bluuebunny/crossref_metadata_2025 huggingface dataset:
Inherited platelet disorders and oral health
Authors: Valera Marie‐Cécile , Kemoun Philippe , Cousty Sarah , Sie Pierre , Payrastre Bernard
Published: May 2012

J Oral Pathol Med (2013)42: 115–124

Platelets play a key role in thrombosis and hemostasis. Accumulation of platelets at the site of vascular injury is the first step in the formation of hemostatic plugs, which play a pivotal role in preventing blood loss after injury. Platelet adhesion at sites of injury results in spreading, secretion, recruitment of additional platelets, and formation of platelet aggregates. Inherited platelet disorders are rare causes of bleeding syndromes, ranging from mild bruising to severe hemorrhage. The defects can reflect deficiency or dysfunction of platelet surface glycoproteins, granule contents, cytoskeletal proteins, platelet pro‐coagulant function, and signaling pathways. For instance, Bernard–Soulier syndrome and Glanzmann thrombasthenia are attributed to deficiencies of glycoprotein Ib/IX/V and GPIIb/IIIa, respectively, and are rare but severe platelet disorders. Inherited defects that impair platelet secretion and/or signal transduction are among the most common forms of mild platelet disorders and include gray platelet syndrome, Hermansky–Pudlak syndrome, and Chediak–Higashi syndrome. When necessary, desmopressin, antifibrinolytic agents, and transfusion of platelets remain the most common treatment of inherited platelet disorders. Alternative therapies such as recombinant activated factor VII are also available for a limited number of situations. In this review, we will discuss the management of patients with inherited platelet disorders in various clinical situations related to dental cares, including surgical intervention.
The electroneutral Na+:HCO3− cotransporter NBCn1 is a major pHi regulator in murine duodenum
Authors: Chen Mingmin , Praetorius Jeppe , Zheng Wen , Xiao Fang , Riederer Brigitte , Singh Anurag Kumar , Stieger Nicole , Wang Jian , Shull Gary E. , Aalkjaer Christian , Seidler Ursula
Published: May 2012

Key points

The mucosa of the proximal duodenum is regularly exposed to the strong acid of gastric juice, and acid damage causes peptic ulceration and bleeding.

The epithelial cells of the duodenum protect themselves against acid‐induced chemical damage by secreting bicarbonate into the lumen and by regulating their intracellular pH, but the molecular mechanisms of duodenal pHi control are incompletely understood.

We have found a high expression of the electroneutral sodium bicarbonate transporter Slc4a7 (NBCn1) in the basolateral membrane of duodenal villous enterocytes.

Genetic knockout of Slc4a7 resulted in a strong defect in duodenocyte pHi recovery from acid loads, and reduced bicarbonate secretory rates.

This suggests that the electroneutral sodium bicarbonate cotransporter Slc4a7 is a major import mechanism for HCO3− from the blood into the duodenal epithelial cells. Defects in this transporter may severely endanger duodenal mucosal integrity

Abstract  Duodenocyte pHi control and HCO3− secretion protects the proximal duodenum against damage by gastric acid. The molecular details of duodenocyte pH control are not well understood. A selective duodenal expression (within the upper GI tract) has been reported for the electroneutral Na+:HCO3− cotransporter NBCn1 (Slc4a7). We aimed to determine the role of NBCn1 and NBCe2 in duodenocyte intracellular pH regulation as well as basal and agonist‐stimulated duodenal bicarbonate secretion (JHCO3−), exploiting mouse models of genetic slc4a7 and slc4a5 disruption. Basal and forskolin (FSK)‐stimulated JHCO3− was measured by single‐pass perfusion in the duodenum of slc4a7−/− and slc4a7+/+ as well as slc4a5−/− and slc4a5+/+ mice in vivo, and by pH‐stat titration in isolated duodenal mucosa in vitro. Duodenocyte HCO3− uptake rates were fluorometrically assessed after acidification of intact villi and of isolated duodenocytes. Slc4a7−/− mice displayed significantly lower basal and FSK‐stimulated duodenal HCO3− secretion than slc4a7+/+ littermates in vivo. FSK‐stimulated HCO3− secretion was significantly reduced in slc4a7−/− isolated duodenal mucosa. Na+‐ and HCO3−‐dependent base uptake rates were significantly decreased in slc4a7−/− compared with slc4a7+/+ villus duodenocytes when measured in intact villi. Carbonic anhydrase (CA)‐mediated CO2 hydration played no apparent role as a HCO3− supply mechanism for basal or FSK‐stimulated secretion in the slc4a7+/+ duodenum, but was an important alternative HCO3− supply mechanism in the slc4a7−/− duodenum. NBCe2 (Slc4a5) displayed markedly lower duodenal mRNA expression levels, and its disruption did not interfere with duodenal HCO3− secretion. The electroneutral Na+:HCO3− cotransporter NBCn1 (slc4a7) is a major duodenal HCO3− importer that supplies HCO3− during basal and FSK‐stimulated HCO3− secretion.
A Coactivator Divided
Authors: VanHook Annalisa M.
Published: May 2012

A gene encoding a nuclear receptor coactivator split into two separate genes in the fly lineage.
Dissecting DNA Repair
Authors: Riddihough Guy
Published: May 2012

