BackgroundIn breast cancer, ErbB receptors play a critical role, and overcoming drug resistance remains a major challenge in the clinic. However, intricate regulatory mechanisms of ErbB family genes are poorly understood. Here, we demonstrate SON as an ErbB-regulatory splicing factor and a novel therapeutic target for ErbB-positive breast cancer.MethodsSON and ErbB expression analyses using public database, patient tissue microarray, and cell lines were performed. SON knockdown assessed its impact on cell proliferation, apoptosis, kinase phosphorylation, RNA splicing, and in vivo tumour growth. RNA immunoprecipitation was performed to measure SON binding.ResultsSON is highly expressed in ErbB2-positive breast cancer patient samples, inversely correlating with patient survival. SON knockdown induced intron retention in selective splice sites within ErbB2 and ErbB3 transcripts, impairing effective RNA splicing and reducing protein expression. SON disruption suppressed downstream kinase signalling of ErbB2/3, including the Akt, p38, and JNK pathways, with increased vulnerability in ErbB2-positive breast cancer cells compared to ErbB2-negative cells. SON silencing in ErbB2-positive breast cancer xenografts led to tumour regression in vivo.ConclusionWe identified SON as a novel RNA splicing factor that plays a critical role in regulating ErbB2/3 expression, suggesting SON is an ideal therapeutic target in ErbB2-positive breast cancers.

Animals are exposed to different visual stimuli that influence how they perceive and interact with their environment. Visual information such as shape and colour can help animals detect, discriminate, and make appropriate behavioural decisions for mate selection, communication, camouflage, and foraging. Previous research indicates that at least some species within all major vertebrate groups prefer and can discriminate among certain colours and that colour may increase the response to a stimulus. However, since colour is often studied together with other potentially confounding factors such as movement and scent, it is still unclear what role colour plays in the perception of and attention to different stimuli. In this study, we test whether colour influences the response that an animal has to an object, and whether this influence changes depending on the type of object shown to the animal. We assessed the response of three gecko species, Correlophus ciliatus , Eublepharis macularius, and Phelsuma laticauda, to familiar and novel objects presented as colour or grayscale images. Our results indicate that colour does not change the response to objects. Specifically, we found that while all species responded more often to novel than to the familiar images, colour did not influence the response. We also found that the duration of interaction with images was significantly longer for the diurnal species, P. laticauda , than for the two nocturnal species, but this was also independent of colouration. Finally, no differences among sexes were observed within or between species. Our results show that geckos discriminate between 2D images of different content independent of colouration, suggesting that colour may not increase detectability or intensity of the response. These results are essential for uncovering which visual stimuli produce responses in animals.

The mammalian STE 20-like protein kinase 4 (MST4) gene is highly expressed in several cancer types, but little is known about the role of MST4 in breast cancer, and the function of MST4 during epithelial-mesenchymal transition (EMT) has not been fully elucidated. Here we report that overexpression of MST4 in breast cancer results in enhanced cell growth, migration, and invasion, whereas inhibition of MST4 expression significantly attenuates these properties. Further study shows that MST4 promotes EMT by activating Akt and its downstream signaling molecules such as E-cadherin/N-cadherin, Snail, and Slug. MST4 also activates AKT and its downstream pro-survival pathway. Furthermore, by analyzing breast cancer patient tissue microarray and silicon datasets, we found that MST4 expression is much higher in breast tumor tissue compared to normal tissue, and significantly correlates with cancer stage, lymph node metastasis and a poor overall survival rate (p < 0.05). Taken together, our findings demonstrate the oncogenic potential of MST4 in breast cancer, highlighting its role in cancer cell proliferation, migration/invasion, survival, and EMT, suggesting a possibility that MST4 may serve as a novel therapeutic target for breast cancer.

