bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain ACE2 overexpression reduces DOCA-salt hypertension independently of endoplasmic reticulum stress
Authors: Xia Huijing , de Queiroz Thyago Moreira , Sriramula Srinivas , Feng Yumei , Johnson Tanya , Mungrue Imran N. , Lazartigues Eric
Published: December 2014

Endoplasmic reticulum (ER) stress was previously reported to contribute to neurogenic hypertension while neuronal angiotensin-converting enzyme type 2 (ACE2) overexpression blunts the disease. To assess which brain regions are important for ACE2 beneficial effects and the contribution of ER stress to neurogenic hypertension, we first used transgenic mice harboring a floxed neuronal hACE2 transgene (SL) and tested the impact of hACE2 knockdown in the subfornical organ (SFO) and paraventricular nucleus (PVN) on deoxycorticosterone acetate (DOCA)-salt hypertension. SL and nontransgenic (NT) mice underwent DOCA-salt or sham treatment while infected with an adenoassociated virus (AAV) encoding Cre recombinase (AAV-Cre) or a control virus (AAV-green fluorescent protein) to the SFO or PVN. DOCA-salt-induced hypertension was reduced in SL mice, with hACE2 overexpression in the brain. This reduction was only partially blunted by knockdown of hACE2 in the SFO or PVN, suggesting that both regions are involved but not essential for ACE2 regulation of blood pressure (BP). DOCA-salt treatment did not increase the protein levels of ER stress and autophagy markers in NT mice, despite a significant increase in BP. In addition, these markers were not affected by hACE2 overexpression in the brain, despite a significant reduction of hypertension in SL mice. To further assess the role of ER stress in neurogenic hypertension, NT mice were infused intracerebroventricularlly with tauroursodeoxycholic acid (TUDCA), an ER stress inhibitor, during DOCA-salt treatment. However, TUDCA infusion failed to blunt the development of hypertension in NT mice. Our data suggest that brain ER stress does not contribute to DOCA-salt hypertension and that ACE2 blunts neurogenic hypertension independently of ER stress.
Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways
Authors: Nishimoto Mitsuhiro , Fujita Toshiro
Published: December 2014

Although salt is a major environmental factor in the development of hypertension, the degree of salt sensitivity varies widely among individuals. The mechanisms responsible for this variation remain to be elucidated. Recent studies have revealed the involvement of two important signaling pathways in renal tubules that play key roles in electrolyte balance and the maintenance of normal blood pressure: the β2-adrenergic stimulant-glucocorticoid receptor (GR)-with-no-lysine kinase (WNK)4-Na+-Cl−cotransporter pathway, which is active in distal convoluted tubule (DCT)1, and the Ras-related C3 botulinum toxin substrate (Rac)1-mineralocorticoid receptor (MR) pathway, which is active in DCT2, connecting tubules, and collecting ducts. β2-Adrenergic stimulation due to increased renal sympathetic activity in obesity- and salt-induced hypertension suppresses histone deacetylase 8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter. This results in the suppression of WNK4 transcription followed by the activation of Na+-Cl−cotransporters in the DCT and elevated Na+retention and blood pressure upon salt loading. Rac1 activates MRs, even in the absence of ligand binding, with this activity increased in the presence of ligand. In salt-sensitive animals, Rac1 activation due to salt loading activates MRs in DCT2, connecting tubules, and collecting ducts. Thus, GRs and MRs are independently involved in two pathways responsible for renal Na+handling and salt-sensitive hypertension. These findings suggest novel therapeutic targets and may lead to the development of diagnostic tools to determine salt sensitivity in hypertensive patients.
Tracking the evolution of crossmodal plasticity and visual functions before and after sight restoration
Authors: Dormal Giulia , Lepore Franco , Harissi-Dagher Mona , Albouy Geneviève , Bertone Armando , Rossion Bruno , Collignon Olivier
Published: December 2014

Visual deprivation leads to massive reorganization in both the structure and function of the occipital cortex, raising crucial challenges for sight restoration. We tracked the behavioral, structural, and neurofunctional changes occurring in an early and severely visually impaired patient before and 1.5 and 7 mo after sight restoration with magnetic resonance imaging. Robust presurgical auditory responses were found in occipital cortex despite residual preoperative vision. In primary visual cortex, crossmodal auditory responses overlapped with visual responses and remained elevated even 7 mo after surgery. However, these crossmodal responses decreased in extrastriate occipital regions after surgery, together with improved behavioral vision and with increases in both gray matter density and neural activation in low-level visual regions. Selective responses in high-level visual regions involved in motion and face processing were observable even before surgery and did not evolve after surgery. Taken together, these findings demonstrate that structural and functional reorganization of occipital regions are present in an individual with a long-standing history of severe visual impairment and that such reorganizations can be partially reversed by visual restoration in adulthood.
The effect of face inversion for neurons inside and outside fMRI-defined face-selective cortical regions
Authors: Taubert Jessica , Van Belle Goedele , Vanduffel Wim , Rossion Bruno , Vogels Rufin
Published: December 2014

