consumption on lipid profile in healthy human volunteers.
Methods. We asked 42 enrolled volunteers to drink 10 cc of verjuice within 30 minutes to 2 hours after lunch and 10 cc of it after dinner. After taking 120 doses of verjuice, another fasting lipid profile was obtained from each participant. The statistical analysis was performed by SPSS 13 software. Results. After analysis of the data, the mean ± standard deviation for all the variables was obtained. Among those improvement of HDL-C was significant after the trial (). TG, TC, and LDL improvement were not significant. Conclusion. Our study declared that verjuice has a dramatic effect on improving HDL-C level of serum but no any other lipid improvement effect was obtained.
Sterile Endophthalmitis after Intravitreal Injections
Authors: Marticorena Joaquín , Romano Vito , Gómez-Ulla Francisco
Published: August 2012

Sterile endophthalmitis appears as an infrequent complication of intravitreal injections and seems to develop mainly in the context of the off-label use of drugs that have not been conceived for intravitreous administration. The aetiology of sterile endophthalmitis, independently of the administered drug, remains uncertain and a multifactorial origin cannot be discarded. Sterile inflammation secondary both to intravitreal triamcinolone acetonide and to intravitreal bevacizumab share many characteristics such as the acute and painless vision loss present in the big majority of the cases. Dense vitreous opacity is a common factor, while anterior segment inflammation appears to be mild to moderate. In eyes with sterile endophthalmitis, visual acuity improves progressively as the intraocular inflammation reduces without any specific treatment. If by any chance the ophthalmologist is not convinced by the sterile origin of the inflammation, this complication must be treated as an acute endophthalmitis because of the devastating visual prognosis of this intraocular infection in the absence of therapy.
The Effects of Tualang Honey on Bone Metabolism of Postmenopausal Women
Authors: Mohd Effendy Nadia , Mohamed Norazlina , Muhammad Norliza , Mohamad Isa Naina , Shuid Ahmad Nazrun
Published: August 2012

Osteoporosis which is characterized by low bone mass and microarchitectural deterioration with a consequent increase in bone fragility can be associated with various stimuli such as oxidative stress and inflammation. Postmenopausal women are more prone to osteoporosis due to reduction in estrogen which may further lead to elevation of oxidative stress and lipid accumulation which will promote osteoblasts apoptosis. Proinflammatory cytokines are elevated following estrogen deficiency. These cytokines are important determinants of osteoclasts differentiation and its bone resorption activity. The main treatment for postmenopausal osteoporosis is estrogen replacement therapy (ERT). Despite its effectiveness, ERT, however, can cause many adverse effects. Therefore, alternative treatment that is rich in antioxidant and can exert an anti-inflammatory effect can be given to replace the conventional ERT. Tualang honey is one of the best options available as it contains antioxidant as well as exerting anti-inflammatory effect which can act as a free radical scavenger, reducing the oxidative stress level as well as inhibiting proinflammatory cytokine. This will result in survival of osteoblasts, reduced osteoclastogenic activity, and consequently, reduce bone loss. Hence, Tualang honey can be used as an alternative treatment of postmenopausal osteoporosis with minimal side effects.
Functional Outcome after Simultaneous Bilateral Four-Part Proximal Humerus Fracture: A Comparison of ORIF and Hemiarthroplasty in an Individual Patient
Authors: Ellanti Prasad , Harrington Paul
Published: August 2012

Simultaneous bilateral four-part proximal humeral fractures are rare. Four-part fractures of the proximal humerus are difficult for the patient and technically demanding for the surgeon. Our surgical tactic is to attempt open reduction and internal fixation where possible. We report the functional outcome in a 56-year-old female who sustained simultaneous bilateral four-part proximal humeral fractures after falling down a flight of stairs. Open reduction and internal fixation using threaded pins and tension band suture was performed on one side, and shoulder replacement hemiarthroplasty was required on the other. Functional assessment was undertaken at two years after surgery, using the Oxford Shoulder Score. Although the objective outcomes assessment revealed little difference, the patient herself expressed a preference for the side treated by internal fixation. We conclude that an attempt to retain the native humeral head and the surgical tactic that favours internal fixation where possible is appropriate in these injuries. Excellent function can be achieved following hemiarthroplasty for trauma in a fit patient.
Do Depressive Traits and Hostility Predict Age-Related Decline in General Intelligence?
Authors: Mortensen Erik Lykke , Barefoot John Calvin , Avlund Kirsten
Published: August 2012

