tbuckley/cabot-search huggingface dataset:
Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets
Authors: Elin Hall, Petr Volkov, Tasnim Dayeh, Jonathan Lou S Esguerra, Sofia Salö, Lena Eliasson, Tina Rönn, Karl Bacos, Charlotte Ling
Journal: Genome biology (2014)

Epigenetic factors regulate tissue-specific expression and X-chromosome inactivation. Previous studies have identified epigenetic differences between sexes in some human tissues. However, it is unclear whether epigenetic modifications contribute to sex-specific differences in insulin secretion and metabolism. Here, we investigate the impact of sex on the genome-wide DNA methylation pattern in human pancreatic islets from 53 males and 34 females, and relate the methylome to changes in expression and insulin secretion.Glucose-stimulated insulin secretion is higher in female versus male islets. Genome-wide DNA methylation data in human islets clusters based on sex. While the chromosome-wide DNA methylation level on the X-chromosome is higher in female versus male islets, the autosomes do not display a global methylation difference between sexes. Methylation of 8,140 individual X-chromosome sites and 470 autosomal sites shows sex-specific differences in human islets. These include sites in/near AR, DUSP9, HNF4A, BCL11A and CDKN2B. 61 X-chromosome genes and 18 autosomal genes display sex-specific differences in both DNA methylation and expression. These include NKAP, SPESP1 and APLN, which exhibited lower expression in females. Functional analyses demonstrate that methylation of NKAP and SPESP1 promoters in vitro suppresses their transcriptional activity. Silencing of Nkap or Apln in clonal beta-cells results in increased insulin secretion. Differential methylation between sexes is associated with altered levels of microRNAs miR-660 and miR-532 and related target genes.Chromosome-wide and gene-specific sex differences in DNA methylation associate with altered expression and insulin secretion in human islets. Our data demonstrate that epigenetics contribute to sex-specific metabolic phenotypes.
Cancer-Derived Mutations in KEAP1 Impair NRF2 Degradation but not Ubiquitination
Authors: Bridgid E. Hast, Erica W. Cloer, Dennis Goldfarb, Heng Li, Priscila F. Siesser, Feng Yan, Vonn Walter, Ning Zheng, D. Neil Hayes, Michael B. Major
Journal: Cancer Research (2013)

Abstract NRF2 is a transcription factor that mediates stress responses. Oncogenic mutations in NRF2 localize to one of its two binding interfaces with KEAP1, an E3 ubiquitin ligase that promotes proteasome-dependent degradation of NRF2. Somatic mutations in KEAP1 occur commonly in human cancer, where KEAP1 may function as a tumor suppressor. These mutations distribute throughout the KEAP1 protein but little is known about their functional impact. In this study, we characterized 18 KEAP1 mutations defined in a lung squamous cell carcinoma tumor set. Four mutations behaved as wild-type KEAP1, thus are likely passenger events. R554Q, W544C, N469fs, P318fs, and G333C mutations attenuated binding and suppression of NRF2 activity. The remaining mutations exhibited hypomorphic suppression of NRF2, binding both NRF2 and CUL3. Proteomic analysis revealed that the R320Q, R470C, G423V, D422N, G186R, S243C, and V155F mutations augmented the binding of KEAP1 and NRF2. Intriguingly, these “super-binder” mutants exhibited reduced degradation of NRF2. Cell-based and in vitro biochemical analyses demonstrated that despite its inability to suppress NRF2 activity, the R320Q “superbinder” mutant maintained the ability to ubiquitinate NRF2. These data strengthen the genetic interactions between KEAP1 and NRF2 in cancer and provide new insight into KEAP1 mechanics. Cancer Res; 74(3); 808–17. ©2013 AACR.
Proteomic Characterization of Breast Cancer Xenografts Identifies Early and Late Bevacizumab-Induced Responses and Predicts Effective Drug Combinations
Authors: Evita M. Lindholm, Marit Krohn, Sergio Iadevaia, Alexandr Kristian, Gordon B. Mills, Gunhild M. Mælandsmo, Olav Engebraaten
Journal: Clinical Cancer Research (2013)