It is widely believed that face processing in the primate brain occurs in a network of category-selective cortical regions. Combined functional MRI (fMRI)-single-cell recording studies in macaques have identified high concentrations of neurons that respond more to faces than objects within face-selective patches. However, cells with a preference for faces over objects are also found scattered throughout inferior temporal (IT) cortex, raising the question whether face-selective cells inside and outside of the face patches differ functionally. Here, we compare the properties of face-selective cells inside and outside of face-selective patches in the IT cortex by means of an image manipulation that reliably disrupts behavior toward face processing: inversion. We recorded IT neurons from two fMRI-defined face-patches (ML and AL) and a region outside of the face patches (herein labeled OUT) during upright and inverted face stimulation. Overall, turning faces upside down reduced the firing rate of face-selective cells. However, there were differences among the recording regions. First, the reduced neuronal response for inverted faces was independent of stimulus position, relative to fixation, in the face-selective patches (ML and AL) only. Additionally, the effect of inversion for face-selective cells in ML, but not those in AL or OUT, was impervious to whether the neurons were initially searched for using upright or inverted stimuli. Collectively, these results show that face-selective cells differ in their functional characteristics depending on their anatomicofunctional location, suggesting that upright faces are preferably coded by face-selective cells inside but not outside of the fMRI-defined face-selective regions of the posterior IT cortex.
Long-range GABAergic neurons in the prefrontal cortex modulate behavior
Authors: Bravo-Rivera Christian , Diehl Maria M. , Roman-Ortiz Ciorana , Rodriguez-Romaguera Jose , Rosas-Vidal Luis E. , Bravo-Rivera Hector , Quiñones-Laracuente Kelvin , Do-Monte Fabricio H.
Published: December 2014

Cortical glutamatergic projections are extensively studied in behavioral neuroscience, whereas cortical GABAergic projections to downstream structures have been overlooked. A recent study by Lee and colleagues (Lee AT, Vogt D, Rubenstein JL, Sohal VS. J Neurosci 34: 11519–11525, 2014) used optogenetic and electrophysiological techniques to characterize a behavioral role for long-projecting GABAergic neurons in the medial prefrontal cortex. In this Neuro Forum, we discuss the potential implications of this study in several learning and memory models.
Synthesis, Characterization, and DNA Binding Studies of Nanoplumbagin
Authors: Shahida Parveen Sheik Dawood , Affrose Abdullah , Suresh Kumar Basuvaraj , Annaraj Jamespandi , Pitchumani Kasi
Published: December 2014

The traditional anticancer medicine plumbagin (PLN) was prepared as nanostructured material (nanoplumbagin, NPn1) from its commercial counterparts, simultaneously coencapsulating with cetyltrimethylammonium bromide or cyclodextrin as stabilizers using ultrasonication technique. Surface morphology of NPn analysed from atomic force microscopy (AFM) indicates that NPn has tunable size between 75 nm and 100 nm with narrow particle size distribution. Its binding efficiency with herring sperm DNA was studied using spectral and electrochemical techniques and its efficiency was found to be more compared to the commercial microcrystalline plumbagin (PLN). DNA cleavage was also studied by gel electrophoresis. The observed results indicate that NPn1 has better solubility in aqueous medium and hence showed better bioavailability compared to its commercial counterparts.
Induced Neurocysticercosis in Rhesus Monkeys (Macaca mulatta) Produces Clinical Signs and Lesions Similar to Natural Disease in Man
Authors: Chowdhury N. , Saleque A. , Sood N. K. , Singla L. D.
Published: December 2014

Neurocysticercosis is a serious endemic zoonosis resulting in increased cases of seizure and epilepsy in humans. The genesis of clinical manifestations of the disease through experimental animal models is poorly exploited. The monkeys may prove useful for the purpose due to their behavior and cognitive responses mimicking man. In this study, neurocysticercosis was induced in two rhesus monkeys each with 12,000 and 6,000 eggs, whereas three monkeys were given placebo. The monkeys given higher dose developed hyperexcitability, epileptic seizures, muscular tremors, digital cramps at 10 DPI, and finally paralysis of limbs, followed by death on 67 DPI, whereas the monkeys given lower dose showed delayed and milder clinical signs. On necropsy, all the infected monkeys showed numerous cysticerci in the brain. Histopathologically, heavily infected monkeys revealed liquefactive necrosis and formation of irregular cystic cavities lined by atrophied parenchymal septa with remnants of neuropil of the cerebrum. In contrast, the monkeys infected with lower dose showed formation of typical foreign body granulomas characterized by central liquefaction surrounded by chronic inflammatory response. It was concluded that the inflammatory and immune response exerted by the host against cysticerci, in turn, led to histopathological lesions and the resultant clinical signs thereof.
Influences of Different Preparation Conditions on Catalytic Activity of Ag2O-Co3O4/γ-Al2O3for Hydrogenation of Coal Pyrolysis
Authors: Zhang Lei , Xiang-ling Sha , Zhang Lei , Rui Wang , Lixin Zhang , Xinqian Shu
Published: December 2014