Certain personality traits are likely to be associated with stress and distress through the lifespan, and as a consequence these traits may influence the rate of age-related cognitive decline. The present study uses data from the Glostrup 1914 cohort to analyze potential effects of personality on decline in general intelligence over a 30-year period. The Minnesota Multiphasic Personality Inventory was administered at a 50-year baseline exam, and from this inventory the Obvious Depression Scale and an abbreviated version of the Cook-Medley Hostility Scale were derived. At the 50-year baseline and at the 60-, 70-, and 80-year followups the full version of Wechsler's Adult Intelligence Scale (WAIS) was administered to 673, 513, 136, and 184 participants. Mixed effects statistical models were used to evaluate both the effect of the personality scores on level of intelligence and the interaction between the personality scores and the time since followup. Analyses were adjusted for demographic background and a wide range of lifestyle factors. Both obvious depression and hostility were negatively associated with level of intelligence, but personality scores did not influence rate of decline in general intelligence.
Targeting the EWSR1-FLI1 Oncogene-Induced Protein Kinase PKC-β Abolishes Ewing Sarcoma Growth
Authors: Surdez Didier , Benetkiewicz Magdalena , Perrin Virginie , Han Zhi-Yan , Pierron Gaëlle , Ballet Stelly , Lamoureux François , Rédini Françoise , Decouvelaere Anne-Valérie , Daudigeos-Dubus Estelle , Geoerger Birgit , de Pinieux Gonzague , Delattre Olivier , Tirode Franck
Published: August 2012

Ewing sarcoma is a rare but aggressive disease most common in young adults. This cancer is driven by a unique chimeric fusion oncogene but targeted strategies have been elusive. Here we report the identification of the protein kinase PKC-ß (PRKCB) as a disease-specific druggable target for treatment of Ewing sarcoma. We found that transcriptional activation of PRKCB was directly regulated by the chimeric fusion oncogene EWSR1-FLI1 that drives this cancer. PRKCB phosphorylated histone H3T6 to permit global maintenance of H3K4 trimethylation at a variety of gene promoters. PRKCB loss induced apoptosis in vitro and prevented tumor growth in vivo. Gene expression profiling revealed a strong overlap between genes modulated by EWSR1-FLI1 and PRKCB in regulating crucial signaling pathways. Taken together, our findings offer a preclinical proof-of-concept for PRKCB as a promising therapeutic target in Ewing sarcoma. Cancer Res; 72(17); 4494–503. ©2012 AACR.
Prognostic Significance of Promoter DNA Methylation in Patients with Childhood Neuroblastoma
Authors: Lau Diana T. , Hesson Luke B. , Norris Murray D. , Marshall Glenn M. , Haber Michelle , Ashton Lesley J.
Published: August 2012

Purpose: To characterize the clinical significance of promoter methylation in a cohort of primary neuroblastoma tumors and investigate the association between DNA methylation and clinical outcome.

Experimental Design: A customized Illumina GoldenGate methylation assay was used to assess methylation status of 96 CpG sites within 48 candidate genes in primary neuroblastoma tumors obtained from 131 children diagnosed in Australia. Genes were selected on the basis of previous reports of altered DNA methylation in embryonal cancers. Levels of DNA methylation were validated in a subset of 48 patient samples using combined bisulfite restriction analysis (CoBRA) and bisulfite sequencing. A Cox proportional hazards model was used to investigate the association between promoter hypermethylation and the risk of relapse/death within 5 years of diagnosis, while adjusting for known prognostic factors including MYCN amplification, age, and stage at diagnosis.

Results: Levels of promoter methylation of DNAJC15, neurotrophic tyrosine kinase receptor 1 or TrkA (NTRK1), and tumor necrosis factor receptor superfamily, member 10D (TNFRSF10D), were higher in older patients at diagnosis (P < 0.01), whereas higher levels of methylation of DNAJC15, NTRK1, and PYCARD were observed in patients with MYCN amplification (P < 0.001). In multivariate analysis, hypermethylation of folate hydrolase (FOLH1), myogenic differentiation-1 (MYOD1), and thrombospondin-1 (THBS1) remained significant independent predictors of poorer clinical outcome after adjusting for known prognostic factors (P ≤ 0.017). Moreover, more than 30% of patients displayed hypermethylation in 2 genes or more and were at least 2 times more likely to relapse or die (HR = 2.72, 95% confidence interval = 1.55–4.78, P = 0.001), independent of MYCN status, age, and stage at diagnosis.