Neoangiogenesis is an important feature in tumor growth and progression, and combining chemotherapy and antiangiogenic drugs have shown clinical efficacy. However, as treatment-induced resistance often develops, our goal was to identify pathways indicating response and/or evolving resistance to treatment and inhibit these pathways to optimize the treatment strategies.To identify markers of response and/or resistance, reverse-phase protein array (RPPA) was used to characterize treatment-induced changes in a bevacizumab-responsive and a nonresponsive human breast cancer xenograft. Results were combined with bioinformatic modeling to predict druggable targets for optimization of the treatment.RPPA analysis showed that both tumor models responded to bevacizumab with an early (day 3) upregulation of growth factor receptors and downstream signaling pathways, with persistent mTOR signaling until the end of the in vivo experiment. Adding doxorubicin to bevacizumab showed significant and superior growth inhibition of basal-like tumors, whereas no additive effect was seen in the luminal-like model. The combination treatment corresponded to a continuous late attenuation of mTOR signaling in the basal-like model, whereas the inhibition was temporary in the luminal-like model. Integrating the bevacizumab-induced dynamic changes in protein levels with bioinformatic modeling predicted inhibition of phosphoinositide 3-kinase (PI3K) pathway to increase the efficacy of bevacizumab monotherapy. In vivo experiments combining bevacizumab and the PI3K/mTOR inhibitor BEZ235 confirmed their significant and additive growth-inhibitory effect in the basal-like model.Treatment with bevacizumab caused compensatory upregulation of several signaling pathways. Targeting such pathways increased the efficacy of antiangiogenic therapy.
Lifelong farm exposure may strongly reduce the risk of asthma in adults
Authors: J. Douwes, N. Travier, K. Huang, S. Cheng, J. McKenzie, G. Le Gros, E. Von Mutius, N. Pearce
Journal: Allergy (2007)

Farm exposures may protect against childhood asthma, hay fever and eczema. Whether farm exposures also confer protection in adult farmers remains unclear. Moreover, little is known about the role of timing of exposure. We assessed the effects of current and childhood farm exposures on asthma, hay fever and eczema in farmers and a rural nonfarming control population.We conducted a cross-sectional questionnaire survey in 2509 farming families (response rate 78%) and 1001 nonfarming families (response rate 67%), which included 4288 farmers and 1328 nonfarmers.Farmers were less likely to have asthma symptoms, hay fever and eczema; no significant differences were observed among dairy, sheep and beef, and horticulture farmers. A combination of current and childhood exposure was more strongly associated with shortness of breath (OR 0.50, CL 0.39-0.66), wheeze (OR 0.60, CL 0.49-0.73), asthma medication (OR 0.48, CL 0.37-0.63); and asthma ever (OR 0.56, CL 0.46-0.68) than current exposure alone (OR 0.63, CL 0.47-0.84; OR 0.80, CL 0.65-0.99; OR 0.68, CL 0.51-0.9; OR 0.69, CL 0.56-0.85 respectively) or childhood exposure alone (OR 0.97, CL0.65-1.44; OR 1.01, CL 0.75-1.34; OR 0.78, CL 0.51-1.19; OR 0.87, CL 0.63-1.19 respectively). Moreover, the combined number of years of farm exposure in childhood and adulthood showed a dose-dependent inverse association with symptom prevalence.Although both current and childhood farm exposures may play a role in the observed low prevalence of asthma symptoms in adult farmers, continued long-term exposure may be required to maintain optimal protection.
Update on Cardiovascular Implantable Electronic Device Infections and Their Management
Authors: Larry M. Baddour, Andrew E. Epstein, Christopher C. Erickson, Bradley P. Knight, Matthew E. Levison, Peter B. Lockhart, Frederick A. Masoudi, Eric J. Okum, Walter R. Wilson, Lee B. Beerman, Ann F. Bolger, N.A. Mark Estes, Michael Gewitz, Jane W. Newburger, Eleanor B. Schron, Kathryn A. Taubert
Journal: Circulation (2010)

Despite improvements in cardiovascular implantable electronic device (CIED) design, application of timely infection control practices, and administration of antibiotic prophylaxis at the time of device placement, CIED infections continue to occur and can be life-threatening. This has prompted the study of all aspects of CIED infections. Recognizing the recent advances in our understanding of the epidemiology, risk factors, microbiology, management, and prevention of CIED infections, the American Heart Association commissioned this scientific statement to educate clinicians about CIED infections, provide explicit recommendations for the care of patients with suspected or established CIED infections, and highlight areas of needed research.
How Do Annuloplasty Rings Affect Mitral Annular Strains in the Normal Beating Ovine Heart?
Authors: Wolfgang Bothe, Manuel K. Rausch, John-Peder Escobar Kvitting, Dominique K. Echtner, Mario Walther, Neil B. Ingels, Ellen Kuhl, D. Craig Miller
Journal: Circulation (2012)