A series of catalysts of Ag2O-Co3O4/γ-Al2O3was prepared by equivalent volume impregnation method. The effects of the metal loading, calcination time, and calcination temperatures of Ag and Co, respectively, on the catalytic activity were investigated. The optimum preparing condition of Ag2O-Co3O4/γ-Al2O3was decided, and then the influence of different preparation conditions on catalytic activity of Ag2O-Co3O4/γ-Al2O3was analyzed. The results showed the following: (1) at the same preparation condition, when silver loading was 8%, the Ag2O-Co3O4/γ-Al2O3showed higher catalyst activity, (2) the catalyst activity had obviously improved when the cobalt loading was 8%, while it was weaker at loadings 5% and 10%, (3) the catalyst activity was influenced by different calcination temperatures of silver, but the influences were not marked, (4) the catalyst activity can be influenced by calcination time of silver, (5) different calcination times of cobalt can also influence the catalyst activity of Ag2O-Co3O4/γ-Al2O3, and (6) the best preparation conditions of the Ag2O-Co3O4/γ-Al2O3were silver loading of 8%, calcination temperature of silver of 450°C, and calcinations time of silver of 4 h, while at the same time the cobalt loading was 8%, the calcination temperature of cobalt was 450°C, and calcination time of cobalt was 4 h.
Alternate Phosphorylation/O-GlcNAc Modification on Human Insulin IRSs: A Road towards Impaired Insulin Signaling in Alzheimer and Diabetes
Authors: Jahangir Zainab , Ahmad Waqar , Shabbiri Khadija
Published: December 2014

Impaired insulin signaling has been thought of as important step in both Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). Posttranslational modifications (PTMs) regulate functions and interaction of insulin with insulin receptors substrates (IRSs) and activate insulin signaling downstream pathways via autophosphorylation on several tyrosine (TYR) residues on IRSs. Two important insulin receptor substrates 1 and 2 are widely expressed in human, and alternative phosphorylation on their serine (Ser) and threonine (Thr) residues has been known to block the Tyr phosphorylation of IRSs, thus inhibiting insulin signaling and promoting insulin resistance. Like phosphorylation, O-glycosylation modification is important PTM and inhibits phosphorylation on same or neighboring Ser/Thr residues, often called Yin Yang sites. Both IRS-1 and IRS-2 have been shown to be O-glycosylated; however exact sites are not determined yet. In this study, by using neuronal network based prediction methods, we found more than 50 Ser/Thr residues that have potential to be O-glycosylated and may act as possible sites as well. Moreover, alternative phosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize the risk of AD and T2DM.
Propofol Infusion Syndrome: A Retrospective Analysis at a Level 1 Trauma Center
Authors: Diaz James H. , Prabhakar Amit , Urman Richard D. , Kaye Alan David
Published: December 2014

Objectives.The propofol infusion syndrome (PRIS), a rare, often fatal, condition of unknown etiology, is defined by development of lipemic serum, metabolic acidosis, rhabdomyolysis, hepatomegaly, cardiac arrhythmias, and acute renal failure.Methods.To identify risk factors for and biomarkers of PRIS, a retrospective chart review of all possible PRIS cases during a 1-year period was conducted at a level 1 trauma hospital in ICU patients over 18 years of age receiving continuous propofol infusions for ≥3 days. Additional study inclusion criteria included vasopressor support and monitoring of serum triglycerides and creatinine.Results.Seventy-two patients, 61 males (84.7%) and 11 females (15.3%), satisfied study inclusion criteria; and of these, 3 males met the study definition for PRIS, with 1 case fatality. PRIS incidence was 4.1% with a case-fatality rate of 33%. The mean duration of propofol infusion was 6.96 days. A positive linear correlation was observed between increasing triglyceride levels and infusion duration, but no correlation was observed between increasing creatinine levels and infusion duration.Conclusions.Risk factors for PRIS were confirmed as high dose infusions over prolonged periods. Increasing triglyceride levels may serve as reliable biomarkers of impending PRIS, if confirmed in future investigations with larger sample sizes.
Green Nanobiotechnology: Factors Affecting Synthesis and Characterization Techniques
Authors: Patra Jayanta Kumar , Baek Kwang-Hyun
Published: December 2014

Nanobiotechnology is gaining tremendous impetus in this era owing to its ability to modulate metals into their nanosize, which efficiently changes their chemical, physical, and optical properties. Accordingly, considerable attention is being given to the development of novel strategies for the synthesis of different kinds of nanoparticles of specific composition and size using biological sources. However, most of the currently available techniques are expensive, environmentally harmful, and inefficient with respect to materials and energy use. Several factors such as the method used for synthesis, pH, temperature, pressure, time, particle size, pore size, environment, and proximity greatly influence the quality and quantity of the synthesized nanoparticles and their characterization and applications. Additionally, characterization of the synthesized nanoparticles is essential to their potential use in various drug delivery and biomedical applications. The present review highlights various parameters affecting the synthesis of nanoparticles by green nanobiotechnology and different techniques used for characterizing the nanoparticles for their potential use in biomedical and environmental applications.
Regulation of UCP1 in the Browning of Epididymal Adipose Tissue byβ3-Adrenergic Agonist: A Role for MicroRNAs
Authors: Zheng Zongji , Liu Xiaomeng , Zhao Qianwei , Zhang Lei , Li Chenzhong , Xue Yaoming
Published: December 2014