An enzyme that binds to damaged DNA undergoes a structural reorganization that enhances its catalytic activity.
Responding to Membrane Stress
Authors: Gough Nancy R.
Published: May 2012

Plasma membrane stress triggers redistribution of Slm proteins among distinct plasma membrane compartments to stimulate TORC2 activity and promote sphingolipid synthesis.
A NOVEL ELECTRICAL STIMULATION PARADIGM FOR THE SUPPRESSION OF EPILEPTIFORM ACTIVITY IN ANIN VIVOMODEL OF MESIAL TEMPORAL LOBE STATUS EPILEPTICUS
Authors: TANG YUANG , DURAND DOMINIQUE M.
Published: May 2012

In this study, we present a novel low-frequency electrical stimulation paradigm for mesial temporal lobe epilepsy (MTLE). The paradigm utilizes the hippocampal commissure as a unique stimulation target to simultaneously influence large portions of the bilateral hippocampal network. When applied to an acute rat model of MTLE, animals that received stimulation exhibited an 88% reduction in the signal power of the bilateral epileptiform activity relative to the control group. In addition, the stimulation entrained the hippocampal network's spontaneous epileptiform activity and disrupted its bilateral synchrony.
NOTIONS OF PURITY AND THE COHOMOLOGY OF QUIVER MODULI
Authors: BRION M. , JOSHUA R.
Published: May 2012

We explore several variations of the notion of purity for the action of Frobenius on schemes defined over finite fields. In particular, we study how these notions are preserved under certain natural operations like quotients for principal bundles and also geometric quotients for reductive group actions. We then apply these results to study the cohomology of quiver moduli. We prove that a natural stratification of the space of representations of a quiver with a fixed dimension vector is equivariantly perfect and from it deduce that each of the l-adic cohomology groups of the quiver moduli space is strongly pure.
Protective Effects of HV-P411 Complex Against D-Galactosamine-Induced Hepatotoxicity in Rats
Authors: Kang Jung-Woo , Kim Seok-Joo , Kim Hyo-Yeon , Cho Soon Hyun , Kim Kyung Nam , Lee Sin Gu , Lee Sun-Mee
Published: May 2012

This study examined the hepatoprotective effect of the HV-P411 complex, an herbal extract mixture from the seeds of Vitis vinifera, Schisandra chinensis and Taraxacum officinale, against D-galactosamine (D-GalN)-induced hepatitis. Hepatotoxicity was induced by D-GalN (700 mg/kg, i.p.), and the HV-P411 complex was administered orally 48, 24, and 2 h before and 6 h after D-GalN injection. Increases in serum aminotransferase activity and lipid peroxidation and a decrease in hepatic glutathione content were attenuated by the HV-P411 complex 24 h after D-GalN treatment. The HV-P411 complex attenuated the increases in serum tumor necrosis factor-α, interleukin (IL)-6 level and cyclooxygenase-2 protein production and their mRNA expressions, while increases in serum IL-10 level and heme oxygenase-1 protein production and their mRNA expressions were augmented by the HV-P411 complex. The increased translocation of nuclear factor-κB and c-Jun phosphorylation were attenuated by treatment with the HV-P411 complex. Our results suggest that the HV-P411 complex prevents D-GalN-induced hepatotoxicity via antioxidative and anti-inflammatory activities.
Hydroxysafflor Yellow A Attenuates Carbon Tetrachloride-Induced Hepatic Fibrosis in Rats by Inhibiting Erk5 Signaling
Authors: Zhang Ying-Bo , Dong Han-Ying , Zhao Xue-Ming , Fan Li , Zou Yu , Zhang Chun , Li Gang , Liu Ji-Cheng , Niu Ying-Cai
Published: May 2012

Hepatic stellate cells (HSCs) undergo activation during the development of liver fibrosis. Transcription factor myocyte enhancer factor (MEF2) 2C plays a key role in this process. In the present study, we investigated the effect of hydroxysafflor yellow A (HSYA) on hepatic fibrosis and further investigated potential mechanisms in vivo. Sprague-Dawley rats were administered with CCl4 together with or without HYSA for 12 weeks. The effect of HYSA on hepatic fibrosis was evaluated using hematoxylin-eosin and Van Gieson staining. Messenger RNA expression was quantified by real-time polymerase chain reaction, and protein was quantified by Western blot or immunohistochemistry. Our results revealed that CCl4 treatment induced micronodular hepatic fibrosis with a pronounced deposition of collagen fibers. Treatment with HYSA resulted in a significant decrease in fibrosis, protein expression of α-SMA, and MEF-2C gene expression. This was accompanied by a decreased expression of Tβ-RI, Tβ-RII, MEKK3, MEK5, and phosphorylation of ERk5. HYSA alone had no effect on the measured parameters. Our findings demonstrate that HSYA protected, at least in part, the rat liver from CCl 4-caused fibrogenesis through inhibition of hepatic stellate cell (HSC) activation, attenuation of transforming growth factor beta (TGF-β) signaling. HSYA may become a novel and promising agent for the inhibition of hepatic fibrosis.
Effect of Electroacupuncture on Leptin Resistance in Rats with Diet-Induced Obesity
Authors: Gong Meirong , Wang Xinjun , Mao Zhen , Shao Qinhua , Xiang Xiaoren , Xu Bin
Published: May 2012