Conclusions: Our findings highlight the potential use of methylation profiling to identify additional prognostic markers and detect new therapeutic targets for selected patient subsets. Clin Cancer Res; 18(20); 5690–700. ©2012 AACR.
CCT244747 Is a Novel Potent and Selective CHK1 Inhibitor with Oral Efficacy Alone and in Combination with Genotoxic Anticancer Drugs
Authors: Walton Mike I. , Eve Paul D. , Hayes Angela , Valenti Melanie R. , De Haven Brandon Alexis K. , Box Gary , Hallsworth Albert , Smith Elizabeth L. , Boxall Kathy J. , Lainchbury Michael , Matthews Thomas P. , Jamin Yann , Robinson Simon P. , Aherne G. Wynne , Reader John C. , Chesler Louis , Raynaud Florence I. , Eccles Suzanne A. , Collins Ian , Garrett Michelle D.
Published: August 2012

Purpose: Many tumors exhibit defective cell-cycle checkpoint control and increased replicative stress. CHK1 is critically involved in the DNA damage response and maintenance of replication fork stability. We have therefore discovered a novel potent, highly selective, orally active ATP-competitive CHK1 inhibitor, CCT244747, and present its preclinical pharmacology and therapeutic activity.

Experimental Design: Cellular CHK1 activity was assessed using an ELISA assay, and cytotoxicity a SRB assay. Biomarker modulation was measured using immunoblotting, and cell-cycle effects by flow cytometry analysis. Single-agent oral CCT244747 antitumor activity was evaluated in a MYCN-driven transgenic mouse model of neuroblastoma by MRI and in genotoxic combinations in human tumor xenografts by growth delay.

Results: CCT244747 inhibited cellular CHK1 activity (IC50 29–170 nmol/L), significantly enhanced the cytotoxicity of several anticancer drugs, and abrogated drug-induced S and G2 arrest in multiple tumor cell lines. Biomarkers of CHK1 (pS296 CHK1) activity and cell-cycle inactivity (pY15 CDK1) were induced by genotoxics and inhibited by CCT244747 both in vitro and in vivo, producing enhanced DNA damage and apoptosis. Active tumor concentrations of CCT244747 were obtained following oral administration. The antitumor activity of both gemcitabine and irinotecan were significantly enhanced by CCT244747 in several human tumor xenografts, giving concomitant biomarker modulation indicative of CHK1 inhibition. CCT244747 also showed marked antitumor activity as a single agent in a MYCN-driven neuroblastoma.

Conclusion: CCT244747 represents the first structural disclosure of a highly selective, orally active CHK1 inhibitor and warrants further evaluation alone or combined with genotoxic anticancer therapies. Clin Cancer Res; 18(20); 5650–61. ©2012 AACR.
Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas
Authors: Cho Hee-Yeon , Wang Weijun , Jhaveri Niyati , Torres Shering , Tseng Joshua , Leong Michelle N. , Lee David Jungpa , Goldkorn Amir , Xu Tong , Petasis Nicos A. , Louie Stan G. , Schönthal Axel H. , Hofman Florence M. , Chen Thomas C.
Published: August 2012