Background.White adipose tissue browning may be a promising strategy to combat obesity. UCP1 is strongly induced in White adipose tissue withβ3-adrenergic agonist treatment, but the causes of this increase have not been fully elucidated. This study aims to explore more miRNAs involved in the process of browning of visceral adipose tissue.Methods.Total of fourteen mice were randomly divided into control and study group. Study group mice were injected intraperitoneally with CL316243 once daily for seven days; meanwhile the control group were treated with 0.9% NaCl. After a 7-day period, the expression of genes involved in WAT browning and potential UCP1-targeting miRNAs in adipose tissues was analyzed by qPCR.Results.qPCR analysis revealed that UCP1, DIO2, CIDEA, and CPT1B in epididymal adipose tissue were overexpressed in CL316243 group. Furthermore, potential UCP1-targeting miR-9 and miR-338-3p in epididymal adipose tissue were significantly decreased in CL316243 group.Conclusion.This suggests that potential UCP1-targeting miR-9 and miR-338-3p may be involved in the browning of epididymal adipose tissue by regulating UCP1 gene expression. In this study, we demonstrated that this increase of UCP1 is due, at least in part, to the decreased expression of certain UCP1-targeting miRNAs in epididymal adipose tissue compared to control.
Evolutionary Optimization Algorithms for Sunlight-Based Positioning Sensor Networks
Authors: Pardeiro Jose , Gómez Javier V. , Brunete Alberto , Sandnes Frode Eika
Published: December 2014

The sunlight intensity-based global positioning system (SGPS) is able to geolocate outdoor objects by means of the sunlight intensity detection. This paper presents the integration of SGPS into a sensor network in order to improve the overall accuracy using evolutionary algorithms. Another contribution of the paper is to theoretically solve both global and relative positioning of the sensors composing the network within the same framework without satellite-based GPS technology. Results show that this approach is promising and has potential to be improved further.
Corrosion Behavior of Carbon Steel in Synthetically Produced Oil Field Seawater
Authors: Paul Subir , Pattanayak Anjan , Guchhait Sujit K.
Published: December 2014

The life of offshore steel structure in the oil production units is decided by the huge corrosive degradation due to SO42-, S2−, and Cl−, which normally present in the oil field seawater. Variation in pH and temperature further adds to the rate of degradation on steel. Corrosion behavior of mild steel is investigated through polarization, EIS, XRD, and optical and SEM microscopy. The effect of all 3 species is huge material degradation with FeSx and FeCl3 and their complex as corrosion products. EIS data match the model of Randle circuit with Warburg resistance. Addition of more corrosion species decreases impedance and increases capacitance values of the Randle circuit at the interface. The attack is found to be at the grain boundary as well as grain body with very prominent sulphide corrosion crack.
Undernutrition and Its Correlates among Children of 3–9 Years of Age Residing in Slum Areas of Bhubaneswar, India
Authors: Panigrahi Ansuman , Das Sai Chandan
Published: December 2014

Undernutrition among children is a major public health concern worldwide, more prevalent in Asia and Africa. It manifests itself in various forms such as wasting or stunting or underweight and retards physical and mental development, increases susceptibility to infection, and reduces educational attainment and productivity. The present study was undertaken to assess the level of wasting, stunting, and underweight and determine its associates among slum children of 3–9 years of age, residing in Bhubaneswar city, India. After obtaining informed consent, a total of 249 children from 249 households were studied and their parents/guardians were interviewed to collect all relevant information. 23.3%, 57.4%, and 45.4% of children were found to have wasting, stunting, and underweight, respectively. Variables like birth order of child, period of initiation of breastfeeding and mother’s education were found to be strong predictors of wasting, whereas toilet facility in household and practice of drinking water storage were significantly associated with stunting among slum children as revealed in multiple regression analysis. Thus, a multipronged approach is needed such as giving priority to improve education for slum community especially for women, creating awareness regarding benefits of early initiation of breastfeeding, small family size, and proper storage of drinking water, and providing toilet facility in slum households which could improve the nutritional status of slum children.
The Roles of CD147 and/or Cyclophilin A in Kidney Diseases
Authors: Qu Xin , Wang Chunting , Zhang Jicheng , Qie Guoqiang , Zhou Jianxin
Published: December 2014

CD147 is a widely expressed integral plasma membrane glycoprotein and has been involved in a variety of physiological and pathological activities in combination with different partners, including cyclophilins, caveolin-1, monocarboxylate transporters, and integrins. Recent data demonstrate that both CyPA and CD147 significantly contribute to renal inflammation, acute kidney injury, renal fibrosis, and renal cell carcinoma. Here we review the current understanding of cyclophilin A and CD147 expression and functions in kidney diseases and potential implications for treatment of kidney diseases.
Numerical Study of the Generic Sports Utility Vehicle Design with a Drag Reduction Add-On Device
Authors: Singh Shubham , Zunaid M. , Ansari Naushad Ahmad , Bahirani Shikha , Dhall Sumit , Kumar Sandeep
Published: December 2014