In the present study, the effects of electroacupuncture (EA) on body weight and sensitivity of leptin in diet-induced obese rats were examined and the underlying mechanisms were explored. After feeding with high-fat (HIF) diet for 12 weeks, the diet-induced obese rats received electroacupuncture stimulation three times per week for four weeks. The expression of the leptin receptor in the hypothalamus was measured using immunohistochemistry. The plasma leptin was detected with ELISA. The leptin and leptin receptor mRNA was examined with real-time PCR. Results showed that electroacupuncture treatment led to a reduction of body weight, decrease in the plasma leptin levels, and an increase in leptin receptor expression in the hypothalamus. Our results suggested that regulating the expression of leptin and the leptin receptor might be one of the molecular mechanisms underlying the reduction of body weight in diet-induced obese rats by electroacupuncture treatment.
M-SP-INJECTIVE MODULES
Authors: Kumar V. , Gupta A. J. , Pandeya B. M. , Patel M. K.
Published: May 2012

In this paper we study M-small principally injective (in short, M-sp-injective) module which is the generalization of M-principally injective module. We prove that if M is finite dimensional and quasi-sp-injective then its endomorphism ring S is semi-local ring. We characterize the M-sp-injective module with the help of epi-retractable modules.
EXTENSIONS OF α-REFLEXIVE RINGS
Authors: Zhao Liang , Zhu Xiaosheng
Published: May 2012

We introduce the notion of an α-reflexive ring to extend the concept of a reflexive ring and that of an α-rigid ring. We first consider some basic properties of α-reflexive rings, including some examples needed in the process. We prove that a ring R is α-rigid if and only if R is a reduced α-reflexive ring with α a monomorphism. We next investigate the α-reflexivity of some kinds of polynomial rings. It is shown that if R is a reduced α-reflexive ring with α(1) = 1, then R[x]/(xn) is an α-reflexive ring, where (xn) is the ideal generated by xn. Moreover, for an Armendariz ring R, we prove that R is α-reflexive if and only if R[x] is α-reflexive if and only if R[x; x-1] is α-reflexive. As a sequence, some known results relating to reflexive rings are obtained as corollaries of these results.
Housing Finance Reform: Private Markets Versus Government Guarantees
Authors: Jaffee Dwight M.
Published: May 2012

This paper evaluates the major alternative proposals for reforming the U.S. home mortgage market assuming that the government sponsored enterprises (GSEs), Fannie Mae and Freddie Mae, will be closed. The paper compares proposals that advocate primary reliance on private markets to take on the GSE functions with proposals that advocate government mortgage guarantees, including a discussion of how these plans differ in terms of duration, scope, and risk-sharing. The paper concludes with a discussion of current government attempts to expedite the modification or refinancing of existing mortgages, including a plan for the transition from the current situation to the long-term reforms.
Unsupervised similarity-based word sense disambiguation using context vectors and sentential word importance
Authors: Abdalgader Khaled , Skabar Andrew
Published: May 2012

The process of identifying the actual meanings of words in a given text fragment has a long history in the field of computational linguistics. Due to its importance in understanding the semantics of natural language, it is considered one of the most challenging problems facing this field. In this article we propose a new unsupervised similarity-based word sense disambiguation (WSD) algorithm that operates by computing the semantic similarity between glosses of the target word and a context vector. The sense of the target word is determined as that for which the similarity between gloss and context vector is greatest. Thus, whereas conventional unsupervised WSD methods are based on measuring pairwise similarity between words, our approach is based on measuring semantic similarity between sentences. This enables it to utilize a higher degree of semantic information, and is more consistent with the way that human beings disambiguate; that is, by considering the greater context in which the word appears. We also show how performance can be further improved by incorporating a preliminary step in which the relative importance of words within the original text fragment is estimated, thereby providing an ordering that can be used to determine the sequence in which words should be disambiguated. We provide empirical results that show that our method performs favorably against the state-of-the-art unsupervised word sense disambiguation methods, as evaluated on several benchmark datasets through different models of evaluation.
Novel Image Analysis Approach Quantifies Morphological Characteristics of 3D Breast Culture Acini with Varying Metastatic Potentials
Authors: McKeen Polizzotti Lindsey , Oztan Basak , Bjornsson Chris S. , Shubert Katherine R. , Yener Bülent , Plopper George E.
Published: May 2012

Prognosis of breast cancer is primarily predicted by the histological grading of the tumor, where pathologists manually evaluate microscopic characteristics of the tissue. This labor intensive process suffers from intra- and inter-observer variations; thus, computer-aided systems that accomplish this assessment automatically are in high demand. We address this by developing an image analysis framework for the automated grading of breast cancer inin vitrothree-dimensional breast epithelial acini through the characterization of acinar structure morphology. A set of statistically significant features for the characterization of acini morphology are exploited for the automated grading of six (MCF10 series) cell line cultures mimicking three grades of breast cancer along the metastatic cascade. In addition to capturing both expected and visually differentiable changes, we quantify subtle differences that pose a challenge to assess through microscopic inspection. Our method achieves 89.0% accuracy in grading the acinar structures as nonmalignant, noninvasive carcinoma, and invasive carcinoma grades. We further demonstrate that the proposed methodology can be successfully applied for the grading ofin vivotissue samples albeit with additional constraints. These results indicate that the proposed features can be used to describe the relationship between the acini morphology and cellular function along the metastatic cascade.
The Height Gain in Scoliotic Deformity Correction: Assessed by New Predictive Formula
Authors: Şarlak Ahmet Yılmaz , Atmaca Halil , Musaoğlu Resul , Veliev Elşen Veli
Published: May 2012

