bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Neonatal Manipulation of Androgen Receptor Function on Endocrine-Metabolic Programming in the Juvenile Female Rat
Authors: Ongaro Luisina , Giovambattista Andres , Spinedi Eduardo
Published: August 2013

The impact of neonatal androgen receptor (AR) stimulation/blockage, due to testosterone propionate (TP)/AR antagonist treatment, on individual anthropometry and neuroendocrine-metabolic function was evaluated in the juvenile female rat. Pups (age 5 days) were s.c. injected with TP (1.25 mg), flutamide (F; 1.75 mg), and TP + F or vehicle (control, CT) and studied on day 30 of age. Body weight (BW), parametrial adipose tissue (PMAT) mass, food intake, adipoinsular axis, and steroidogenic functions were examined. Opposite to TP-rats, F-treated rats developed hypophagia, grew slowly (BW and PMAT), and displayed heightened peripheral insulin sensitivity. These F effects were abrogated in TP + F animals. Accordingly, TP rats displayed hyperleptinemia, an effect fully prevented by F cotreatment. Finally, androgen-treated animals bore an irreversible ovarian dysfunction (reduced circulating levels of 17HOP4 and ovary 17HOP4 content and P450c17 mRNA abundance). These data indicate that early stimulation of AR enhanced energy store, blockage of AR activity resulted in some beneficial metabolic effects, and neonatally androgenized rats developed a severe ovarian dysfunction. Our study highlights the important role of AR in the early organizational programming of metabolic and neuroendocrine functions.
Nonhyperbolic Periodic Orbits of Vector Fields in the Plane Revisited
Authors: Braga Denis de Carvalho , Mello Luis Fernando , Zambroni de Souza Antonio Carlos
Published: August 2013

The main goal of this paper is to present a theory of approximation of periodic orbits of vector fields in the plane. From the theory developed here, it is possible to obtain an approximation to the curve of nonhyperbolic periodic orbits in the bifurcation diagram of a family of differential equations that has a transversal Hopf point of codimension two. Applications of the developed theory are made in Liénard-type equations and in Bazykin’s predator-prey system.
Primary Malignant Melanoma of the Genitourinary Tract with Upper and Lower Tracts Involvement
Authors: Sutton Broderick , Chan Robert , Sutton Mark , Boone Timothy
Published: August 2013

A 91-year-old female presented with lower extremity swelling and shortness of breath. Laboratory analysis revealed elevations in blood urea nitrogen and creatinine along with microscopic hematuria on urinalysis. Computed tomography imaging showed moderate right hydronephrosis with dilatation of the proximal ureter with a soft tissue density at a transition point. Endoscopic evaluation revealed multiple raised, fleshy, and hemorrhagic masses throughout the bladder which are present in both ureters. Biopsy of these lesions revealed malignant melanoma invading the lamina propria. No dermatologic lesions were identified suggesting a primary malignant melanoma of the genitourinary system.
Proteomic Analysis and Label-Free Quantification of the Large Clostridium difficile Toxins
Authors: Moura Hercules , Terilli Rebecca R. , Woolfitt Adrian R. , Williamson Yulanda M. , Wagner Glauber , Blake Thomas A. , Solano Maria I. , Barr John R.
Published: August 2013

Clostridium difficile is the leading cause of antibiotic-associated diarrhea in hospitals worldwide, due to hypervirulent epidemic strains with the ability to produce increased quantities of the large toxins TcdA and TcdB. Unfortunately, accurate quantification of TcdA and TcdB from different toxinotypes using small samples has not yet been reported. In the present study, we quantify C. difficile toxins in <0.1 mL of culture filtrate by quantitative label-free mass spectrometry (MS) using data-independent analysis (MSE). In addition, analyses of both purified TcdA and TcdB as well as a standard culture filtrate were performed using gel-based and gel-independent proteomic platforms. Gel-based proteomic analysis was then used to generate basic information on toxin integrity and provided sequence confirmation. Gel-independent in-solution digestion of both toxins using five different proteolytic enzymes with MS analysis generated broad amino acid sequence coverage (91% for TcdA and 95% for TcdB). Proteomic analysis of a culture filtrate identified a total of 101 proteins, among them TcdA, TcdB, and S-layer proteins.
On the Aleksandrov-Rassias Problems on Linearn-Normed Spaces
Authors: Ma Yumei
Published: August 2013

This paper generalizes T. M. Rassias' results in 1993 ton-normed spaces. IfXandYare two realn-normed spaces andYisn-strictly convex, a surjective mappingf:X→Ypreserving unit distance in both directions and preserving any integer distance is ann-isometry.
Combinatorial Control of Gene Expression
Authors: Bhattacharjee Soumya , Renganaath Kaushik , Mehrotra Rajesh , Mehrotra Sandhya
Published: August 2013

The complexity and diversity of eukaryotic organisms are a feat of nature’s engineering. Pulling the strings of such an intricate machinery requires an even more masterful and crafty approach. Only the number and type of responses that they generate exceed the staggering proportions of environmental signals perceived and processed by eukaryotes. Hence, at first glance, the cell’s sparse stockpile of controlling factors does not seem remotely adequate to carry out this response. The question as to how eukaryotes sense and respond to environmental cues has no single answer. It is an amalgamation, an interplay between several processes, pathways, and factors—a combinatorial control. A short description of some of the most important elements that operate this entire conglomerate is given in this paper.
Formal Development of System of Systems
Authors: Kamali Maryam , Neovius Mats , Petre Luigia , Sandvik Petter
Published: August 2013