CFD simulations using ANSYS FLUENT 6.3.26 have been performed on a generic SUV design and the settings are validated using the experimental results investigated by Khalighi. Moreover, an add-on inspired by the concept presented by Englar at GTRI for drag reduction has been designed and added to the generic SUV design. CFD results of add-on model and the basic SUV model have been compared for a number of aerodynamic parameters. Also drag coefficient, drag force, mean surface pressure, mean velocities, and Cp values at different locations in the wake have been compared for both models. The main objective of the study is to present a new add-on device which may be used on SUVs for increasing the fuel efficiency of the vehicle. Mean pressure results show an increase in the total base pressure on the SUV after using the device. An overall reduction of 8% in the aerodynamic drag coefficient on the add-on SUV has been investigated analytically in this study.
Experimental Investigation on Use of Wheat Straw Ash and Bentonite in Self-Compacting Cementitious System
Authors: Khushnood Rao Arsalan , Rizwan Syed Ali , Memon Shazim Ali , Tulliani Jean-Marc , Ferro Giuseppe Andrea
Published: December 2014

In this research, we evaluated the feasibility of wheat straw ash and bentonite (raw and heated at 150°C for 8 hrs) as secondary raw materials in self-compacting paste (SCP). The fresh and hardened properties of SCP formulations including water and superplasticizer demand, flow behavior, compressive and flexural strength development, water absorption, and acid attack resistance were evaluated. Moreover, porosity, microstructural, and mineralogical investigations were also carried out on SCP formulations. Test results showed that the properties of SCP formulations in fresh state depend on the morphology of secondary raw materials. For heated bentonite and wheat straw ash formulations, the 28 days of compressive and flexural strength were higher or almost similar to reference SCP formulation. Among SCP formulations, wheat straw ash formulation was found to be more effective in consuming free lime and showed significant decrease in porosity with time, which in turn improved the resistance of this SCP formulation against water absorption and acid attack. Based on the test results, it can be concluded that the successful utilization of wheat straw ash and bentonite SCP formulations will offer durable and environmental friendly option to construction industry.
A Hybrid Artificial Bee Colony Algorithm for the Service Selection Problem
Authors: Zhang Changsheng , Zhang Bin
Published: December 2014

To tackle the QoS-based service selection problem, a hybrid artificial bee colony algorithm calledh-ABC is proposed, which incorporates the ant colony optimization mechanism into the artificial bee colony optimization process. In this algorithm, a skyline query process is used to filter the candidates related to each service class, which can greatly shrink the search space in case of not losing good candidates, and a flexible self-adaptive varying construct graph is designed to model the search space based on a clustering process. Then, based on this construct graph, different foraging strategies are designed for different groups of bees in the swarm. Finally, this approach is evaluated experimentally using different standard real datasets and synthetically generated datasets and compared with some recently proposed related service selection algorithms. It reveals very encouraging results in terms of the quality of solutions.
Utilization of Recycled Concrete Aggregates in Stone Mastic Asphalt Mixtures
Authors: Pourtahmasb Mohammad Saeed , Karim Mohamed Rehan
Published: December 2014

Recycled concrete aggregate (RCA) is considered as one of the largest wastes in the entire world which is produced by demolishing concrete structures such as buildings, bridges, and dams. It is the intention of scientists and researchers, as well as people in authority, to explore waste material recycling for environmental and economic advantages. The current paper presents an experimental research on the feasibility of reusing RCA in stone mastic asphalt (SMA) mixtures as a partial replacement of coarse and fine aggregates. The engineering properties of SMA mixtures containing RCA have been evaluated for different percentages of binders based on the Marshall mix design method. The outcomes were statistically analyzed using two-factor analysis of variance (ANOVA). Test results revealed that the performance of SMA mixtures is affected by RCA due to higher porosity and absorption of RCA in comparison with virgin granite aggregates. However, the engineering properties of SMA mixtures containing a particular amount of RCA showed the acceptable trends and could satisfy the standard requirements. Moreover, to achieve desirable performance characteristics, more caution should be made on properties of SMA mixtures containing RCA.
Hemorrhagic Complications of Paracentesis: A Systematic Review of the Literature
Authors: Sharzehi Kaveh , Jain Vishal , Naveed Ammara , Schreibman Ian
Published: December 2014