Height gain after scoliosis correction is of a special interest for the patient and family. Ylikoski was the first to suggest a formula predicting height loss in untreated scoliotic patients. Stokes has recently suggested a new formula by using Cobb angle to determine height loss in idiopathic curves. We hypothesized that new additional variables to Cobb angle such as apical vertebral translation (AVT), number of instrumented segments (N), and disc heights may increase the accuracy of predicted height gain. According to our findings simple expression for height gain by simplified version of the formula is:SPΔH=0.0059X1θ1 + 2.3(1−(θ2/θ1))N, whereθ1is preoperative Cobb angle,X1is preoperative AVT,θ2is postoperative Cobb angle, andNis the number of instrumented vertebra. The purpose of this study is to analyze a new mathematical formula to predict height gain after scoliotic deformity correction.
Mean‐Square Exponential Synchronization of Markovian Switching Stochastic Complex Networks with Time‐Varying Delays by Pinning Control
Authors: Wang Jingyi , Xu Chen , Feng Jianwen , Kwong Man Kam , Austin Francis
Published: May 2012

This paper investigates the mean‐square exponential synchronization of stochastic complex networks with Markovian switching and time‐varying delays by using the pinning control method. The switching parameters are modeled by a continuous‐time, finite‐state Markov chain, and the complex network is subject to noise perturbations, Markovian switching, and internal and outer time‐varying delays. Sufficient conditions for mean‐square exponential synchronization are obtained by using the Lyapunov‐Krasovskii functional, Itö’s formula, and the linear matrix inequality (LMI), and numerical examples are given to demonstrate the validity of the theoretical results.
Expression of Neutral Endopeptidase, Endothelin-1, and Nuclear Factor Kappa B in Prostate Cancer: Interrelations and Associations with Prostate-Specific Antigen Recurrence after Radical Prostatectomy
Authors: Vlachostergios Panagiotis J. , Karasavvidou Foteini , Kakkas Grigorios , Moutzouris George , Patrikidou Anna , Voutsadakis Ioannis A. , Daliani Danai D. , Zintzaras Elias , Melekos Michael D. , Papandreou Christos N.
Published: May 2012

Objective. To study the impact of the neutral endopeptidase (NEP)/neuropeptides (NPs) axis and nuclear factor kappa B (NFκB) as predictors of prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP).Patients and Methods. 70 patients with early-stage PC were treated with RP and their tumor samples were evaluated for expression of NEP, endothelin-1 (ET-1) and NFκB (p65). Time to PSA recurrence was correlated with the examined parameters and combined with preoperative PSA level, Gleason score, pathological TNM (pT) stage, and surgical margin (SM) assessment.Results and Limitations. Membranous expression of NEP (P<0.001), cytoplasmic ET-1 (P=0.002), and cytoplasmic NFκB (P<0.001) were correlated with time to PSA relapse. NEP was associated with ET-1 (P<0.001) and NFκB (P<0.001). ET-1 was also correlated with NFκB (P<0.001). NEP expression (P=0.017), pT stage (P=0.013), and SMs (P=0.036) were independent predictors of time to PSA recurrence.Conclusions. There seems to be a clinical model of NEP/NPs and NFκB pathways interconnection, with their constituents following inverse patterns of expression in accordance with their biological roles and molecular interrelations.
Ocular Manifestations of Alzheimer’s Disease in Animal Models
Authors: Parnell Miles , Guo Li , Abdi Mohamed , Cordeiro M. Francesca
Published: May 2012

Alzheimer’s disease (AD) is the most common form of dementia, and the pathological changes of senile plaques (SPs) and neurofibrillary tangles (NFTs) in AD brains are well described. Clinically, a diagnosis remains a postmortem one, hampering both accurate and early diagnosis as well as research into potential new treatments. Visual deficits have long been noted in AD patients, and it is becoming increasingly apparent that histopathological changes already noted in the brain also occur in an extension of the brain; the retina. Due to the optically transparent nature of the eye, it is possible to image the retina at a cellular level noninvasively and thus potentially allow an earlier diagnosis as well as a way of monitoring progression and treatment effects. Transgenic animal models expressing amyloid precursor protein (APP) presenilin (PS) and tau mutations have been used successfully to recapitulate the pathological findings of AD in the brain. This paper will cover the ocular abnormalities that have been detected in these transgenic AD animal models.
HCCI Intelligent Rapid Modeling by Artificial Neural Network and Genetic Algorithm
Authors: Validi AbdoulAhad , Chen Jyh-Yuan , Ghafourian Akbar
Published: May 2012