Characterising for contemporary systems is their dependence on constituent systems to provide information, functionality, and scalability. Moreover, as the tasks that systems perform are ever more intimate and critical in their nature, reliability and correctness are great concerns. On these matters, we outline a methodology for formal integration of systems. We claim this formal approach to assist in managing the complexity and correctness, in preserving reliability and in respecting the independence of the constituent systems. As a proof of concept, we integrate two in-house control systems specified independently in the Event-B language with the Rodin Platform tool. Moreover, we show how to introduce a new functionality that is only possible due to the integration. Hence, we formally construct a system of systems and provide the methods for hierarchical integration of those.
BWR/5 Pressure-Suppression Pool Response during an SBO
Authors: Ortiz-Villafuerte Javier , Rodríguez-Hernández Andrés , Araiza-Martínez Enrique , Fuentes-Márquez Luis , Viais-Juárez Jorge
Published: August 2013

RELAP/SCDAPSIM Mod 3.4 has been used to simulate a station blackout occurring at a BWR/5 power station. Further, a simplified model of a wet well and dry well has been added to the NSSS model to study the response of the primary containment during the evolution of this accident. The initial event leading to severe accident was considered to be a LOOP with simultaneous scram. The results show that RCIC alone can keep the core fully covered, but even in this case about 30% of the original liquid water inventory in the PSP is vaporized. During the SBO, without RCIC, this inventory is reduced about 5% more within six hours. Further, a significant pressure rise occurs in containment at about the time when a sharp increase of heat generation occurs in RPV due to cladding oxidation. Failure temperature of fuel clad is also reached at this point. As the accident progresses, conditions for containment venting can be reached in about nine hours, although there still exists considerable margin before reaching containment design pressure. Detailed information of accident progress in reactor vessel and containment is presented and discussed.
3D Imaging of Buried Dielectric Targets with a Tomographic Microwave Approach Applied to GPR Synthetic Data
Authors: Galli Alessandro , Comite Davide , Catapano Ilaria , Gennarelli Gianluca , Soldovieri Francesco , Pettinelli Elena
Published: August 2013

Effective diagnostics with ground penetrating radar (GPR) is strongly dependent on the amount and quality of available data as well as on the efficiency of the adopted imaging procedure. In this frame, the aim of the present work is to investigate the capability of a typical GPR system placed at a ground interface to derive three-dimensional (3D) information on the features of buried dielectric targets (location, dimension, and shape). The scatterers can have size comparable to the resolution limits and can be placed in the shallow subsurface in the antenna near field. Referring to canonical multimonostatic configurations, the forward scattering problem is analyzed first, obtaining a variety of synthetic GPR traces and radargrams by means of a customized implementation of an electromagnetic CAD tool. By employing these numerical data, a full 3D frequency-domain microwave tomographic approach, specifically designed for the inversion problem at hand, is applied to tackle the imaging process. The method is tested here by considering various scatterers, with different shapes and dielectric contrasts. The selected tomographic results illustrate the aptitude of the proposed approach to recover the fundamental features of the targets even with critical GPR settings.
A 10-Week Multimodal Nutrition Education Intervention Improves Dietary Intake among University Students: Cluster Randomised Controlled Trial
Authors: Shahril Mohd Razif , Wan Dali Wan Putri Elena , Lua Pei Lin
Published: August 2013

The aim of the study was to evaluate the effectiveness of implementing multimodal nutrition education intervention (NEI) to improve dietary intake among university students. The design of study used was cluster randomised controlled design at four public universities in East Coast of Malaysia. A total of 417 university students participated in the study. They were randomly selected and assigned into two arms, that is, intervention group (IG) or control group (CG) according to their cluster. The IG received 10-week multimodal intervention using three modes (conventional lecture, brochures, and text messages) while CG did not receive any intervention. Dietary intake was assessed before and after intervention and outcomes reported as nutrient intakes as well as average daily servings of food intake. Analysis of covariance (ANCOVA) and adjusted effect size were used to determine difference in dietary changes between groups and time. Results showed that, compared to CG, participants in IG significantly improved their dietary intake by increasing their energy intake, carbohydrate, calcium, vitamin C and thiamine, fruits and 100% fruit juice, fish, egg, milk, and dairy products while at the same time significantly decreased their processed food intake. In conclusion, multimodal NEI focusing on healthy eating promotion is an effective approach to improve dietary intakes among university students.
Evaluation of the HB&L System for the Microbiological Screening of Storage Medium for Organ-Cultured Corneas
Authors: Camposampiero D. , Grandesso S. , Zanetti E. , Mazzucato S. , Solinas M. , Parekh M. , Frigo A. C. , Gion M. , Ponzin D.
Published: August 2013