Introduction. Large volume paracentesis is considered a safe procedure carrying minimal risk of complications and rarely causing morbidity or mortality. The most common complications of the procedure are ascitic fluid leakage, hemorrhage, infection, and perforation. The purpose of this study was to evaluate all hemorrhagic complications and their outcomes and to identify any common variables.Methods. A literature search for all reported hemorrhagic complications following paracentesis was conducted. A total of 61 patients were identified. Data of interest were extracted and analyzed. The primary outcome of the study was 30-day mortality, with secondary endpoints being achievement of hemostasis after intervention and mortality based on type of intervention.Results. 90% of the patients undergoing paracentesis had underlying cirrhosis. Three types of hemorrhagic complications were identified: abdominal wall hematomas (52%), hemoperitoneum (41%), and pseudoaneurysm (7%). Forty percent of the patients underwent either a surgical (35%) or an IR guided intervention (65%). Patients undergoing a surgical intervention had a significantly higher rate of mortality at day 30 compared to those undergoing IR intervention.Conclusion. Abdominal wall hematomas and hemoperitoneum are the most common hemorrhagic complications of paracentesis. Transcatheter coiling and embolization appear to be superior to both open and laparoscopic surgery in treatment of these complications.
Nottingham Clinico-Pathological Response Index (NPRI) after Neoadjuvant Chemotherapy (Neo-ACT) Accurately Predicts Clinical Outcome in Locally Advanced Breast Cancer
Authors: Abdel-Fatah Tarek M. , Ball Graham , Lee Andrew H.S. , Pinder Sarah , MacMilan R. Douglas , Cornford Eleanor , Moseley Paul M. , Silverman Rafael , Price James , Latham Bruce , Palmer David , Chan Arlene , Ellis Ian O. , Chan Stephen Y.T.
Published: December 2014

Purpose: There is a need to identify more sensitive clinicopathologic criteria to assess the response to neoadjuvant chemotherapy (Neo-ACT) and guide subsequent adjuvant therapy.

Experimental Design: We performed a clinicopathologic assessment of 426 patients who had completed Neo-ACT for locally advanced breast cancer (LABC) with a median follow-up of 70 months. Patients were divided into a training set treated with anthracycline combination chemotherapy (n = 172); an internal validation set treated with anthracycline and taxane (n = 129); and an external validation set treated with anthracycline with or without taxane (n = 125).

Results: A multivariate Cox regression model demonstrated the absence of fibrosis, presence of lymphovascular invasion, increasing number of lymph node metastases, and administration of hormone therapy were significantly associated with short breast cancer–specific survival (BCSS) and disease-free survival (DFS); Ps < 0.01, while reduction of tumor size was associated with DFS (P = 0.022). Nottingham Clinico-Pathological Response Indexes (NPRI) were calculated, and four prognostic groups (NPRI-PG) were identified. Patients in prognostic group 2 (NPRI-PG2) for BCSS (66 of 172; 38.4%) have the same prognosis as those who achieved pathologic complete response (pCR; NPRI-PG1; 15%). Receiver-operating characteristic (ROC) curves indicated that the NPRI outperformed the currently used prognostic factors and adding the NPRI improved their performance as a predictor for both BCSS (area under the curve [AUC], 0.88) and DFS (AUC, 0.87).

Conclusions: The NPRI predicts BCSS and DFS, with a higher sensitivity than pCR. The NPRI can also improve the sensitivity and specificity of clinicopathologic response as a study endpoint, for assessing response to Neo-ACT, and can serve as a valuable tool for the discovery of future predictive molecular markers. Clin Cancer Res; 21(5); 1052–62. ©2014 AACR.
Gene Expression Markers of Efficacy and Resistance to Cetuximab Treatment in Metastatic Colorectal Cancer: Results from CALGB 80203 (Alliance)
Authors: Cushman Stephanie M. , Jiang Chen , Hatch Ace J. , Shterev Ivo , Sibley Alexander B. , Niedzwiecki Donna , Venook Alan P. , Owzar Kouros , Hurwitz Herbert I. , Nixon Andrew B.
Published: December 2014

Purpose: Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis–related genes to identify prognostic or predictive biomarkers for cetuximab treatment.

Patients and Methods: Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.

Results: High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).

Conclusions: Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity. Clin Cancer Res; 21(5); 1078–86. ©2014 AACR.
Interactions of Multitargeted Kinase Inhibitors and Nucleoside Drugs: Achilles Heel of Combination Therapy?
Authors: Damaraju Vijaya L. , Kuzma Michelle , Mowles Delores , Cass Carol E. , Sawyer Michael B.
Published: December 2014