A Dynamic model of Homogeneous Charge Compression Ignition (HCCI), based on chemical kinetics principles and artificial intelligence, is developed. The model can rapidly predict the combustion probability, thermochemistry properties, and exact timing of the Start of Combustion (SOC). A realization function is developed on the basis of the Sandia National Laboratory chemical kinetics model, and GRI3.0 methane chemical mechanism. The inlet conditions are optimized by Genetic Algorithm (GA), so that combustion initiates and SOC timing posits in the desired crank angle. The best SOC timing to achieve higher performance and efficiency in HCCI engines is between 5 and 15 degrees crank angle (CAD) after top dead center (TDC). To achieve this SOC timing, in the first case, the inlet temperature and equivalence ratio are optimized simultaneously and in the second case, compression ratio is optimized by GA. The model’s results are validated with previous works. The SOC timing can be predicted in less than 0.01 second and the CPU time savings are encouraging. This model can successfully be used for real engine control applications.
The Use of Buccal Fat Pad in the Treatment of Oral Submucous Fibrosis: A Newer Method
Authors: Saravanan K. , Narayanan Vinod
Published: May 2012

Purpose of the study. This study was to evaluate the use of buccal fat pad as an interpositioning material in surgical management of oral sub mucous fibrosis.Materials and methods. A series of 8 cases with proven oral sub mucous fibrosis, with mouth opening less than 20 mm, involving the buccal mucosa were treated surgically in the Department of Oral and Maxillofacial Surgery, College of Dental Surgery, Saveetha University, Chennai. Pedicled buccal fat pad was used as an interpositioning material to cover the raw areas in the oral cavity after incision and release of fibrous bands.Results. In 8 patients, the range of pre operative mouth opening was 3–18 mm (mean 14 mm). As the result of the successful surgical procedure, the size of the intra operative mouth opening was ranged from 25–38 mm (mean 33.25 mm). The patients were discharged 5–7 days after the operation. The range of the mouth opening at this time was 25–36 mm (mean 30.63 mm). The results were evaluated using student’s t test and found to be statistically significant. The pedicled grafts took up uneventfull.
Dinitroazetidines Are a Novel Class of Anticancer Agents and Hypoxia-Activated Radiation Sensitizers Developed from Highly Energetic Materials
Authors: Ning Shoucheng , Bednarski Mark , Oronsky Bryan , Scicinski Jan , Saul Gordon , Knox Susan J.
Published: May 2012

In an effort to develop cancer therapies that maximize cytotoxicity, while minimizing unwanted side effects, we studied a series of novel compounds based on the highly energetic heterocyclic scaffold, dinitroazetidine. In this study, we report the preclinical validation of 1-bromoacetyl-3,3-dinitroazetidine (ABDNAZ), a representative lead compound currently in a phase I clinical trial in patients with cancer. In tumor cell culture, ABDNAZ generated reactive free radicals in a concentration- and time-dependent manner, modulating intracellular redox status and triggering apoptosis. When administered to mice as a single agent, ABDNAZ exhibited greater cytotoxicity than cisplatin or tirapazamine under hypoxic conditions. However, compared with cisplatin, ABDNAZ was better tolerated at submaximal doses, yielding significant tumor growth inhibition in the absence of systemic toxicity. Similarly, when combined with radiation, ABDNAZ accentuated antitumor efficacy along with the therapeutic index. Toxicity studies indicated that ABDNAZ was not myelosuppressive and no dose-limiting toxicity was apparent following daily administration for 14 days. Taken together, our findings offer preclinical proof-of-concept for ABDNAZ as a promising new anticancer agent with a favorable toxicity profile, either as a chemotherapeutic agent or a radiosensitizer. Cancer Res; 72(10); 2600–8. ©2012 AACR.
A Comprehensive Survey of Ras Mutations in Cancer
Authors: Prior Ian A. , Lewis Paul D. , Mattos Carla
Published: May 2012

All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, and N-Ras, that promote oncogenesis when they are mutationally activated at codon 12, 13, or 61. Although there is a high degree of similarity among the isoforms, K-Ras mutations are far more frequently observed in cancer, and each isoform displays preferential coupling to particular cancer types. We examined the mutational spectra of Ras isoforms curated from large-scale tumor profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino-acid substitution biases. These findings were unexpected given that these mutations occur in regions that share 100% amino-acid sequence identity among the 3 isoforms. Of importance, many of these mutational biases were not due to differences in exposure to mutagens, because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms, as well as isoform-specific differences in protein structure and signaling, that may promote these distinct mutation patterns and differential coupling to specific cancers. Cancer Res; 72(10); 2457–67. ©2012 AACR.
Using Germline Genomics to Individualize Pediatric Cancer Treatments
Authors: Pinto Navin , Cohn Susan L. , Dolan M. Eileen
Published: May 2012

The amazing successes in cure rates for children with cancer over the last century have come in large part from identifying clinical, genetic, and molecular variables associated with response to therapy in large cooperative clinical trials and stratifying therapies according to the predicted risk of relapse. There is an expanding interest in identifying germline genomic variants, as opposed to genetic variants within the tumor, that are associated with susceptibility to toxicity and for risk of relapse. This review highlights the most important germline pharmacogenetic and pharmacogenomic studies in pediatric oncology. Incorporating germline genomics into risk-adapted therapies will likely lead to safer and more effective treatments for children with cancer. Clin Cancer Res; 18(10); 2791–800. ©2012 AACR.
Evaluating iPhone Recordings for Acoustic Voice Assessment
Authors: Lin Emily , Hornibrook Jeremy , Ormond Tika
Published: May 2012