Aims. To compare HB&L and BACTEC systems for detecting the microorganisms contaminating the corneal storage liquid preserved at 31°C.Methods. Human donor corneas were stored at 4°C followed by preservation at 31°C. Samples of the storage medium were inoculated in BACTEC Peds Plus/F (aerobic microorganisms), BACTEC Plus Anaerobic/F (anaerobic microorganisms), and HB&L bottles. The tests were performed (a) after six days of storage, (b) end of storage, and (c) after 24 hours of preservation in deturgescent liquid sequentially. 10,655 storage and deturgescent media samples were subjected to microbiological control using BACTEC (6-day incubation) and HB&L (24-hour incubation) systems simultaneously. BACTEC positive/negative refers to both/either aerobic and anaerobic positives/negatives, whereas HB&L can only detect the aerobic microbes, and therefore the positives/negatives depend on the presence/absence of aerobic microorganisms.Results. 147 (1.38%) samples were identified positive with at least one of the two methods. 127 samples (134 identified microorganisms) were positive with both HB&L and BACTEC. 14 HB&L+/BACTEC− and 6 BACTEC+/HB&L− were identified. Sensitivity (95.5%), specificity (99.8%), and positive (90.1%) and negative predictive values (99.9%) were high with HB&L considering a 3.5% annual contamination rate.Conclusion. HB&L is a rapid system for detecting microorganisms in corneal storage medium in addition to the existing methods.
Increased Frequency of Bone Marrow T Follicular Helper Cells in Patients with Immune-Related Pancytopenia
Authors: Yu Hong , Zhang Jiangbo , Fu Rong , Liu Hui , Wang Huaquan , Ding Kai , Wang Yihao , Li Lijuan , Wang Honglei , Shao Zonghong
Published: August 2013

Immune-related pancytopenia (IRP) is one kind of bone marrow failure diseases which is related to autoantibodies. Autoantibodies have been detected on the membrane of various bone marrow (BM) hemopoietic cells by BM mononuclear-cell-Coombs test or flow cytometric analysis. There are autoantibodies in the BM supernatant of IRP patients, which can target several antigens on hematopoietic cells membranes by western blot. T follicular helper (Tfh) cells are the true helper cells for Ab responses, which represent one of the most numerous and important subsets of effector T cells. Dysregulation of Tfh cell function or expression of Tfh cell-associated molecules could contribute to the pathogenesis of autoimmune diseases. Currently, there are no studies regarding the role of Tfh cells in IRP patients. The percentages of Tfh cells, Tfh-related molecules ICOS, CD40L, IL-21, and Bcl-6 in BM were investigated in 90 patients with IRP, and 25 healthy controls. We observed that there exist increased quantity and hyperfunction of Tfh cells in IRP, and the results were correlated with patient characteristics. It was indicated that dysregulated Tfh cells might be involved in the pathogenesis of IRP and that inhibition of Tfh cells effector molecules might provide opportunities for new therapeutic approaches to IRP and even other human autoimmune diseases.
A Computational Method for n-Dimensional Laplace Transforms Involved with Fourier Cosine Transform
Authors: Saberi-Nadjafi Jafar
Published: August 2013

In 2007, the author published some results on n-dimensional Laplace transform involved with the Fourier sine transform. In this paper, we propose some new result in n-dimensional Laplace transforms involved with Fourier cosine transform; these results provide few algorithms for evaluating some n-dimensional Laplace transform pairs. In addition, some examples are also presented, which explain the useful applications of the obtained results. Therefore, one can produce some two- and three- as well as n-dimensional Laplace transforms pairs.
An Accurate and Efficient Method to Predict Y-NO Bond Homolysis Bond Dissociation Energies
Authors: Li Hong Zhi , Li Lin , Zhong Zi Yan , Han Yi , Hu LiHong , Lu Ying Hua
Published: August 2013

The paper suggests a new method that combines the Kennard and Stone algorithm (Kenstone, KS), hierarchical clustering (HC), and ant colony optimization (ACO)-based extreme learning machine (ELM) (KS-HC/ACO-ELM) with the density functional theory (DFT) B3LYP/6-31G(d) method to improve the accuracy of DFT calculations for the Y-NO homolysis bond dissociation energies (BDE). In this method, Kenstone divides the whole data set into two parts, the training set and the test set; HC and ACO are used to perform the cluster analysis on molecular descriptors; correlation analysis is applied for selecting the most correlated molecular descriptors in the classes, and ELM is the nonlinear model for establishing the relationship between DFT calculations and homolysis BDE experimental values. The results show that the standard deviation of homolysis BDE in the molecular test set is reduced from 4.03 kcal mol−1calculated by the DFT B3LYP/6-31G(d) method to 0.30, 0.28, 0.29, and 0.32 kcal mol−1by the KS-ELM, KS-HC-ELM, and KS-ACO-ELM methods and the artificial neural network (ANN) combined with KS-HC, respectively. This method predicts accurate values with much higher efficiency when compared to the larger basis set DFT calculation and may also achieve similarly accurate calculation results for larger molecules.
A Decentralized Virtual Machine Migration Approach of Data Centers for Cloud Computing
Authors: Wang Xiaoying , Liu Xiaojing , Fan Lihua , Jia Xuhan
Published: August 2013

As cloud computing offers services to lots of users worldwide, pervasive applications from customers are hosted by large-scale data centers. Upon such platforms, virtualization technology is employed to multiplex the underlying physical resources. Since the incoming loads of different application vary significantly, it is important and critical to manage the placement and resource allocation schemes of the virtual machines (VMs) in order to guarantee the quality of services. In this paper, we propose a decentralized virtual machine migration approach inside the data centers for cloud computing environments. The system models and power models are defined and described first. Then, we present the key steps of the decentralized mechanism, including the establishment of load vectors, load information collection, VM selection, and destination determination. A two-threshold decentralized migration algorithm is implemented to further save the energy consumption as well as keeping the quality of services. By examining the effect of our approach by performance evaluation experiments, the thresholds and other factors are analyzed and discussed. The results illustrate that the proposed approach can efficiently balance the loads across different physical nodes and also can lead to less power consumption of the entire system holistically.
Controllability of Neutral Fractional Functional Equations with Impulses and Infinite Delay
Authors: Ganesh R. , Sakthivel R. , Ren Yong , Anthoni S. M. , Mahmudov N. I.
Published: August 2013