We hypothesized that annuloplasty ring implantation alters mitral annular strains in a normal beating ovine heart preparation.Sheep had 16 radiopaque markers sewn equally spaced around the mitral annulus. Edwards Cosgrove partial flexible band (COS; n=12), St Jude complete rigid saddle-shaped annuloplasty ring (RSA; n=10), Carpentier-Edwards Physio (PHY; n=11), Edwards IMR ETlogix (ETL; n=11), and GeoForm (GEO; n=12) annuloplasty rings were implanted in a releasable fashion. Four-dimensional marker coordinates were obtained using biplane videofluoroscopy with the ring inserted (ring) and after ring release (control). From marker coordinates, a functional spatio-temporal representation of each annulus was generated through a best fit using 16 piecewise cubic Hermitian splines. Absolute total mitral annular ring strains were calculated from the relative change in length of the tangent vector to the annular curve as strains occurring from control to ring state at end-systole. In addition, average Green-Lagrange strains occurring from control to ring state at end-systole along the annulus were calculated. Absolute total mitral annular ring strains were smallest for COS and greatest for ETL. Strains for RSA, PHY, and GEO were similar. Except for COS in the septal mitral annular segment, all rings induced compressive strains along the entire annulus, with greatest values occurring at the lateral mitral annular segment.In healthy, beating ovine hearts, annuloplasty rings (COS, RSA, PHY, ETL, and GEO) induce compressive strains that are predominate in the lateral annular region, smallest for flexible partial bands (COS) and greatest for an asymmetrical rigid ring type with intrinsic septal-lateral downsizing (ETL). However, the ring type with the most drastic intrinsic septal-lateral downsizing (GEO) introduced strains similar to physiologically shaped rings (RSA and PHY), indicating that ring effects on annular strain profiles cannot be estimated from the degree of septal-lateral downsizing.
Phase 3 Trial of Flutemetamol Labeled With Radioactive Fluorine 18 Imaging and Neuritic Plaque Density
Authors: Craig Curtis, Jose E. Gamez, Upinder Singh, Carl H. Sadowsky, Teresa Villena, Marwan N. Sabbagh, Thomas G. Beach, Ranjan Duara, Adam S. Fleisher, Kirk A. Frey, Zuzana Walker, Arvinder Hunjan, Clive Holmes, Yavir M. Escovar, Carla X. Vera, Marc E. Agronin, Joel Ross, Andrea Bozoki, Mary Akinola, Jiong Shi, Rik Vandenberghe, Milos D. Ikonomovic, Paul F. Sherwin, Igor D. Grachev, Gillian Farrar, Adrian P. L. Smith, Christopher J. Buckley, Richard McLain, Stephen Salloway
Journal: JAMA Neurology (2015)