Perillyl alcohol (POH) is a monoterpene that has been used orally for the treatment of systemic cancer. However, when used orally significant gastrointestinal side effects and lack of overall efficacy were documented. Recently, in a phase II trial in Brazil for the treatment of temozolomide (TMZ)-resistant malignant gliomas, POH was well tolerated when administered intranasally. The present study explores the effects and mechanisms of POH on TMZ-sensitive and TMZ-resistant glioma cells. In vitro studies showed that POH was cytotoxic to TMZ-resistant as well as TMZ-sensitive glioma cells, and this effect was independent of O6-methylguanine-DNA methyltransferase expression. POH induced cytotoxicity, in part, through the endoplasmic reticulum (ER) stress pathway as shown by the increased expression of glucose-regulated protein-78 (GRP78), activating transcription factor 3, and C/EBP-homologous protein. In addition, POH impeded survival pathways, such as mTOR and Ras. As well, POH reduced the invasive capacity of sensitive and resistant glioma cells. POH alone and/or in combination with other ER stress–inducing cytotoxic drugs (i.e., 2, 5-dimethyl-celecoxib, nelfinavir) further induced apoptosis in TMZ-sensitive and TMZ-resistant glioma cells. To show whether intranasal delivery of POH was effective for the treatment of TMZ-resistant gliomas, animals bearing intracranial tumors were given POH intranasally. Animals treated through intranasal administration of POH exhibited a decrease in tumor growth and an increase in survival. Our data show that POH is an effective anti-glioma cytotoxic agent for TMZ-resistant gliomas when administered intranasally. Mol Cancer Ther; 11(11); 2462–72. ©2012 AACR.
Genome-wide DNA Methylation Events in TMPRSS2–ERG Fusion-Negative Prostate Cancers Implicate an EZH2-Dependent Mechanism with miR-26a Hypermethylation
Authors: Börno Stefan T. , Fischer Axel , Kerick Martin , Fälth Maria , Laible Mark , Brase Jan C. , Kuner Ruprecht , Dahl Andreas , Grimm Christina , Sayanjali Behnam , Isau Melanie , Röhr Christina , Wunderlich Andrea , Timmermann Bernd , Claus Rainer , Plass Christoph , Graefen Markus , Simon Ronald , Demichelis Francesca , Rubin Mark A. , Sauter Guido , Schlomm Thorsten , Sültmann Holger , Lehrach Hans , Schweiger Michal R.
Published: August 2012

Prostate cancer is the second most common cancer among men worldwide. Alterations in the DNA methylation pattern can be one of the leading causes for prostate cancer formation. This study is the first high-throughput sequencing study investigating genome-wide DNA methylation patterns in a large cohort of 51 tumor and 53 benign prostate samples using methylated DNA immunoprecipitation sequencing. Comparative analyses identified more than 147,000 cancer-associated epigenetic alterations. In addition, global methylation patterns show significant differences based on the TMPRSS2–ERG rearrangement status. We propose the hypermethylation of miR-26a as an alternative pathway of ERG rearrangement-independent EZH2 activation. The observed increase in differential methylation events in fusion–negative tumors can explain the tumorigenic process in the absence of genomic rearrangements.

Significance: In contrast to TMPRSS2–ERG-rearranged tumors, the pathomechanism for gene fusion–negative tumors is completely unclear. Using a sequencing-based approach, our work uncovers significant global epigenetic alterations in TMPRSS2–ERG gene fusion–negative tumors and provides a mechanistic explanation for the tumor formation process. Cancer Discov; 2(11); 1024–35. ©2012 AACR.

Read the Commentary on this article by Alumkal and Herman, p. 979.

This article is featured in Highlights of This Issue, p. 961
Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials
Authors: Modest Dominik P. , Brodowicz Thomas , Stintzing Sebastian , Jung Andreas , Neumann Jens , Laubender Ruediger P. , Ocvirk Janja , Kurteva Galina , Papai Zsuzsanna , Knittelfelder Regina , Kirchner Thomas , Heinemann Volker , Zielinski Christoph C.
Published: August 2012

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14–18 months; hazard ratio 0.66, range 0.43–1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy.
Relationship between Neurocognition and Regional Brain Volumes in Traumatized Adolescents with and without Posttraumatic Stress Disorder
Authors: Ahmed Fatima , Spottiswoode Bruce S. , Carey Paul D. , Stein Dan J. , Seedat Soraya
Published: August 2012