Purpose This study investigated the impact of age and sex on mastication performance in healthy, nondysphagic, community-dwelling adults as observed during videofluoroscopy. Method Videofluoroscopic swallowing study imaging and mastication performance metrics (cycles, duration) were used to evaluate 185 healthy individuals (102 women, 83 men) aged 21–89 years. Results A significant effect of age on mastication cycles was not observed; however, a significant but weak effect of age on mastication duration was found. Female participants were observed to have significantly more mastication cycles and longer mastication durations compared to male participants. Three behavioral patterns of mastication performance emerged. Conclusions The results of this study contribute to normative data of mastication performance. An individual's sex was found to have a significant effect on mastication performance, although, in contrast to previous studies, age was not observed to significantly alter mastication performance. Differences in study methodologies likely explain the latter finding.

Objectives: The purpose of this study was to examine age-related effects on esophageal transit times (ETT) among healthy adult participants. Methods: A total of 175 healthy, non-dysphagic participants underwent a modified barium swallow study (MBSS), and ETT was recorded for two standardized swallowing tasks. Differences across age groups were determined using Kruskal-Wallis test. Relationships between an Esophageal Clearance (Modified Barium Swallow Impairment Profile Component 17) score and ETT were also explored. Results: No significant differences were observed in ETT across age groups for nectar-thickened liquid (P = .335) or pudding (P = .231) consistencies. No significant differences were observed between males and females in ETT for either the nectar (P = .112) or pudding trial (P = .817). For nectar, the mean ETT for patients with Component 17 scores of 2 or greater were significantly higher than that of participants with a score of 0 (P < .0001). For pudding, participants with a score >0 demonstrated significantly higher mean ETT compared to participants with a score of 0 (with P = .0008 and P < .0001, respectively). Conclusion: Study findings failed to support age-related or sex-related differences in ETT for two standardized swallowing tasks administered during a MBSS in healthy individuals. The normative values following a standardized protocol in this study provide guidance in clinical interpretation of esophageal function.

Background: Neurotypical young adults show task-based modulation and stability of their eye movements across tasks. This study aimed to determine whether persons with aphasia (PWA) modulate their eye movements and show stability across tasks similarly to control participants. Methods: Forty-eight PWA and age-matched control participants completed four eye-tracking tasks: scene search, scene memorization, text-reading, and pseudo-reading. Results: Main effects of task emerged for mean fixation duration, saccade amplitude, and standard deviations of each, demonstrating task-based modulation of eye movements. Group by task interactions indicated that PWA produced shorter fixations relative to controls. This effect was most pronounced for scene memorization and for individuals who recently suffered a stroke. PWA produced longer fixations, shorter saccades, and less variable eye movements in reading tasks compared to controls. Three-way interactions of group, aphasia subtype, and task also emerged. Text-reading and scene memorization were particularly effective at distinguishing aphasia subtype. Persons with anomic aphasia showed a reduction in reading saccade amplitudes relative to their respective control group and other PWA. Persons with conduction/Wernicke's aphasia produced shorter scene memorization fixations relative to controls or PWA of other subtypes, suggesting a memorization specific effect. Positive correlations across most tasks emerged for fixation duration and did not significantly differ between controls and PWA. Conclusion: PWA generally produced shorter fixations and smaller saccades relative to controls particularly in scene memorization and text-reading, respectively. The effect was most pronounced recently after a stroke. Selectively in reading tasks, PWA produced longer fixations and shorter saccades relative to controls, consistent with reading difficulty. PWA showed task-based modulation of eye movements, though the pattern of results was somewhat abnormal relative to controls. All subtypes of PWA also demonstrated task-based modulation of eye movements. However, persons with anomic aphasia showed reduced modulation of saccade amplitude and smaller reading saccades, possibly to improve reading comprehension. Controls and PWA generally produced stabile fixation durations across tasks and did not differ in their relationship across tasks. Overall, these results suggest there is potential to differentiate among PWA with varying subtypes and from controls using eye movement measures of task-based modulation, especially reading and scene memorization tasks.