In vivo imaging of brain β-amyloid, a hallmark of Alzheimer disease, may assist in the clinical assessment of suspected Alzheimer disease. To determine the sensitivity and specificity of positron emission tomography imaging with flutemetamol injection labeled with radioactive fluorine 18 to detect β-amyloid in the brain using neuropathologically determined neuritic plaque levels as the standard of truth. Open-label multicenter imaging study that took place at dementia clinics, memory centers, and hospice centers in the United States and England from June 22, 2010, to November 23, 2011. Participants included terminally ill patients who were 55 years or older with a life expectancy of less than 1 year. Flutemetamol injection labeled with radioactive fluorine 18 (Vizamyl; GE Healthcare) administration followed by positron emission tomography imaging and subsequent brain donation. Sensitivity and specificity of flutemetamol injection labeled with radioactive fluorine 18 positron emission tomography imaging for brain β-amyloid. Images were reviewed without and with computed tomography scans and classified as positive or negative for β-amyloid by 5 readers who were blind to patient information. In patients who died, neuropathologically determined neuritic plaque levels were used to confirm scan interpretations and determine sensitivity and specificity. Of 176 patients with evaluable images, 68 patients (38%) died during the study, were autopsied, and had neuritic plaque levels determined; 25 brains (37%) were β-amyloid negative; and 43 brains (63%) were β-amyloid positive. Imaging was performed a mean of 3.5 months (range, 0 to 13 months) before death. Sensitivity without computed tomography was 81% to 93% (median, 88%). Median specificity was 88%, with 4 of 5 of the readers having specificity greater than 80%. When scans were interpreted with computed tomography images, sensitivity and specificity improved for most readers but the differences were not significant. The area under the receiver operating curve was 0.90. There were no clinically meaningful findings in safety parameters. This study showed that flutemetamol injection labeled with radioactive fluorine 18 was safe and had high sensitivity and specificity in an end-of-life population. In vivo detection of brain β-amyloid plaque density may increase diagnostic accuracy in cognitively impaired patients.
Cetuximab with Irinotecan or Oxaliplatin for 1St-Line Metastatic Colorectal Cancer: Updated Data of Effectiveness in the Erebus Cohort Compared to Pivotal Trials
Authors: Smith Denis, Rouyer Magali, François Eric, Mitry Emmanuel, Monnereau Alain, Sa-cunha Antonio, Bignon Emmanuelle, Balestra Aurélie, Jové Jérémy, Noize Pernelle, Moore Nicholas, Annie Fourrier-Reglat
Journal: Annals of Oncology (2014)
Investigating music tempo as a feedback mechanism for closed-loop BCI control
Authors: Ian Daly, Duncan Williams, Faustina Hwang, Alexis Kirke, Asad Malik, Etienne Roesch, James Weaver, Eduardo Miranda, Slawomir J. Nasuto
Journal: Brain-Computer Interfaces (2014)

The feedback mechanism used in a brain-computer interface (BCI) forms an integral part of the closed-loop learning process required for successful operation of a BCI. However, ultimate success of the BCI may be dependent upon the modality of the feedback used. This study explores the use of music tempo as a feedback mechanism in BCI and compares it to the more commonly used visual feedback mechanism. Three different feedback modalities are compared for a kinaesthetic motor imagery BCI: visual, auditory via music tempo, and a combined visual and auditory feedback modality. Visual feedback is provided via the position, on the y-axis, of a moving ball. In the music feedback condition, the tempo of a piece of continuously generated music is dynamically adjusted via a novel music-generation method. All the feedback mechanisms allowed users to learn to control the BCI. However, users were not able to maintain as stable control with the music tempo feedback condition as they could in the visual feedback and combined conditions. Additionally, the combined condition exhibited significantly less inter-user variability, suggesting that multi-modal feedback may lead to more robust results. Finally, common spatial patterns are used to identify participant-specific spatial filters for each of the feedback modalities. The mean optimal spatial filter obtained for the music feedback condition is observed to be more diffuse and weaker than the mean spatial filters obtained for the visual and combined feedback conditions.
Molecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction
Authors: Abdulrahman K. Doughan, David G. Harrison, Sergey I. Dikalov
Journal: Circulation Research (2007)

Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO · ) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO · was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography –based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H 2 O 2 production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor), N G -nitro- l -arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22 phox subunit of NADPH oxidase with small interfering RNA also inhibited Ang II–mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II–induced decrease in endothelial NO · and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C–dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO · and generation, which in turn has ramifications for development of endothelial dysfunction.
A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: implications for antiviral therapy
Authors: M-F Yuen
Journal: Gut (2003)