Objectives: Studies using convergent neurocognitive and structural imaging paradigms in adolescent posttraumatic stress disorder (PTSD) are limited; in the current study we used both voxel-based morphometry (VBM) to obtain between-group volumetric differences, and Freesurfer to examine the relationship between cognition and regional brain volumes. Methods: Participants were 21 traumatized adolescents with PTSD matched with 32 traumatized adolescents without PTSD. Magnetic resonance images were obtained on a 1.5-Tesla MAGNETOM Siemens Symphony scanner. VBM implemented on FSL was then used to compare between-group grey matter volumes, after which Freesurfer was used to obtain global volume and thickness measurements in different brain regions. Results: Significant between-group neurocognitive differences were found for tests of attention, delayed recall and visual reconstruction. On VBM, reduced grey matter was found in three regions in the PTSD group: left insula, right precuneus and right cingulate gyrus, using uncorrected values (p < 0.001), while no statistically significant between-group differences were found on the initial Freesurfer stream. Further Freesurfer analysis on Qdec revealed significant reductions in the insula for the PTSD group. In addition, volumetric changes in the corpus callosum and insula were significantly associated with deficits in logical memory and visual reproduction on Freesurfer analysis. Conclusions: Trauma exposure of itself may be sufficient to cause structural changes in adolescents regardless of PTSD development.
Ultra-High-Frequency Left Prefrontal Transcranial Magnetic Stimulation as Augmentation in Severely Ill Patients with Depression: A Naturalistic Sham-Controlled, Double-Blind, Randomized Trial
Authors: Ullrich Heiko , Kranaster Laura , Sigges Erich , Andrich Jürgen , Sartorius Alexander
Published: August 2012

Background and Aim: Repetitive transcranial magnetic stimulation (rTMS) is supposed to be not as effective in severe depression as it is in medium depression. We evaluated the treatment response to an ultra-high-frequency (UHF; 30 Hz) approach, which was used to maximize the rTMS efficacy in severely ill patients. Methods: 43 severely depressed patients were included in the randomized, double-blind study and received either rTMS with 30 Hz over the left dorsolateral prefrontal cortex or sham condition for 3 weeks as an add-on therapy to stable antidepressant medication. Hamilton Depression Rating Scale (HDRS) and cognitive performance were evaluated before and after the intervention. Results: In the active UHF group, the HRDS score was reduced by about 7.2, whereas the sham condition showed a smaller reduction of the HDRS score with 3.9. However, lithium as a covariant was responsible for the outcome difference, not the group of stimulation. No adverse events were reported. Comparing the differences of both groups in the pre- and post-study performance in a trail-making test, a group effect for the UHF group that was not influenced by the lithium intake was observed. Conclusion: A 30-Hz left prefrontal rTMS in severely depressed patients was safe and no adverse events occurred. Due to a strong effect of lithium as a covariate, we could not demonstrate favorable antidepressant effects of the UHF stimulation compared to sham. However, we found an improvement of processing speed performance in the UHF group, which covaried with improvement of psychomotor retardation.
Association between Diastolic Dysfunction by Color Tissue Doppler Imaging and Vascular Calcification on Plain Radiographs in Dialysis Patients
Authors: An Won Suk , Lee Su Mi , Park Tae Ho , Kim Seong Eun , Kim Ki Hyun , Park Young Jin , Son Young Ki
Published: August 2012

Background/Aim: Diastolic dysfunction is frequently associated with left ventricular hypertrophy, which is indicative of future cardiovascular events. Vascular calcification (VC) is known to be associated with coronary artery disease in dialysis patients. The present study was to determine the interrelationship between LV diastolic dysfunction by tissue Doppler imaging and VC on plain radiographs in dialysis patients. Methods: Fifty-six dialysis patients were recruited and VC scores were evaluated by plain radiographic film. The ratio of early diastolic transmitral inflow velocity (E) to early diastolic mitral annular velocity (E′) was measured by tissue Doppler imaging. We defined diastolic dysfunction as an E/E′ ratio >15 on tissue Doppler imaging. Results: Patients with diastolic dysfunction showed a higher percentage of coronary artery disease history, abdominal aortic calcification (AAC) scores ≥5, high LV mass index, and high left atrium volume compared to patients without diastolic dysfunction. The E/E′ ratio was significantly higher in patients with significant VC, VC scores of the pelvis and hands ≥3, and AAC scores ≥5 on plain radiographs. AAC scores ≥5 were considered an independent predictor of diastolic dysfunction. Conclusion: VC on plain radiographs is associated with the E/E′ ratio and AAC scores ≥5 are important clues for LV diastolic dysfunction in dialysis patients.
Effect of Ursodeoxycholic Acid Administration after Liver Transplantation on Serum Liver Tests and Biliary Complications: A Randomized Clinical Trial
Authors: Wang Shu-Yun , Tang Hua-Mei , Chen Guo-Qing , Xu Jun-Ming , Zhong Lin , Wang Zhao-Wen , Deng Gui-Long , Xing Tong-Hai , Lu Lun-Gen , Peng Zhi-Hai
Published: August 2012