We examine the controllability problem for a class of neutral fractional integrodifferential equations with impulses and infinite delay. More precisely, a set of sufficient conditions are derived for the exact controllability of nonlinear neutral impulsive fractional functional equation with infinite delay. Further, as a corollary, approximate controllability result is discussed by assuming compactness conditions on solution operator. The results are established by using solution operator, fractional calculations, and fixed point techniques. In particular, the controllability of nonlinear fractional control systems is established under the assumption that the corresponding linear control system is controllable. Finally, an example is given to illustrate the obtained theory.
Morphology Characterisation of Pitting Corrosion on Sensitized Austenitic Stainless Steel by Digital Image Analysis
Authors: Ribeiro R. B. , Silva J. W. J. , Hein L. R. O. , Pereira M. C. , Codaro E. N. , Matias N. T.
Published: August 2013

Pit morphology on sensitized 310S stainless steel has been studied using an image processing method based on reflected light microscopy. Salt Spray (fog)
test has been used to induce the pitting corrosion. Morphological pits characters do not depend on sensitization heat treatments applied here. Nucleation rates and growth may
be associated with quantity and distribution of chromium carbides. This being so, condition I (heating up to 1065°C during 1 h and air cooling) and
condition II (heating up to 1065°C during 1 h and air cooling followed by reheating up to 670°C during 5 h and again
air cooling) are the most susceptible to pitting, in particular the first one. In these two conditions, pits are nucleated in grains and in grain boundaries, while in condition III
(heating up to 1065°C during 1 h and air cooling followed by reheating up to 620°C during 24 h and again air cooling),
pits are preferentially nucleated in boundaries of small grains. Thence, pits usually grow more rapidly in depth than in width, being able to occur partial or total grains separation.
Pits are mainly hemispherical, near-hemispherical, near-conical, and near-cylindrical without significant geometric transition associated with an increasing exposure period.
Research on Quantitative Models of Electric Vehicle Charging Stations Based on Principle of Energy Equivalence
Authors: Wang Zhenpo , Liu Peng , Cui Jia , Xi Yue , Zhang Lei
Published: August 2013

In order to adapt the matching and planning requirements of charging station in the electric vehicle (EV) marketization application, with related layout theories of the gas stations, a location model of charging stations is established based on electricity consumption along the roads among cities. And a quantitative model of charging stations is presented based on the conversion of oil sales in a certain area. Both are combining the principle based on energy consuming equivalence substitution in process of replacing traditional vehicles with EVs. Defined data are adopted in the example analysis of two numerical case models and analyze the influence on charging station layout and quantity from the factors like the proportion of vehicle types and the EV energy consumption at the same time. The results show that the quantitative model of charging stations is reasonable and feasible. The number of EVs and the energy consumption of EVs bring more significant impact on the number of charging stations than that of vehicle type proportion, which provides a basis for decision making for charging stations construction layout in reality.
A Comparative Genomic Approach for Identifying Synthetic Lethal Interactions in Human Cancer
Authors: Deshpande Raamesh , Asiedu Michael K. , Klebig Mitchell , Sutor Shari , Kuzmin Elena , Nelson Justin , Piotrowski Jeff , Ho Shin Seung , Yoshida Minoru , Costanzo Michael , Boone Charles , Wigle Dennis A. , Myers Chad L.
Published: August 2013

Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We describe a comparative genomic strategy for identifying cancer-relevant synthetic lethal interactions whereby candidate interactions are prioritized on the basis of genetic interaction data available in yeast, followed by targeted testing of candidate interactions in human cell lines. As a proof of principle, we describe two novel synthetic lethal interactions in human cells discovered by this approach, one between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2. These results suggest therapeutic targets for cancers harboring mutations in SMARCB1 or ASPSCR1 and highlight the potential of a targeted, cross-species strategy for identifying synthetic lethal interactions relevant to human cancer. Cancer Res; 73(20); 6128–36. ©2013 AACR.
Preclinical Efficacy of the Anti-Hepatocyte Growth Factor Antibody Ficlatuzumab in a Mouse Brain Orthotopic Glioma Model Evaluated by Bioluminescence, PET, and MRI
Authors: Mittra Erik S. , Fan-Minogue Hua , Lin Frank I. , Karamchandani Jason , Sriram Venkataraman , Han May , Gambhir Sanjiv S.
Published: August 2013

Purpose: Ficlatuzumab is a novel therapeutic agent targeting the hepatocyte growth factor (HGF)/c-MET pathway. We summarize extensive preclinical work using this agent in a mouse brain orthotopic model of glioblastoma.

Experimental Design: Sequential experiments were done using eight- to nine-week-old nude mice injected with 3 × 105 U87 MG (glioblastoma) cells into the brain. Evaluation of ficlatuzumab dose response for this brain tumor model and comparison of its response to ficlatuzumab and to temozolamide were conducted first. Subsequently, various small-animal imaging modalities, including bioluminescence imaging (BLI), positron emission tomography (PET), and MRI, were used with a U87 MG-Luc 2 stable cell line, with and without the use of ficlatuzumab, to evaluate the ability to noninvasively assess tumor growth and response to therapy. ANOVA was conducted to evaluate for significant differences in the response.