<b>Background and aim:</b> Clinical data on spontaneous hepatitis B e antigen (HBeAg) seroconversion and acute exacerbation of chronic hepatitis B (CHB) virus infection from large population studies are lacking. In the present study we examined the clinical features and significance of HBeAg seroconversion and acute exacerbation in 3063 Chinese CHB patients. <b>Methods:</b> Clinical assessment, liver biochemistry, hepatitis B virus (HBV) serology and HBV DNA, time of HBeAg seroconversion, and acute exacerbation were monitored. <b>Results:</b> Median age at HBeAg seroconversion was 34.5 years. The cumulative HBeAg seroconversion rate significantly increased with alanine aminotransferase (ALT) levels on presentation (p&lt;0.0001). For patients with ALT levels more than twice the upper limit of normal (ULN) on presentation, the HBeAg seroconversion rate at the fifth year of follow up was 72.4%. After HBeAg seroconversion, 65.2% (73/110) of patients had undetectable HBV DNA levels by the Digene Hybrid Capture assay. Of these, 78.1% still had HBV DNA levels detectable by the Amplicor HBV Monitor Test. We found that 37.5% antibody to HBeAg (anti-HBe) positive patients had undetectable HBV DNA levels by the Digene Hybrid Capture assay before acute exacerbation. Acute exacerbations of longer duration, with higher peak ALT, bilirubin, and α fetoprotein levels were associated with an increased HBeAg seroconversion rate (p&lt;0.0001–0.045). Acute exacerbation with peak ALT levels more than five times the ULN carried a 46.4% chance of HBeAg seroconversion within three months. HBeAg sero<i>re</i>version and mortality occurred in 2.7% and 0.7% of acute exacerbations, respectively. <b>Conclusion:</b> In the present study we have provided information on HBeAg seroconversion and acute exacerbation, which are important in decision making for CHB treatment and in designing clinical trials.
Measurement of pedal pressures. An illustration of a method.
Authors: W J Collis, M I Jayson
Journal: Annals of the Rheumatic Diseases (1972)

Although the feet are submitted to constant use, studies of the forces acting during walking have been limited.In this paper we present a technique for measuring the pressures under the different parts of the foot and describe the pressure pattern for normal feet and some of the changes that occur in rheumatoid disease. MethodThe pressures under the various parts of the foot were serially recorded by means of a thin transducer.This specially constructed transducer measured 11 by 12 mm.and was 2 mm.thick.It contained a silicon semiconductor strain gauge (Ether Electronics) mounted on Araldite between two plates of beryllium-copper.The remaining cavity was filled with silicone rubber.The strain gauge was distorted by any deflection of the front surface of the transducer and therefore in proportion to any applied pressure.The device formed one arm of a Wheatstone bridge, and the output from the bridge was amplified and recorded.Calibration using known pressures showed that, over the required range, a linear relationship existed be- tween the applied pressure and the deflection of the recorder trace.By careful palpation, the metatarsal heads were identified and the transducer applied and fixed in position with thin adhesive tape.Similarly the device was applied to the heel.The subject walked barefoot in a straight line and recordings were made over many paces.The maximum pressure developed at each site during walking was estimated from the mean of twenty successive paces.Indeed there was increased pressure over the fifth MT-P head associated with subluxation of this joint.
Exposure of Melanoma Cells to Dacarbazine Results in Enhanced Tumor Growth and Metastasis In Vivo
Authors: Dina Chelouche Lev, Amir Onn, Vladislava O. Melinkova, Claudia Miller, Valerie Stone, Maribelis Ruiz, Eric C. McGary, Honnavara N. Ananthaswamy, Janet E. Price, Menashe Bar-Eli
Journal: Journal of Clinical Oncology (2004)

In recent years, the incidence of cutaneous melanoma has increased more than that of any other cancer. Dacarbazine is considered the gold standard for treatment, having a response rate of 15% to 20%, but most responses are not sustained. Previously, we have shown that short exposure of primary cutaneous melanoma cells to dacarbazine resulted in the upregulation of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The purpose of the present study was to determine how long-term exposure of melanoma cells to dacarbazine would affect their tumorigenic and metastatic potential in vivo.The primary cutaneous melanoma cell lines SB2 and MeWo were repeatedly exposed in vitro to increasing concentrations of dacarbazine, and dacarbazine-resistant cell lines SB2-D and MeWo-D were selected and examined for their ability to grow and metastasize in nude mice.The dacarbazine-resistant cell lines SB2-D and MeWo-D exhibited increased tumor growth and metastatic behavior in vivo. This increase could be explained by the activation of RAF, MEK, and ERK, which led to the upregulation of IL-8 and VEGF. More IL-8, VEGF, matrix metalloproteinase-2 (MMP-2), and microvessel density (CD-31) were found in tumors produced by SB2-D and MeWo-D in vivo than in those produced by their parental counterparts. No mutations were observed in BRAF.Our results have significant clinical implications. Treatment of melanoma patients with dacarbazine could select for a more aggressive melanoma phenotype. We propose that combination treatment with anti-VEGF/IL-8 or MEK inhibitors may potentiate the therapeutic effects of dacarbazine.