Background/Aims: Endogenous hydrophobic bile acids are suspected to be one of the pathogenetic factors of biliary complications after orthotopic liver transplantation (OLT). This study was designed to investigate the effects of hydrophilic ursodeoxycholic acid (UDCA) administration early after OLT on serum liver tests and the incidence of biliary complications. Methods: 112 adult patients undergoing OLT from donation after cardiac death (DCD) were randomized to UDCA (13–15 mg/kg/day for 4 weeks; 56 patients) or placebo (56 patients). Serum liver tests and serum bile acids of all patients and biliary bile acids in patients with T-tube drainage were determined during the 4 weeks after OLT. Biliary complications as well as patient and graft survival were analyzed during a mean follow-up of 41.6 months. Results: UDCA treatment decreased ALT, AST and GGT (p < 0.05) during the 4 weeks after OLT and the incidence of biliary sludge and casts within the 1st year (p < 0.05). However, no differences in the incidence of other biliary complications as well as 1-, 3- and 5-year graft and patient survival were observed. Conclusions: UDCA administration early after DCD-OLT improves serum liver tests and decreases the incidence of biliary sludge and casts within the 1st postoperative year but does not affect overall outcome up to 5 years after OLT.
Soluble Epoxide Hydrolase Inhibition Exhibits Antihypertensive Actions Independently of Nitric Oxide in Mice with Renovascular Hypertension
Authors: Kopkan Libor , Husková Zuzana , Sporková Alexandra , Varcabová Šárka , Honetschlägerová Zuzana , Hwang Sung Hee , Tsai Hsing-Ju , Hammock Bruce D. , Imig John D. , Kramer Herbert J. , Bürgelová Marcela , Vojtíšková Alžběta , Kujal Petr , Vernerová Zdenka , Červenka Luděk
Published: August 2012

Objective: The present study was performed to examine whether the blood pressure (BP)-lowering effects of soluble epoxide hydrolase (sEH) inhibition in two-kidney, one-clip (2K1C) Goldblatt hypertension are nitric oxide (NO) dependent. Methods: Mice lacking the endothelial NO synthase (eNOS) gene (eNOS–/–) and their wild-type controls (eNOS+/+) underwent clipping of one renal artery. BP was monitored by radiotelemetry and the treatment with the sEH inhibitor cis-4-[4-(3-adamantan-1-yl-ureido)cyclohex-yloxy]-benzoic acid (c-AUCB) was initiated on day 25 after clipping and lasted for 14 days. Renal concentrations of epoxyeicosatrienoic acids (EETs) and their inactive metabolite dihydroxyeicosatrienoic acids (DHETs) were measured in the nonclipped kidney. Renal NO synthase (NOS) activity was determined by measuring the rate of formation of L-[14C]citruline from L-[14C]arginine. Results: Treatment with the sEH inhibitor elicited similar BP decreases that were associated with increases in daily sodium excretion in 2K1C eNOS+/+ as well as 2K1C eNOS–/– mice. In addition, treatment with the sEH inhibitor increased the ratio of EETs/DHETs in the nonclipped kidney of 2K1C eNOS+/+ as well as 2K1C eNOS–/– mice. Treatment with the sEH inhibitor did not alter renal NOS activity in any of the experimental groups. Conclusions: Collectively, our present data suggest that the BP-lowering effects of chronic sEH inhibition in 2K1C mice are mainly associated with normalization of the reduced availability of biologically active EETs in the nonclipped kidney and their direct natriuretic actions.
Parameter Estimation and Quantitative Parametric Linkage Analysis with GENEHUNTER-QMOD
Authors: Künzel Thomas , Strauch Konstantin
Published: August 2012