Results: There was a survival benefit with ficlatuzumab alone or in combination with temozolamide. BLI was more sensitive than PET in detecting tumor cells. Fluoro-D-thymidine (FLT) PET provided a better signal-to-background ratio than 2[18F]fluoro-2-deoxy-d-glucose (FDG) PET. In addition, both BLI and FLT PET showed significant changes over time in the control group as well as with response to therapy. MRI does not disclose any time-dependent change. Also, the MRI results showed a temporal delay in comparison to the BLI and FLT PET findings, showing similar results one drug cycle later.

Conclusions: Targeting the HGF/c-MET pathway with the novel agent ficlatuzumab appears promising for the treatment of glioblastoma. Various clinically applicable imaging modalities including FLT, PET, and MRI provide reliable ways of assessing tumor growth and response to therapy. Given the clinical applicability of these findings, future studies on patients with glioblastoma may be appropriate. Clin Cancer Res; 19(20); 5711–21. ©2013 AACR.
Arginine Deiminase Resistance in Melanoma Cells Is Associated with Metabolic Reprogramming, Glucose Dependence, and Glutamine Addiction
Authors: Long Yan , Tsai Wen-Bin , Wangpaichitr Medhi , Tsukamoto Takashi , Savaraj Niramol , Feun Lynn G. , Kuo Macus Tien
Published: August 2013

Many malignant human tumors, including melanomas, are auxotrophic for arginine due to reduced expression of argininosuccinate synthetase-1 (ASS1), the rate-limiting enzyme for arginine biosynthesis. Pegylated arginine deiminase (ADI-PEG20), which degrades extracellular arginine, resulting in arginine deprivation, has shown favorable results in clinical trials for treating arginine-auxotrophic tumors. Drug resistance is the major obstacle for effective ADI-PEG20 usage. To elucidate mechanisms of resistance, we established several ADI-PEG20–resistant (ADIR) variants from A2058 and SK-Mel-2 melanoma cells. Compared with the parental lines, these ADIR variants showed the following characteristics: (i) all ADIR cell lines showed elevated ASS1 expression, resulting from the constitutive binding of the transcription factor c-Myc on the ASS1 promoter, suggesting that elevated ASS1 is the major mechanism of resistance; (ii) the ADIR cell lines exhibited enhanced AKT signaling and were preferentially sensitive to PI3K/AKT inhibitors, but reduced mTOR signaling, and were preferentially resistant to mTOR inhibitor; (iii) these variants showed enhanced expression of glucose transporter-1 and lactate dehydrogenase-A, reduced expression of pyruvate dehydrogenase, and elevated sensitivity to the glycolytic inhibitors 2-deoxy-glucose and 3-bromopyruvate, consistent with the enhanced glycolytic pathway (the Warburg effect); (iv) the resistant cells showed higher glutamine dehydrogenase and glutaminase expression and were preferentially vulnerable to glutamine inhibitors. We showed that c-Myc, not elevated ASS1 expression, is involved in upregulation of many of these enzymes because knockdown of c-Myc reduced their expression, whereas overexpressed ASS1 by transfection reduced their expression. This study identified multiple targets for overcoming ADI-PEG resistance in cancer chemotherapy using recombinant arginine-degrading enzymes. Mol Cancer Ther; 12(11); 2581–90. ©2013 AACR.
Dietary Energy Balance Modulation of Kras- and Ink4a/Arf+/−-Driven Pancreatic Cancer: The Role of Insulin-like Growth Factor-I
Authors: Lashinger Laura M. , Harrison Lauren M. , Rasmussen Audrey J. , Logsdon Craig D. , Fischer Susan M. , McArthur Mark J. , Hursting Stephen D.
Published: August 2013

New molecular targets and intervention strategies for breaking the obesity–pancreatic cancer link are urgently needed. Using relevant spontaneous and orthotopically transplanted murine models of pancreatic cancer, we tested the hypothesis that dietary energy balance modulation impacts pancreatic cancer development and progression through an insulin-like growth factor (IGF)-I−dependent mechanism. In LSL-KrasG12D/Pdx-1-Cre/Ink4a/Arflox/+ mice, calorie restriction versus overweight- or obesity-inducing diet regimens decreased serum IGF-I, tumoral Akt/mTOR signaling, pancreatic desmoplasia, and progression to pancreatic ductal adenocarcinoma (PDAC), and increased pancreatic tumor-free survival. Serum IGF-I, Akt/mTOR signaling, and orthotopically transplanted PDAC growth were decreased in liver-specific IGF-I−deficient mice (vs. wild-type mice), and rescued with IGF-I infusion. Thus, dietary energy balance modulation impacts spontaneous pancreatic tumorigenesis induced by mutant Kras and Ink4a deficiency, the most common genetic alterations in human pancreatic cancer. Furthermore, IGF-I and components of its downstream signaling pathway are promising mechanistic targets for breaking the obesity–pancreatic cancer link. Cancer Prev Res; 6(10); 1046–55. ©2013 AACR.
Prevalence and Disease Burden of Hyperhidrosis in the Adult Population
Authors: Augustin M. , Radtke M.A. , Herberger K. , Kornek T. , Heigel H. , Schaefer I.
Published: August 2013