IntroductionA brief resolved unexplained event (BRUE) describes an event associated with a change in muscle tone, color, respiration, and responsiveness that is unexplained after an appropriate examination. Some infants with higher risk BRUE may undergo endoscopy as part of their evaluation.ObjectiveThis retrospective study aimed to identify the endoscopic findings in infants who have experienced a higher risk BRUE. We also compared the characteristics, prenatal, natal, and postnatal risk factors between 23 infants who underwent endoscopic evaluation and 23 race-matched/sex-matched/term-matched/preterm-matched infants who did not undergo endoscopic evaluation.MethodsThis was a retrospective descriptive study. Infants were identified from a query of medical records using the ICD-10 code for BRUE (R68.13).ResultsOf 119 infants with BRUE, 23 infants with higher risk BRUE underwent an esophagogastroduodenoscopy and flexible sigmoidoscopy. Apnea (87%) was the most common presentation of BRUE. Most were female (57%) with a mean age at BRUE presentation of 2.73 months. We found 10 (43.5%) term infants and 13 (56.5%) preterm infants in our study. There were no significant differences in characteristics, prenatal, natal, and postnatal risk factors between the infants who underwent endoscopy and those who did not undergo endoscopy. The most common abnormal endoscopic finding was lymphonodular hyperplasia (LNH) associated with eosinophilia in the rectosigmoid colon. The proportion of females in the LNH group was significantly higher than the non-LNH group.ConclusionRectosigmoid LNH and eosinophilia, which are associated with milk soy protein intolerance (MSPI), were the most common findings on endoscopic evaluation. Although there is no proof of causation between MSPI and BRUE, MSPI should be considered in the differential diagnosis for higher risk BRUE.

BACKGROUND:Pediatric patients with inflammatory bowel disease (IBD) are at risk for psychiatric symptoms that impact quality of life (QoL) and psychosocial functioning. Sleep disturbance has been reported to impose adverse effects on host defense mechanisms by affecting the magnitude and characteristics of the inflammatory response. The current study sought to assess the relationships among sleep disturbance, QoL, and psychosocial functioning in children with IBD.METHODS:Pediatric IBD patients completed multiple measures of sleep and daytime functioning as well as measures of QoL and psychosocial functioning. The parents completed complementary measures of sleep, QoL, and psychosocial functioning. The HRQOL results for subjects with IBD were compared to a healthy control group.RESULTS:Fifty-three children with pediatric IBD and their parents were enrolled in the study. QoL was positively associated with sleep quality, based on significant negative correlations between QoL and both sleep quality and daytime sleepiness scales (r = -0.62, -0.57; p value <0.001, respectively). Patients with CD reported significantly better QoL and psychosocial functioning than patients with UC. The QoL was similar between IBD patients and healthy controls.CONCLUSIONS:The present study suggests that a positive association exists between sleep functioning and QoL in pediatric patients with IBD. Patients with pediatric IBD should be screened for sleep disturbance, QoL and psychosocial functioning. Prevention and intervention strategies of sleep disturbance aimed at improving QoL and psychosocial functioning in children with IBD should be developed and evaluated.