Objective: We present a parametric method for linkage analysis of quantitative phenotypes. The method provides a test for linkage as well as an estimate of different phenotype parameters. We have implemented our new method in the program GENEHUNTER-QMOD and evaluated its properties by performing simulations. Methods: The phenotype is modeled as a normally distributed variable, with a separate distribution for each genotype. Parameter estimates are obtained by maximizing the LOD score over the normal distribution parameters with a gradient-based optimization called PGRAD method. Results: The PGRAD method has lower power to detect linkage than the variance components analysis (VCA) in case of a normal distribution and small pedigrees. However, it outperforms the VCA and Haseman-Elston regression for extended pedigrees, nonrandomly ascertained data and non-normally distributed phenotypes. Here, the higher power even goes along with conservativeness, while the VCA has an inflated type I error. Parameter estimation tends to underestimate residual variances but performs better for expectation values of the phenotype distributions. Conclusion: With GENEHUNTER-QMOD, a powerful new tool is provided to explicitly model quantitative phenotypes in the context of linkage analysis. It is freely available at http://www.helmholtz-muenchen.de/genepi/downloads.
Serum Ghrelin Levels and the Effects of Antidepressants in Major Depressive Disorder and Panic Disorder
Authors: Ishitobi Yoshinobu , Kohno Kentaro , Kanehisa Masayuki , Inoue Ayako , Imanaga Junko , Maruyama Yoshihiro , Ninomiya Taiga , Higuma Haruka , Okamoto Shizuko , Tanaka Yoshihiro , Tsuru Jusen , Hanada Hiroaki , Isogawa Koichi , Akiyoshi Jotaro
Published: August 2012

Background: Two opposing models for the action of ghrelin in the behavioral responses to stress were recently proposed. Some studies suggest that an increase in ghrelin contributes to the mechanisms responsible for the development of stress-induced depression and anxiety, while others suggest that it helps minimize what otherwise would be more severe manifestations of depression and anxiety following stress. Methods: We measured serum ghrelin levels, Profile of Mood States (POMS) scores and State-Trait Anxiety Inventory scores in nonresponders (treatment-resistant patients; 30) and responders (38) with major depressive disorder (MDD), nonresponders (29) and responders (51) with panic disorder and 97 healthy controls. Results: The ghrelin concentration in nonresponders with MDD was higher than that of responders with MDD and normal controls. The ghrelin concentration in nonresponders with panic disorder was higher than that of normal controls. POMS vigor scores in patients with MDD and panic disorder were significantly decreased compared with those in healthy controls. Other POMS scores in patients with MDD and panic disorder were significantly increased compared with those of healthy controls. Trait and state anxiety of the State-Trait Anxiety Inventory in MDD and panic disorder patients were higher than those in healthy controls. Conclusions: These results indicate that decreased serum ghrelin levels might be associated with antidepressant treatment to confer the maximum therapeutic effect in patients with MDD and panic disorder.
Going Against the Tide – How Encephalitogenic T Cells Breach the Blood-Brain Barrier
Authors: Lyck Ruth , Engelhardt Britta
Published: August 2012

During multiple sclerosis or its animal model, experimental autoimmune encephalomyelitis, circulating immune cells enter the central nervous system (CNS) causing neuroinflammation. Extravasation from the blood circulation across the vessel wall occurs through a multistep process regulated by adhesion and signal transducing molecules on the immune cells and on the endothelium. Since the CNS is shielded by the highly specialized blood-brain barrier (BBB), immune cell extravasation into the CNS requires breaching this particularly tight endothelial border. Consequently, travelling into the CNS demands unique adaptations which account for the extreme tightness of the BBB. Modern imaging tools have shown that after arresting on BBB endothelium, in vivo or in vitro encephalitogenic effector/memory T cells crawl for long distances, possibly exceeding 150 µm along the surface of the BBB endothelium before rapidly crossing the BBB. Interestingly, in addition to the distance of crawling, the preferred direction of crawling against the flow is unique for T cell crawling on the luminal surface of CNS microvessels. In this review, we will summarize the cellular and molecular mechanisms involved in the unique T cell behavior that is obviously required for finding a site permissive for diapedesis across the unique vascular bed of the BBB.
The Search for Secreted Proteins in Prostate Cancer by the Escherichia coli Ampicillin Secretion Trap: Expression of NBL1 Is Highly Restricted to the Prostate and Is Related to Cancer Progression
Authors: Hayashi Tetsutaro , Sentani Kazuhiro , Oue Naohide , Ohara Shinya , Teishima Jun , Anami Katsuhiro , Sakamoto Naoya , Matsubara Akio , Yasui Wataru
Published: August 2012