Background: Although hyperhidrosis is a common and burdensome condition, little is known about the population-based prevalence. Objective: To evaluate the epidemiology, disease burden and medical care of hyperhidrosis in German adults. Methods: Employees of fifty-two companies underwent skin screenings and interviews including hyperhidrosis questions. Results: 14,336 individuals were investigated (36% women, mean age 42 years) of whom 2,340 (16.3%) reported hyperhidrosis, including 869 (6.1%) with frequent or continuous disturbing sweating. 28% showed focal hyperhidrosis, whilst 68% had a generalized condition. Predictors of hyperhidrosis were male gender and concomitant drug medication. Moreover, persons with psoriasis and with metabolic comorbidity were at increased risk. Only 27% of those with focal hyperhidrosis had consulted a physician, and only 28% used prescribed medication or self-medication. Conclusion: Hyperhidrosis is a frequent skin condition predicted by medical and personal factors. In spite of the disease burden, few individuals utilize medical care. Affected individuals should be encouraged to refer to a dermatologist.
CXCR4 Expression in Bladder Transitional Cell Carcinoma and Its Relationship with Clinicopathological Features
Authors: Li Yangle , Chen Minfeng , Yuan Junbin , Zhou Xu , He Wei , Zu Xiongbing , Qi Lin
Published: August 2013

Objective: To elucidate the role of CXCR4 in the metastasis of bladder transitional cell carcinoma (BTCC) by examining CXCR4 expression in BTCC tissue and its correlation with clinicopathological features. Methods: The expression of CXCR4 was assessed in bladder tissues from 70 BTCC patients and 18 normal controls, respectively, using immunohistochemistry. The correlation of CXCR4 expression with lymph node metastasis was also examined by determining the lymphatic vessel density (LVD). Results: Overexpression of CXCR4 was detected in 58/70 (82.9%) BTCC tissues, whereas only in 3/18 (16.7%) normal bladder tissues. The expression was significantly higher in BTCC than that in normal controls (p < 0.01). CXCR4 expression level was closely associated with tumor size, pathological grades, clinical stages, and pelvic lymph node metastasis (p < 0.05). Multivariate analysis indicated that CXCR4 expression and lymph node metastasis were independent predictors for disease-free survival (both p < 0.05). The disease-free survival rate among the patients with high CXCR4 expression level was remarkably lower than that among the patients with no or low level expression (p < 0.01). Conclusion: Highly expressed in BTCC tissues, CXCR4 may play a critical role in the metastasis of BTCC, and the expression level in biopsy specimens might be a good indicator of lymph node metastasis.
Maternal Endotoxin Exposure Results in Abnormal Neuronal Architecture in the Newborn Rabbit
Authors: Balakrishnan Bindu , Dai Hui , Janisse James , Romero Roberto , Kannan Sujatha
Published: August 2013

Maternal intrauterine inflammation/infection is a potential risk factor for the development of neurologic disorders such as cerebral palsy (CP) in preterm and term infants. CP is associated with white matter and grey matter injury. In the current study, we used a rabbit model of CP in which pregnant rabbits are administered intrauterine injections of the endotoxin lipopolysaccharide. We then investigated the extent of neuronal damage in the newborn kit brain. We observed an overall decrease in the number of MAP2-stained neurons and an increase in Fluoro-Jade C-stained cells in the anterior thalamus of 1-day-old rabbit brain. We also observed an overall decrease in the number of branching points and spine density in the retrosplenial cortex, a major output region of the anterior thalamus that is involved in cognition and memory. The loss of spines and dendritic atrophy in the retrosplenial cortex may be caused by loss of presynaptic input from the thalamus. Our study indicates that the cognitive impairments seen in patients with CP may be related to the degeneration of neurons and abnormal arborization of the thalamic and cortical neurons.
Characteristics of Medically and Surgically Treated Empyema Patients: A Retrospective Cohort Study
Authors: Dusemund F. , Weber M.D. , Nagel W. , Schneider T. , Brutsche M.H. , Schoch O.D.
Published: August 2013

Background: The role of drainage, intrapleural fibrinolytics, and/or surgery in the management of thoracic empyema is controversial. Objectives: We aimed to investigate the operational practice of empyema management at our hospital. Methods: Between January 2001 and December 2008, all patients with thoracic empyema were retrieved. After exclusion of patients with malignant effusion, traumatic or iatrogenic empyema, and a history of pleurodesis or tuberculosis, we compared the characteristics of medically versus surgically treated empyema patients. Results: Seventy-eight of 215 retrieved patients were acute bacterial empyema cases. All received intravenous antibiotics. Fifty-eight (74.4%) initially received tube thoracostomy, 34 (43.6%) were treated with intrapleural urokinase, and 30 (38.5%) were operated on. Of 20 patients without initial tube thoracostomy, 15 (75%) were operated on, compared to 9 (37.5%) who were initially treated by tube thoracostomy without intrapleural fibrinolytics (OR 5; 95% CI 1.4-18.5, p = 0.01) and 6 (17.7%) who were initially treated with tube thoracostomy and intrapleural urokinase (OR 14; 95% CI 3.6-53.6, p < 0.001). The surgery patients were not different in demographic and clinical characteristics but were more likely to describe significant chest pain 12 months after discharge. Conclusions: In this retrospective cohort study of thoracic empyema patients, initial chest tube insertion and intrapleural fibrinolytics were associated with less surgical therapy. Other predictors of the need for surgery could not be identified. Surgery patients were more likely to suffer from residual chest pain 12 months after discharge. Initial treatment with IV antibiotics, chest tube, and intrapleural fibrinolytics was successful in the majority of patients.
Association between Lean and Fat Mass and Indicators of Bone Health in Prepubertal Caucasian Children
Authors: Kâ Khady , Rousseau Marie-Claude , Lambert Marie , O'Loughlin Jennifer , Henderson Mélanie , Tremblay Angelo , Alos Nathalie , Nicolau Belinda
Published: August 2013