Multitargeted tyrosine kinase inhibitors (TKI) axitinib, pazopanib, and sunitinib are used to treat many solid tumors. Combination trials of TKIs with gemcitabine, a nucleoside anticancer drug, in pancreas, renal, lung, ovarian, and other malignancies resulted in little benefit to patients. TKI interactions with human nucleoside transporters (hNT) were studied by assessing inhibition of [3H]uridine uptake in yeast producing recombinant hNTs individually and in cultured human cancer cell lines. Axitinib, pazopanib, and sunitinib inhibited hENT1 at low micromolar concentrations. In A549, AsPC-1, and Caki-1 cells, [3H]uridine, [3H]thymidine, [3H]gemcitabine, and [3H]fluorothymidine (FLT) accumulation was blocked by all three TKIs. Pazopanib > axitinib ≥ sunitinib inhibited hENT1 with IC50 values of 2, 7, and 29 μmol/L, respectively, leading to reduced intracellular gemcitabine and FLT accumulation. Pretreatment or cotreatment of Caki-1 cells with TKIs reduced cellular accumulation of [3H]nucleosides, suggesting that TKI scheduling with nucleoside drugs would influence cytotoxicity. In combination cytotoxicity experiments that compared sequential versus simultaneous addition of drugs in Caki-1 cells, cytotoxicity was greatest when gemcitabine was added before TKIs. In clinical settings, TKI inhibitor concentrations in tumor tissues are sufficient to inhibit hENT1 activity, thereby reducing nucleoside chemotherapy drug levels in cancer cells and reducing efficacy in combination schedules. An additional unwanted interaction may be reduced FLT uptake in tumor tissues that could lead to aberrant conclusions regarding tumor response. Mol Cancer Ther; 14(1); 236–45. ©2014 AACR.
DNA-Directed Polymerase Subunits Play a Vital Role in Human Telomeric Overhang Processing
Authors: Diotti Raffaella , Kalan Sampada , Matveyenko Anastasiya , Loayza Diego
Published: December 2014

Telomeres consist of TTAGGG repeats bound by the shelterin complex and end with a 3′ overhang. In humans, telomeres shorten at each cell division, unless telomerase (TERT) is expressed and able to add telomeric repeats. For effective telomere maintenance, the DNA strand complementary to that made by telomerase must be synthesized. Recent studies have discovered a link between different activities necessary to process telomeres in the S phase of the cell cycle to reform a proper overhang. Notably, the human CST complex (CTC1/STN1/TEN1), known to interact functionally with the polymerase complex (POLA/primase), was shown to be important for telomere processing. Here, focus was paid to the catalytic (POLA1/p180) and accessory (POLA2/p68) subunits of the polymerase, and their mechanistic roles at telomeres. We were able to detect p68 and p180 at telomeres in S-phase using chromatin immunoprecipitation. We could also show that the CST, shelterin, and polymerase complexes interact, revealing contacts occurring at telomeres. We found that the polymerase complex could associate with telomerase activity. Finally, depletion of p180 by siRNA led to increased overhang amounts at telomeres. These data support a model in which the polymerase complex is important for proper telomeric overhang processing through fill-in synthesis, during S phase. These results shed light on important events necessary for efficient telomere maintenance and protection.

Implications: This study describes the interplay between DNA replication components with proteins that associate with chromosome ends, and telomerase. These interactions are proposed to be important for the processing and protection of chromosome ends. Mol Cancer Res; 13(3); 402–10. ©2014 AACR.
Changes in Tinnitus after Cochlear Implantation and Its Relation with Psychological Functioning
Authors: Kloostra Francka J.J. , Arnold Rosemarie , Hofman Rutger , Van Dijk Pim
Published: December 2014

This study retrospectively assessed the prevalence of tinnitus in cochlear implant patients and the changes after implantation in 212 patients implanted between 2000 and 2009. Patients were included at least 6 months after implantation and received 2 sets of questionnaires, one about the situation before implantation and one about the situation after implantation. Mostly standardized questionnaires assessed tinnitus handicap (Tinnitus Handicap Inventory, THI, and Tinnitus Handicap Questionnaire, THQ), tinnitus characteristics, hearing loss (Abbreviated Profile of Hearing Aid Benefit) and anxiety/depression (Hospital Anxiety and Depression Scale). Of the approached patients, 117 completed the full sets of questionnaires and 35 completed a short version. Preoperative tinnitus was reported by 51.3% of these patients, of which 55.6% reported a reduction or cessation of their tinnitus after implantation. However, 8.2% of the patients with tinnitus reported a postoperative deterioration of their tinnitus. In addition, among the patients without preoperative tinnitus, 19.6% reported the start of tinnitus after implantation. The self-reported change of tinnitus correlated with the pre- and postoperative scores on the THI and THQ. The THQ showed slightly more changes in scores after cochlear implantation compared to the THI. Overall hearing handicap and feelings of anxiety and depression decreased after implantation. In conclusion, tinnitus is reduced after cochlear implantation in an important part of the patients, but in a small part implantation has a negative effect on tinnitus. When tinnitus starts after implantation, the tinnitus handicap is mild.
Mechanisms and Models for Intestinal Fibrosis in IBD
Authors: De Salvo Carlo , Ray Shuvra , Pizarro Theresa T.
Published: December 2014

Intestinal fibrosis is a common outcome in IBD leading to significant morbidity that, to date, has no effective medical treatment. Current knowledge regarding potential mechanism(s) of intestinal fibrogenesis and stricture formation is limited, due in large part to the lack of relevant animal models. Although conventional models possess aspects that are advantageous to study specific mechanisms involved in gut fibrosis, most lack the features of a spontaneously occurring process leading to the formation of intestinal fibrotic lesions following mucosal inflammatory events and the ability to investigate the natural course of disease over time. This review aims to discuss established and novel animal models of gut fibrosis, particularly focusing on the advantages and disadvantages of each model system and the insights they bring to our understanding of the mechanisms of fibrogenesis. In fact, recent enhancements to existing models and the expansion of novel animal models of gut fibrosis is opening up multiple avenues for investigation which should stimulate progress in our mechanistic understanding of intestinal fibrogenesis and facilitate the development of effective pharmacotherapy in an area of significant unmet need.
Trichuris suis Ova, Lecithin and Other Fancy Molecules
Authors: Schölmerich Jürgen
Published: December 2014