Aims: This study examined the viability of using iPhone recordings for acoustic measurements of voice quality. Methods: Acoustic measures were compared between voice signals simultaneously recorded from 11 normal speakers (6 females and 5 males) through an iPhone (model A1303, Apple, USA) and a comparison recording system. Comparisons were also conducted between the pre- and post-operative voices recorded from 10 voice patients (4 females and 6 males) through the iPhone. Participants aged between 27 and 79 years. Results: Measures from iPhone and comparison signals were found to be highly correlated. Findings of the effects of vowel type on the selected measures were consistent between the two recording systems and congruent with previous findings. Analysis of the patient data revealed that a selection of acoustic measures, such as vowel space area and voice perturbation measures, consistently demonstrated a positive change following phonosurgery. Conclusion: The present findings indicated that the iPhone device tested was useful for tracking voice changes for clinical management. Preliminary findings regarding factors such as gender and type of pathology suggest that intra-subject, instead of norm-referenced, comparisons of acoustic measures would be more useful in monitoring the progression of a voice disorder or tracking the treatment effect.
Genetic Variation in the Neuropeptide Y Gene Promoter Is Associated with Increased Risk of Tobacco Smoking
Authors: Mutschler Jochen , Abbruzzese Elvira , von der Goltz Christoph , Dinter Christina , Mobascher Arian , Thiele Holger , Diaz-Lacava Amalia , Dahmen Norbert , Gallinat Jürgen , Majic Tomislav , Petrovsky Nadine , Kornhuber Johannes , Thuerauf Norbert , Gründer Gerhard , Brinkmeyer Jürgen , Wienker Thomas , Wagner Michael , Winterer Georg , Kiefer Falk
Published: May 2012

Background: Neuropeptide Y (NPY) is a strong candidate gene regarding the pathophysiology of tobacco dependence. It has been associated with various addictive and psychiatric disorders, and closely interacts with the brain reward system. The aim of the present study was to test for association between a functional genetic variant in the NP-Y promoter gene (SNP rs16147) and tobacco smoking. Methods: In a population-based case-control multicenter study designed for tobacco addiction research, a total of 550 Caucasian current smokers, and 544 never-smokers were genotyped for SNP rs16147 and behaviorally characterized with the State-Trait Anxiety Inventory (STAI). Results: Subjects with TT genotype of the SNP rs16147 were significantly more frequently smokers than never-smokers (p = 0.046). In addition, TT genotype exhibited increased state anxiety scores compared to carriers of the C allele (p = 0.037). Conclusions: Our results provide evidence for an involvement of the functionally relevant SNP rs16147 in the pathophysiology of tobacco dependence. Further studies are needed to confirm our findings.
The Effect of Type 2 Diabetes Risk Loci on Insulin Requirements in Type 1 Diabetes
Authors: Moosavi Mandana , Séguin Jade , Li Quan , Polychronakos Constantin
Published: May 2012

Objective: To analyze the correlation between insulin requirements of type 1 diabetic (T1D) patients and genotype at type 2 diabetes (T2D) risk loci, obtained in our genome-wide association study. Methods: From a database of detailed insulin dosing of 567 patients, we selected 177 for whom we also had genome-wide genotyping data. Using PLINK software, we examined the association between insulin requirement as a quantitative trait and nineteen T2D risk loci. Results: Out of 19 single-nucleotide polymorphisms (SNPs), rs13266634 on chromosome 8 and rs7901695 on chromosome 10 showed nominal significance of association (p < 0.05). The first SNP is nonsynonymous (325 Arg>Trp) and maps to the SLC30A8 gene encoding the β-cell-specific ZnT8 zinc transporter, while the second is an intronic SNP in TCF7L2, the strongest known T2D association. Both loci exert their effect on β-cells and, in both, the T2D risk allele is associated with lower insulin requirements. Conclusion: We identified two T2D susceptibility loci that modulate insulin requirements in T1D patients. Our results are consistent with the association of lower insulin secretion with higher insulin sensitivity. To explain the continuation of this correlation after β-cell destruction, we hypothesize an epigenetic mechanism that alters insulin responsiveness in T1D patients based on β-cell function in early life. Such knowledge may allow a more precise approach to treatment.
Neuropsychopathology in 7 Patients with the 22q13 Deletion Syndrome: Presence of Bipolar Disorder and Progressive Loss of Skills
Authors: Denayer A. , Van Esch H. , de Ravel T. , Frijns J.-P. , Van Buggenhout G. , Vogels A. , Devriendt K. , Geutjens J. , Thiry P. , Swillen A.
Published: May 2012