Background/Aims: Childhood and adolescence are critical periods for bone growth. The independent association between lean and fat mass and indicators of bone health in children is not yet known. We aim to examine the association between each of lean and fat mass and indicators of bone health in 8- to 10-year-old prepubertal Caucasian children. Methods: We present a cross-sectional analysis of baseline data from the QUebec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort which study the natural history of obesity. Study participants (n = 483) included prepubertal children aged 8-10 years and their biological parents. Whole-body bone mineral content (BMC, g), bone area (cm2), bone mineral density (BMD, g/cm2), lean mass (kg), and fat mass (kg) were measured by dual-energy X-ray absorptiometry. Data analyses include multiple linear regressions adjusted for potential confounding variables. Results: A 1-kg increase in lean mass was associated with 28.42 g, 19.88 cm2, and 0.007 g/cm2 increase in whole-body BMC, bone area and BMD respectively. A 1-kg increase in fat mass was associated with 9.32 g, 8.02 cm2, and 0.002 g/cm2 increase in whole-body BMC, bone area and BMD, respectively. Conclusion: Increasing lean mass in children may help optimize bone acquisition and prevent future osteoporosis.
Male Breast Cancer: 20-Year Survival Data for Post-Mastectomy Radiotherapy
Authors: Eggemann Holm , Ignatov Atanas , Stabenow Roland , von Minckwitz Gunter , Röhl Friedrich Wilhelm , Hass Peter , Costa Serban-Dan
Published: August 2013

Background: The goal of this population-based study was to determine the impact of post-mastectomy radiation therapy on long-term overall survival (OS) of male patients with breast cancer. Patients and Methods: We investigated 20-year OS rates of 664 patients diagnosed with primary stage I-III breast cancer in former East Germany between 1970 and 1989. Patients had a radical mastectomy with axillary lymph node dissection without systemic adjuvant therapy. Results: Median follow-up time was 26.2 years (range 19-38 years). 52.4% of the patients had post-mastectomy radiotherapy. Radiotherapy showed different effects in each stage group after 20 years. Whereas there was an OS trend for radiotherapy to harm patients with stage I disease (hazard ratio (HR) 1.45; 95% confidence interval (CI) 0.98-2.15; p = 0.065), radiotherapy showed no benefit in patients with stage II disease (HR 0.82; 95% CI 0.62-1.1; p = 0.15). There was a significant survival benefit for patients with stage III disease receiving radiotherapy (HR 0.60; 95% CI 0.41-0.88; p = 0.008). Conclusion: Post-mastectomy radiotherapy is associated with longer OS in male patients with stage III breast cancer. Male breast cancer patients at stages I and II do not seem to benefit from radiotherapy, but obsolete irradiation techniques might explain adverse long-term effects in earlier stages.
Predictive Factors for Different Subgroups of Central Lymph Node Metastasis in Unilateral Papillary Thyroid Carcinoma
Authors: Miao SuSheng , Mao XiongHui , Pei Rong , Xiang Cheng , Lv YuanJing , Shi QingTao , Zhao Shu , Sun Ji , Jia ShenShan
Published: August 2013

Aims: We aimed to investigate the incidence rates and risk factors for different subgroups of central neck lymph node (LN) metastasis (prelaryngeal, ipsilateral paratracheal, pretracheal, and contralateral paratracheal) in unilateral papillary thyroid carcinoma (PTC) patients with clinically negative neck nodes (cN₀). Methods: We evaluated 184 patients from 2007 to 2009. The relationships between different subgroups of LN metastasis and clinical pathological factors were analyzed. Results: The incidence rates of different central LN metastases were diverse. Multivariate analysis indicated that lymphovascular invasion, perithyroidal invasion, and tumor size were risk factors for ipsilateral paratracheal central LN metastasis; tumor size was an independent risk factor for pretracheal central LN metastasis, and pretracheal or/and ipsilateral paratracheal central LN metastasis were risk factors for contralateral paratracheal central LN metastasis. Conclusion: The extent of elective central LN dissection (CLND) should be decided based on different clinical pathological factors in cN₀ PTC patients. Moreover, elective prelaryngeal CLND may be unnecessary.
Epigenetics Meets the Tumor Microenvironment
Authors: Dey Pranab
Published: August 2013

It is known that tumor cells undergo genetic and epigenetic alterations. Recent evidence suggests that epigenetic changes in the tumor microenvironment play a significant role in carcinogenesis. In this brief review, we discuss the epigenetic changes of the microenvironment in different malignancies and their clinical significance.
Role of p66shc in Renal Toxicity of Oleic Acid
Authors: Arany Istvan , Clark Jeb S. , Reed Dustin K. , Juncos Luis A. , Dixit Mehul
Published: August 2013