Introduction: Patients' understanding of their disease processes correlates with better outcomes in many chronic diseases. Such knowledge can positively influence quality of life, social activity, and ability to cope and comply with treatment. To our knowledge, no study has determined if a correlation exists between patients' inflammatory bowel disease (IBD) knowledge and their medication adherence. Methods: 201 consecutive outpatients at a large academic IBD center were enrolled. All patients completed the validated Crohn's and Colitis Knowledge Score (CCKNOW) and Medication Adherence Questionnaire (MAQ) surveys at an office visit. Physicians then completed a validated Clinical Rating Scale (CRS), scored 1-7, to assess their perception of the patients' medication adherence. Results: There were 87 (43.3%) males and 114 (56.7%) females, with average age 40.2 years. 122 (61.6%) had Crohn disease, 68 (34.4%) had ulcerative colitis, 8 (4.0%) had indeterminate colitis. There were 104 (55.6%) Caucasians, 65 (34.8%) Hispanics, 10 African-Americans (5.3%), and 8 (4.3%) who self-identifi ed as Other. Baseline CCKNOW scores differed significantly by age group as the 60-80 age group (p = 0.001), had lower CCKNOW scores compared to the 10-30 and 30-60 groups. There was a unimodal distribution of CCKNOW and duration of IBD illness. CCKNOW increased significantly (p = 0.005) from patients with disease 10-20 years compared to those with IBD for 21-30 years; CCKNOW scores then non-significantly decreased progressively in those with IBD 31-40 and 40+ years. Non-Hispanics had significantly higher CCKNOW than Hispanics (p = 0.041), and Caucasians scored higher than Hispanics (p = 0.040). There was no association of gender or IBD subtype with CCKNOW. CCKNOW was not associated with medication adherence based on the MAQ completed by patients or CRS completed by physicians. Females had lower medication adherence than males (p = 0.011). BMI was not associated with CCKNOW, MAQ, or CRS. Conclusion: Patients' knowledge of their IBD appears to increase over time and then decrease. There is no association between patients' disease knowledge and patient or physician perception of medication compliance. As greater knowledge of disease seems to positively impact other chronic illnesses, research investigating other factors contributing to optimal medication adherence should be undertaken.

Background: Stroke volume variation (SVV), a dynamic index, shows high sensitivity and specificity in predicting the fluid responsiveness of patients undergoing mechanical ventilation. Previous studies have shown that SVV-oriented fluid management performs positive effect in the perioperative maintenance of hemodynamic and better prognosis. It also could be used to predict the fluid responsiveness under one-lung ventilation with constant volume. The present study was aimed to determine the feasibility of stroke volume variation as a predictor for fluid responsiveness under pressure-controlled one-lung ventilation. Methods: Seventy patients were enrolled and divided into two groups with distinct ventilation pressures (20 cmH(2)O and 25 cmH(2)O). ROC curve analysis was performed to evaluate the capacity of SVV for prediction. Results: Sixty-three out of 70 patients completed the study. SVV showed weak correlation with dSVV and dSVI. The optimal threshold value of SVV to discriminate between responders and nonresponders was 9.5% (sensitivity 75.6% and specificity 54.5%). The optimal threshold value of SVV to discriminate between responders and non-responders remains to be 9.5% for both subgroups with 20 cmH(2)O and 25 cmH(2)O. Conclusion: SVV is a poor predictor of fluid responsiveness for patients undergoing pressurecontrolled one-lung ventilation.

Objective. Our objective was to evaluate the surgical trend towards increased MIS in the management of endometrial cancer in regard to improvements in patient outcomes.Methods. Using the American College of Surgeons-National Surgical Quality Improvement Project's database, patients who underwent hysterectomy for endometrial cancer from 2006-2010 were identified and categorized into exploratory laparotomy (XLAP) or MIS. Comparative analyses were performed and stratified by year of surgery to evaluate demographics, surgical outcomes, and 30-day surgical morbidity.Results. A total of 2076 patients (1269 XLAP and 807 MIS) underwent hysterectomy for endometrial cancer between 2006 and 2010. Longer operative times were seen in MIS compared to XLAP (192 vs. 148 min; p <0.001) as well as significant increase in mean hospital stay in the XLAP group of 3.8 days compared to 1.6 days in MIS (p < 0.0001). When controlling for preoperative comorbidities, significant increases in postoperative complications were observed in XLAP compared to MIS group (total 396 vs. 91; p < 0.0001). MIS increased from 16% in 2006 to 48% in 2010, which correlated to decreases in complications and hospital stays. Each 10% increase in MIS would save $2.8 million and 41 postoperative complications. If used exclusively, MIS would save 6434 hospital days and 416 complications.Conclusions. Despite increases in operative times, MIS for the treatment of endometrial cancer significantly reduces perioperative complications and hospital stay. Considering the improvements in patient outcomes and the potential savings to the health care system, MIS should be the preferred route for the surgical treatment of this disease when feasible. (C) 2014 Published by Elsevier Inc.