Aims: Genes expressed only in cancer tissue or specific organs will be useful molecular markers. To identify genes that encode secreted proteins present in prostate cancer (PCa), we generated Escherichia coli ampicillin secretion trap (CAST) libraries from PCa and normal prostate (NP). Methods and Results: We identified 15 candidate genes that encode secreted proteins present in PCa and NP. Quantitative RT-PCR analysis revealed that MSMB, NBL1 and AZGP1 were expressed with much higher specificity in PCa and NP than in 14 other kinds of normal tissue. We focused on NBL1, which was originally identified as a putative tumor suppressor gene. Western blot analysis revealed that NBL1 protein was highly expressed in both cell lysate and culture media of the DU145 PCa cell line. Immunohistochemical analysis showed that NBL1 expression was highly detected in and restricted to NP and PCa and was significantly down-regulated in PCa. NBL1 expression was significantly reduced according to the tumor stage, Gleason grade and preoperative prostate-specific antigen (PSA) value. Conclusion: NBL1 is a secreted protein that is highly restricted to the prostate. Underexpression of NBL1 correlated with PCa progression. NBL1 might be a candidate tumor marker for PCa in addition to PSA.
LEOPARD Syndrome: Clinical Features and Gene Mutations
Authors: Martínez-Quintana E. , Rodríguez-González F.
Published: August 2012

The RAS/MAPK pathway proteins with germline mutations in their respective genes are associated with some disorders such as Noonan, LEOPARD (LS), neurofibromatosis type 1, Costello and cardio-facio-cutaneous syndromes. LEOPARD is an acronym, mnemonic for the major manifestations of this disorder, characterized by multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness. Though it is not included in the acronym, hypertrophic cardiomyopathy is the most frequent cardiac anomaly observed, representing a potentially life-threatening problem in these patients. PTPN11, RAF1 and BRAF are the genes known to be associated with LS, identifying molecular genetic testing of the 3 gene mutations in about 95% of affected individuals. PTPN11 mutations are the most frequently found. Eleven different missense PTPN11 mutations (Tyr279Cys/Ser, Ala461Thr, Gly464Ala, Thr468Met/Pro, Arg498Trp/Leu, Gln506Pro, and Gln510Glu/Pro) have been reported so far in LS, 2 of which (Tyr279Cys and Thr468Met) occur in about 65% of the cases. Here, we provide an overview of clinical aspects of this disorder, the molecular mechanisms underlying pathogenesis and major genotype-phenotype correlations.
Cost-Effectiveness of Computed Tomographic Angiography Before Reoperative Coronary Artery Bypass Grafting
Authors: Gada Hemal , Desai Milind Y. , Marwick Thomas H.
Published: August 2012

Background—

The risks of repeat thoracotomy can be reduced if thoracic multidetector computed tomographic angiography (CTA) is used to guide preventive surgical strategies (PSS: peripheral cardiopulmonary bypass, circulatory arrest, and nonmedian sternotomy). We sought to define the cost-effectiveness of CTA using a Markov model.

Methods and Results—

We studied outcomes and costs of CTA and non-CTA strategies in a modeled cohort of 10 000 patients undergoing redo coronary artery bypass grafting. Rates of PSS implementation were anticipated to follow identification of risk by CTA. Transitions, costs, and utilities were informed by our experience and the literature. Sensitivity analyses included testing a range of costs of CTA and PSS on model outcome. In the reference case, cost and quality-adjusted life years accrued with the use of CTA ($74 869, 4.63 quality-adjusted life-years) were slightly higher than nonuse ($73 471, 4.59 quality-adjusted life-years), yielding an incremental cost-effectiveness ratio of $34 950/quality-adjusted life-years. Cost of PSS (equipment and operating time) was the most significant determinant of incremental cost-effectiveness ratio. In the reference case (cost of CTA ≈$300), identification and avoidance of potential procedural difficulties with CTA rendered it cost-effective if the cost of PSS was <$12 000. Across a range of CTA costs, incremental cost-effectiveness ratio was not materially influenced by outcomes across a broad range of imputed values.

Conclusions—

The cost of CTA appears justified in the setting of isolated reoperative coronary artery bypass grafting, because it aids in appropriate selection of PSS. The cost-effectiveness of this imaging seems more influenced by the costs of subsequent PSS than by the cost of CTA.