Background/Aims: Adult and childhood obesity is an independent risk factor in development of chronic kidney disease (CKD) and its progression to end-stage kidney disease. Pathologic consequences of obesity include non-esterified fatty acid-induced oxidative stress and consequent injury. Since the serine36-phosphorylated p66shc is a newly recognized mediator of oxidative stress and kidney injury, we studied its role in oleic acid (OA)-induced production of reactive oxygen species (ROS), mitochondrial depolarization and injury in cultured renal proximal tubule cells. Methods: Renal proximal tubule cells were used and treated with OA: ROS production, mitochondrial depolarization as well as injury were determined. Transcriptional effects of OA on the p66shc gene were determined in a reporter luciferase assay. The role of p66shc in adverse effects of OA was determined using knockdown, p66shc serine36 phosphorylation and cytochrome c binding-deficient cells. Results: We found that OA increased ROS production via the mitochondria - and to a less extent via the NADPH oxidase - resulting in ROS-dependent mitochondrial depolarization and consequent injury. Interestingly, OA also stimulated the promoter of p66shc. Hence, knockdown of p66shc, impairment its Ser36 phosphorylation (mutation of Ser36 residue to alanine) or cytochrome c binding (W134F mutation) significantly attenuated OA-dependent lipotoxicity. Conclusion: These results offer a novel mechanism by which obesity may lead to renal tubular injury and consequently development of CKD. Manipulation of this pathway may offer therapeutic means to ameliorate obesity-dependent renal lipotoxicity.
Depressing Mitochondria-Reticulum Interactions Protects Cardiomyocytes From Lethal Hypoxia-Reoxygenation Injury
Authors: Paillard Melanie , Tubbs Emily , Thiebaut Pierre-Alain , Gomez Ludovic , Fauconnier Jeremy , Crola Da Silva Claire , Teixeira Geoffrey , Mewton Nathan , Belaidi Elise , Durand Annie , Abrial Maryline , Lacampagne Alain , Rieusset Jennifer , Ovize Michel
Published: August 2013

Background—

Under physiological conditions, Ca
2+
transfer from the endoplasmic reticulum (ER) to mitochondria might occur at least in part at contact points between the 2 organelles and involves the VDAC1/Grp75/IP3R1 complex. Accumulation of Ca
2+
into the mitochondrial matrix may activate the mitochondrial chaperone cyclophilin D (CypD) and trigger permeability transition pore opening, whose role in ischemia/reperfusion injury is well recognized. We questioned here whether the transfer of Ca
2+
from ER to mitochondria might play a role in cardiomyocyte death after hypoxia-reoxygenation.

Methods and Results—

We report that CypD interacts with the VDAC1/Grp75/IP3R1 complex in cardiomyocytes. Genetic or pharmacological inhibition of CypD in both H9c2 cardiomyoblasts and adult cardiomyocytes decreased the Ca
2+
transfer from ER to mitochondria through IP3R under normoxic conditions. During hypoxia-reoxygenation, the interaction between CypD and the IP3R1 Ca
2+
channeling complex increased concomitantly with mitochondrial Ca
2+
content. Inhibition of either CypD, IP3R1, or Grp75 decreased protein interaction within the complex, attenuated mitochondrial Ca
2+
overload, and protected cells from hypoxia-reoxygenation. Genetic or pharmacological inhibition of CypD provided a similar effect in adult mice cardiomyocytes. Disruption of ER-mitochondria interaction via the downregulation of Mfn2 similarly reduced the interaction between CypD and the IP3R1 complex and protected against hypoxia-reoxygenation injury.

Conclusions—

Our data (1) point to a new role of CypD at the ER-mitochondria interface and (2) suggest that decreasing ER-mitochondria interaction at reperfusion can protect cardiomyocytes against lethal reperfusion injury through the reduction of mitochondrial Ca
2+
overload via the CypD/VDAC1/Grp75/IP3R1 complex.
Dispatcher-Assisted Cardiopulmonary Resuscitation
Authors: Lewis Miranda , Stubbs Benjamin A. , Eisenberg Mickey S.
Published: August 2013

Background—

Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR), in which 9-1-1 dispatchers provide CPR instructions over the telephone, has been shown to nearly double the rate of bystander CPR. We sought to identify factors that hampered the identification of cardiac arrest by 9-1-1 dispatchers and prevented or delayed the provision of dispatcher-assisted CPR chest compressions.

Methods and Results—

We reviewed dispatch recordings for 476 out-of-hospital cardiac arrests occurring between January 1, 2011, and December 31, 2011. We found that the dispatcher correctly identified cardiac arrest in 80% of reviewed cases and 92% of cases in which they were able to assess patient consciousness and breathing. The median time to recognition of the arrest was 75 seconds. Chest compressions following dispatcher-assisted CPR instructions occurred in 62% of cases when the dispatcher had the opportunity to asses for consciousness and breathing and bystander CPR was not already started. The median time to first dispatcher-assisted CPR chest compression was 176 seconds.

Conclusions—

Dispatchers are able to accurately diagnose cardiac arrest over the telephone, but recognition is likely not possible in all circumstances. In some cases, recognition of cardiac arrest may be improved through training in the detection of agonal respirations. Delays in the delivery of dispatcher-assisted CPR chest compressions are common and are attributable to a mixture of dispatcher behavior and factors beyond the control of the dispatcher. Performance standards for the successful and quick recognition of cardiac arrest and delivery of first chest compressions should be adopted as metrics against which emergency medical services systems can measure their performance.