Germline mutations of BRCA1 confer hereditary susceptibility to breast and ovarian cancer. However, somatic mutation of BRCA1 is infrequent in sporadic breast cancers. The BRCA1 protein C terminus (BRCT) domains interact with multiple proteins and are required for BRCA1's tumor-suppressor function. In this study, we demonstrated that Abraxas, a BRCA1 BRCT domain-interacting protein, plays a role in tumor suppression. Abraxas exerts its function through binding to BRCA1 to regulate DNA repair and maintain genome stability. Both homozygous and heterozygous Abraxas knockout mice exhibited decreased survival and increased tumor incidence. The gene encoding Abraxas suffers from gene copy loss and somatic mutations in multiple human cancers including breast, ovarian, and endometrial cancers, suggesting that mutation and loss of function of Abraxas may contribute to tumor development in human patients.

This population-based descriptive epidemiology study demonstrates that rates of conjoined twins, teratomas, neural tube defects, microcephaly, and microphthalmia in the Rivne province of Ukraine are among the highest in Europe. The province is 200 km distant from the Chornobyl site and its northern half, a region known as Polissia, is significantly polluted by ionizing radiation. The rates of neural tube defects, microcephaly and microphthalmia in Polissia are statistically significantly higher than in the rest of the province. A survey of at-birth head size showed that values were statistically smaller in males and females born in one Polissia county than among neonates born in the capital city. These observations provide clues for confirmatory and cause-effect prospective investigations. The strength of this study stems from a reliance on international standards prevalent in Europe and a decade-long population-based surveillance of congenital malformations in two distinct large populations. The limitations of this study, as those of other descriptive epidemiology investigations, is that identified cause-effect associations require further assessment by specific prospective investigations designed to address specific teratogenic factors.

Rounding of data is common in practice. The problem of estimating the underlying density function based on data with rounding errors is addressed. A parametric maximum likelihood estimator and a nonparametric bootstrap kernel density estimator are proposed. Simulations indicate that the maximum likelihood approach performs well when prior information on the functional form of the underlying distribution is available, while the kernel-type estimator attains stable and good performance in various cases. The proposed methods are further applied to detect the distributional difference of head circumferences from two Chernobyl impacted regions of Ukraine.

The M2 isoform of pyruvate kinase (PKM2) plays an important role in aerobic glycolysis and is a mediator of the Warburg effect in tumors. It was previously thought that tumor cells switch expression of PKM from normal tissue-expressed PKM1 to tumor-specific PKM2 via an alternative splicing mechanism. This view was challenged by a recent report demonstrating that PKM2 is already the major PKM isoform expressed in many differentiated normal tissues. Here, through analyses on sixteen tumor types using the cancer genome atlas RNA-Seq and exon array datasets, we confirmed that isoform switch from PKM1 to PKM2 occurred in glioblastomas but not in other tumor types examined. Despite lacking of isoform switches, PKM2 expression was found to be increased in all cancer types examined, and correlated strongly to poor prognosis in head and neck cancers. We further demonstrated that elevated PKM2 expression correlated well with the hypomethylation status of intron 1 of the PKM gene in multiple cancer types, suggesting epigenetic regulation by DNA methylation as a major mechanism in controlling PKM transcription in tumors. Our study suggests that isoform switch of PKM1 to PKM2 in cancers is tissue-specific and targeting PKM2 activity in tumors remains a promising approach for clinical intervention of multiple cancer types.