During the last 20 years, treatment paradigms as well as drugs used for IBD have changed significantly. However, there are still many unmet needs and a significant number of patients needing better therapy. It is obvious from this situation that many attempts have been made to implement new drugs and treatment algorithms including biologicals, new formulations of old drugs and ‘fancy molecules or approaches'. For about 10 years, the application of Trichuris suis ova has been promoted and used in quite a number of patients. Two early studies suggested positive effects in ulcerative colitis as well as in Crohn's disease. These studies were based on experimental data in animal models as well as in vitro experiments. However, two large randomized controlled trials were not able to provide significant clinical effects in active Crohn's disease as compared to placebo, although a biological reaction (eosinophilia) was found. Another approach is the use of locally released phosphatidylcholine in ulcerative colitis. This approach is based on decreased phosphatidylcholine concentrations in the colonic mucus in patients, and showed positive effects in a number of monocentric trials in steroid-refractory and chronic active ulcerative colitis. A dose-finding study gave a positive signal in the highest-dose group and this approach is being tested further in controlled trials. Many other ‘fancy molecules' including cannabis, vitamin D, thalidomide, hyaluronic acid, lidocaine, clonidine, chondroitin sulfate, naltrexone and melatonin have been tested in patients with claims of success. For most of those, however, controlled data in appropriate studies are lacking. Many more substances have been used in animal models and are probably applied in individual patients. Results of preliminary studies on some of the molecules mentioned are presented.
Tailoring Treatment to the Individual Patient: Drug Monitoring
Authors: Sandborn William J.
Published: December 2014

Understanding why drug concentrations vary between patients and which drug concentrations are associated with efficacy allow the development of rational treatment algorithms. Factors that affect the clearance of monoclonal antibodies include: (1) the presence of antidrug antibodies (increased clearance), (2) concomitant immunosuppression (decreased clearance), (3) increased serum CRP concentration (increased clearance), (4) decreased serum albumin concentration (increased clearance), (5) decreased body weight (increased clearance), and (6) increased fecal infliximab concentration (increased clearance). These factors can result in marked variability in drug clearance. Higher serum infliximab and adalimumab concentrations are associated with increased rates of clinical response and mucosal healing, and lower rates of colectomy. Treatment algorithms incorporate the following principles: (1) patients who have symptoms of active disease and in whom high concentrations of antibodies to infliximab or adalimumab are present should switch to another TNF antagonist, (2) patients who have symptoms of active disease and in whom there are low concentrations of infliximab or adalimumab should have dose intensification, and (3) patients who are negative for antidrug antibody and who have a therapeutic drug concentration should undergo evaluation to confirm the presence of active disease by endoscopy or radiology studies, and if active disease is confirmed, then these patients should discontinue anti-TNF therapy and switch to another class of medications or consider surgical options.
Abdominal Abscess in Crohn's Disease: Multidisciplinary Management
Authors: de Groof E. Joline , Carbonnel Frank , Buskens Christianne J. , Bemelman Willem A.
Published: December 2014

Crohn's disease (CD) is characterized by full-thickness inflammation of the bowel. For this reason, perforating complications such as intra-abdominal abscesses or fistulas are common. A concomitant intra-abdominal abscess with active CD of the small bowel is a challenging dilemma for gastroenterologists and surgeons. Since there is active and severe disease, this should be treated with immunosuppressive drugs. However, in the presence of an intra-abdominal abscess, immunosuppression can be dangerous. There are several treatment options for intra-abdominal abscesses in CD. Nowadays, the first-line treatment is antibiotic therapy with or without percutaneous drainage. Historically, patients were treated with surgical drainage. With the development of percutaneous drainage, treatment shifted to a more nonsurgical approach. Success rates for percutaneous drainage in the literature vary from 74 to 100%, and it is considered to be a relatively safe procedure. It has been reported that surgery can be avoided after successful percutaneous drainage in a variable number of patients (14-85%). If sepsis is controlled, CD medication should be started to prevent recurrence. It is important to monitor the effect upon CD lesions to avoid further perforating complications. Finally, an undrainable or small abscess can be treated with antibiotics alone, although high recurrence rates have been described with this approach. Patients with a concomitant stenosis, an enterocutaneous fistula or refractory active disease are likely to require surgery. Percutaneous drainage in combination with delayed surgery is useful to improve the patient's condition prior to surgery and is associated with less morbidity, a lower stoma rate and more limited resection. In conclusion, when feasible, percutaneous drainage and antibiotics should be the treatment of choice in patients with an intra-abdominal abscess in CD. If surgery is inevitable, this must be delayed to reduce postoperative septic complications and high stoma rates.