The 22q13 deletion syndrome is characterised by intellectual disability (ID), delayed or absent speech, autistic-like behaviour and minor, nonspecific dysmorphic features. The deletion of the SHANK3 gene is thought to be responsible for these features. In this study, the clinical data of 7 patients with the 22q13 deletion syndrome are presented, obtained by clinical genetic examination, direct behavioural observation and by interview of family members and/or caregivers, complemented by behavioural questionnaires. The specific focus was on behaviour, psychopathology and the level of functioning during life course in order to determine common features that might contribute to the delineation of the syndrome. Major findings were a high incidence of psychiatric disorders, more in particular bipolar disorder (BPD) and attention deficit hyperactivity disorder (ADHD), and a sudden deterioration after acute events, in addition to a progressive loss of skills over years. Therefore, a deletion of SHANK3 may result in a dysfunctional nervous system, more susceptible to developmental problems and psychiatric disorders on the one hand, less able to recuperate after psychiatric and somatic events, and more vulnerable to degeneration at long term on the other hand. These results are exploratory and need to be confirmed in a larger sample.
Renal Sympathetic Denervation Suppresses Postapneic Blood Pressure Rises and Atrial Fibrillation in a Model for Sleep Apnea
Authors: Linz Dominik , Mahfoud Felix , Schotten Ulrich , Ukena Christian , Neuberger Hans-Ruprecht , Wirth Klaus , Böhm Michael
Published: May 2012

The aim of this study was to identify the relative impact of adrenergic and cholinergic activity on atrial fibrillation (AF) inducibility and blood pressure (BP) in a model for obstructive sleep apnea. Obstructive sleep apnea is associated with sympathovagal disbalance, AF, and postapneic BP rises. Renal denervation (RDN) reduces renal efferent and possibly also afferent sympathetic activity and BP in resistant hypertension. The effects of RDN compared with β-blockade by atenolol on atrial electrophysiological changes, AF inducibility, and BP during obstructive events and on shortening of atrial effective refractory period (AERP) induced by high-frequency stimulation of ganglionated plexi were investigated in 20 anesthetized pigs. Tracheal occlusion with applied negative tracheal pressure (NTP; at −80 mbar) induced pronounced AERP shortening and increased AF inducibility in all of the pigs. RDN but not atenolol reduced NTP-induced AF-inducibility (20% versus 100% at baseline;
P
=0.0001) and attenuated NTP-induced AERP shortening more than atenolol (27±5 versus 43±3 ms after atenolol;
P
=0.0272). Administration of atropine after RDN or atenolol completely inhibited NTP-induced AERP shortening. AERP shortening induced by high-frequency stimulation of ganglionated plexi was not influenced by RDN, suggesting that changes in sensitivity of ganglionated plexi do not play a role in the antiarrhythmic effect of RDN. Postapneic BP rise was inhibited by RDN and not modified by atenolol. We showed that vagally mediated NTP-induced AERP shortening is modulated by RDN or atenolol, which emphasizes the importance of autonomic disbalance in obstructive sleep apnea-associated AF. Renal denervation displays antiarrhythmic effects by reducing NTP-induced AERP shortening and inhibits postapneic BP rises associated with obstructive events.
Multiple SNP testing improves risk prediction of first venous thrombosis
Authors: de Haan Hugoline G. , Bezemer Irene D. , Doggen Carine J. M. , Le Cessie Saskia , Reitsma Pieter H. , Arellano Andre R. , Tong Carmen H. , Devlin James J. , Bare Lance A. , Rosendaal Frits R. , Vossen Carla Y.
Published: May 2012

There are no risk models available yet that accurately predict a person's risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study, including 2712 patients and 4634 controls (Multiple Environmental and Genetic Assessment). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves [AUCs] of 0.70 and 0.69, respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% confidence interval [CI], 0.25-0.53) for persons with 0 risk alleles to 7.48 (95% CI, 4.49-12.46) for persons with more than or equal to 6 risk alleles. The AUC of a risk model based on known nongenetic risk factors was 0.77 (95% CI, 0.76-0.78). Combining the nongenetic and genetic risk models improved the AUC to 0.82 (95% CI, 0.81-0.83), indicating good diagnostic accuracy. To become clinically useful, subgroups of high-risk persons must be identified in whom genetic profiling will also be cost-effective.
Global attractivity for fractional order delay partial integro-differential equations
Authors: Abbas Saïd , Baleanu Dumitru , Benchohra Mouffak
Published: May 2012

Our aim in this work is to study the existence and the attractivity of solutions for a system of delay partial integro-differential equations of fractional order. We use the Schauder fixed point theorem for the existence of solutions, and we prove that all solutions are locally asymptotically stable.

AMS (MOS) Subject Classifications: 26A33.
CytoITMprobe: a network information flow plugin for Cytoscape
Authors: Stojmirović Aleksandar , Bliskovsky Alexander , Yu Yi-Kuo
Published: May 2012

Background

Cytoscape is a well-developed flexible platform for visualization, integration and analysis of network data. Apart from the sophisticated graph layout and visualization routines, it hosts numerous user-developed plugins that significantly extend its core functionality. Earlier, we developed a network information flow framework and implemented it as a web application, called ITM Probe. Given a context consisting of one or more user-selected nodes, ITM Probe retrieves other network nodes most related to that context. It requires neither user restriction to subnetwork of interest nor additional and possibly noisy information. However, plugins for Cytoscape with these features do not yet exist. To provide the Cytoscape users the possibility of integrating ITM Probe into their workflows, we developed CytoITMprobe, a new Cytoscape plugin.

Findings

CytoITMprobe maintains all the desirable features of ITM Probe and adds additional flexibility not achievable through its web service version. It provides access to ITM Probe either through a web server or locally. The input, consisting of a Cytoscape network, together with the desired origins and/or destinations of information and a dissipation coefficient, is specified through a query form. The results are shown as a subnetwork of significant nodes and several summary tables. Users can control the composition and appearance of the subnetwork and interchange their ITM Probe results with other software tools through tab-delimited files.