Microarray is a high throughput discovery tool that has been broadly used for genomic research. Probe-target hybridization is the central concept of this technology to determine the relative abundance of nucleic acid sequences through fluorescence-based detection. In microarray experiments, variations of expression measurements can be attributed to many different sources that influence the stability and reproducibility of microarray platforms. Normalization is an essential step to reduce non-biological errors and to convert raw image data from multiple arrays (channels) to quality data for further analysis. In general, for the traditional microarray analysis, most established normalization methods are based on two assumptions: (1) the total number of target genes is large enough (>10,000); and (2) the expression level of the majority of genes is kept constant. However, microRNA (miRNA) arrays are usually spotted in low density, due to the fact that the total number of miRNAs is less than 2,000 and the majority of miRNAs are weakly or not expressed. As a result, normalization methods based on the above two assumptions are not applicable to miRNA profiling studies. In this review, we discuss a few representative microarray platforms on the market for miRNA profiling and compare the traditional methods with a few novel strategies specific for miRNA microarrays.

MicroRNA is a set of small RNA molecules mediating gene expression at post-transcriptional/translational levels. Most of well-established high throughput discovery platforms, such as microarray, real time quantitative PCR, and sequencing, have been adapted to study microRNA in various human diseases. The total number of microRNAs in humans is approximately 1,800, which challenges some analytical methodologies requiring a large number of entries. Unlike messenger RNA, the majority of microRNA (60%) maintains relatively low abundance in the cells. When analyzed using microarray, the signals of these low-expressed microRNAs are influenced by other non-specific signals including the background noise. It is crucial to distinguish the true microRNA signals from measurement errors in microRNA array data analysis. In this study, we propose a novel measurement error model-based normalization method and differentially-expressed microRNA detection method for microRNA profiling data acquired from locked nucleic acids (LNA) microRNA array. Compared with some existing methods, the proposed method significantly improves the detection among low-expressed microRNAs when assessed by quantitative real-time PCR assay.

Data from many scientific areas often come with measurement error. Density or distribution function estimation from contaminated data and nonparametric regression with errors-in-variables are two important topics in measurement error models. In this paper, we present a new software package decon for R, which contains a collection of functions that use the deconvolution kernel methods to deal with the measurement error problems. The functions allow the errors to be either homoscedastic or heteroscedastic. To make the deconvolution estimators computationally more efficient in R, we adapt the fast Fourier transform algorithm for density estimation with error-free data to the deconvolution kernel estimation. We discuss the practical selection of the smoothing parameter in deconvolution methods and illustrate the use of the package through both simulated and real examples.

MOTIVATION:Compared with complementary DNA (cDNA) or messenger RNA (mRNA) microarray data, microRNA (miRNA) microarray data are harder to normalize due to the facts that the total number of miRNAs is small, and that the majority of miRNAs usually have low expression levels. In bead-based microarrays, the hybridization is completed in several pools. As a result, the number of miRNAs tested in each pool is even smaller, which poses extra difficulty to intrasample normalization and ultimately affects the quality of the final profiles assembled from various pools. In this article, we consider a measurement error model-based method for bead-based microarray intrasample normalization.RESULTS:In this study, results from quantitative real-time PCR (qRT-PCR) assays are used as 'gold standards' for validation. The performance of the proposed measurement error model-based method is evaluated via a simulation study and real bead-based miRNA expression data. Simulation results show that the new method performs well to assemble complete profiles from subprofiles from various pools. Compared with two intrasample normalization methods recommended by the manufacturer, the proposed approach produces more robust final complete profiles and results in better agreement with the qRT-PCR results in identifying differentially expressed miRNAs, and hence improves the reproducibility between the two microarray platforms. Meaningful results are obtained by the proposed intrasample normalization method, together with quantile normalization as a subsequent complemental intersample normalization method.AVAILABILITY:Datasets and R package are available at http://gauss.usouthal.edu/publ/beadsme/.