Conclusions

The main strength of CytoITMprobe is its flexibility. It allows the user to specify as input any Cytoscape network, rather than being restricted to the pre-compiled protein-protein interaction networks available through the ITM Probe web service. Users may supply their own edge weights and directionalities. Consequently, as opposed to ITM Probe web service, CytoITMprobe can be applied to many other domains of network-based research beyond protein-networks. It also enables seamless integration of ITM Probe results with other Cytoscape plugins having complementary functionality for data analysis.
Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection
Authors: Smalley Stephen R. , Benedetti Jacqueline K. , Haller Daniel G. , Hundahl Scott A. , Estes Norman C. , Ajani Jaffer A. , Gunderson Leonard L. , Goldman Bryan , Martenson James A. , Jessup J. Milburn , Stemmermann Grant N. , Blanke Charles D. , Macdonald John S.
Published: May 2012

Purpose

Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses.

Patients and Methods

In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy.

Results

Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect.

Conclusion

Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.
Human Epidermal Growth Factor Receptor 2 Status and Interval Breast Cancer in a Population-Based Cancer Registry Study
Authors: Musolino Antonino , Michiara Maria , Conti Giovanni Maria , Boggiani Daniela , Zatelli Marella , Palleschi Dario , Bella Maria Angela , Sgargi Paolo , Di Blasio Beatrice , Ardizzoni Andrea
Published: May 2012

Purpose

To determine whether human epidermal growth factor receptor 2 (HER2) –positive status is associated with risk of breast cancer diagnosis in the interval between mammographic screening, we estimated the distribution of features of aggressive tumor behavior in a general population with newly diagnosed breast cancer and known screening status.

Patients and Methods

We evaluated all invasive breast cancers (N = 641) that were systematically collected by the Parma Province Cancer Registry and diagnosed in women age 50 to 69 years from 2004 to 2007. From this population, 292 screen-detected cancers and 48 interval cases with negative screening mammograms on expert rereading (true interval cancers) were selected for study purposes. Unconditional logistic regression adjusted for age and tumor size was used to determine whether interval cancers were associated with selected clinicobiologic characteristics.

Results

Tumors with a high histologic grade (odds ratio [OR], 1.8; 95% CI, 1.2 to 3.8), high proliferative rate (OR, 2.4; 95% CI, 1.2 to 4.5), negative estrogen receptor status (OR, 1.6; 95% CI, 1.1 to 3.1), or HER2-positive status (OR, 3.4; 95% CI, 1.7 to 7.1) were more likely to be diagnosed in the interval between screening. Women age less than 60 years with HER2-positive breast cancer were four times more likely to be diagnosed in the interval between screening compared with only a two-fold increased risk for older women.

Conclusion

This population-based cancer registry study demonstrated that HER2-positive tumors account for a substantial proportion of mammographic screening failure. The distribution of biologic characteristics in screen-detected cancers differs from that observed in interval cancers and may account in part for the more aggressive behavior of interval-detected cases.
Preface: Learning to Read
Authors: Carson Luke , White Heather Cass
Published: May 2012

Because for us “learning to read” is synonymous with “learning to read poetry,” we framed this issue of Genre with that one generic restriction. We invited our contributors to discuss the idea of “learning to read” with reference either to a critic who has or should have taught us about reading poems or to a poet or group of poets who involve us in their own reading. Given a common focus on poetry, these essays revisit the idea of lyric and its various attributes: individuality, originality, subjectivity, and feeling (especially in relation to tradition and convention). Our introduction focuses on the multiple lines of interconnection between the essays and the character of the story they tell together. Taken as a whole, the story about the fate of lyric poetry at the turn of the twentieth century is rich in the elements of romance: danger, conflict, rescue, hope, and love. In the broadest terms the imperiled object of this romance is the continued writing of poetry itself, a practice beset with dangers, according to these essays, from both within and without.
Mixed Feelings: Ashbery, Duchamp, Roussel, and the Animation of Cliché
Authors: Rosenbaum Susan
Published: May 2012

The association of the cliché with a devalorized and feminized sentimentality—with feeling regarded as excessive, insincere, mechanized, or commercially debased—emerged in the late nineteenth century and was instrumental to the canonization of literary modernism in the 1940s and 1950s. This essay proposes a different reading of clichés by focusing on artists who approach the cliché not with grimness but with fascination. Raymond Roussel, Marcel Duchamp, and John Ashbery recognized the cliché's constitutive function in modern culture; its ties to print, photography, and mechanical reproduction; and its vital role in mediating feeling. Rather than bemoan or attack the cliché, each artist put it at the center of their experiments, punning on and playing with clichés to generate a new language of feeling. For this trio of artists, the mechanical origin and mixed nature of the cliché facilitates rather than impedes their efforts to animate “dead metaphors.” Ashbery, a dedicated reader, translator, and critic of Roussel, adapts Roussel's methods, but his adaptations owe much to the work of a crucial intermediary, Duchamp, whose “bachelor machines” originated in his reading of Roussel. By reading Ashbery through Roussel and Duchamp, this essay illuminates an overlooked genealogy for the New York School poets' experiments with feeling.