tbuckley/cabot-search huggingface dataset:
OC-053 Can<i>Helicobacter pylori</i>lipopolysaccharide lipid a composition affect its ability to induce an inflammatory response through Toll-like receptor 4: Abstract OC-053
Authors: M P FitzGerald, S Wehmeier, M Gangloff, N Gay, S H Berry, G P Ferguson, E M El-Omar, G L Hold
Journal: Gut (2010)

<h3>Introduction</h3> <i>H pylori</i> recognition by the host is poorly understood, although there is evidence that lipid A recognition occurs via Toll-like receptor 4. <i>H pylori</i> produces two lipid A species, a minor <i>E coli</i>-like hexa-acylated species and a major tetra-acylated species. The latter is thought to be important for immune evasion, with many laboratory strains thought to lack the minor more immunogenic species which is present in clinical strains. <h3>Aim</h3> To assess whether changes in lipid A alter <i>H pylori9s</i> ability to induce an inflammatory response. <h3>Methods</h3> <i>H pylori</i> strains were repeatedly subcultured on blood agar and structural changes in the lipopolysaccharide were analysed using Deoxycholate Polyacrylamide Gel Electrophoresis (DOC-PAGE) and Gas Chromatography Mass Spectrometry (GC-MS). Additional ultracentrifugation removed contaminating lipoproteins and capsular polysaccharides. A monocyte/LPS challenge system was used to assess pro-inflammatory cytokine production by the different <i>H pylori</i> LPS preparations. Prediction of the orientations adopted by <i>H pylori</i> LPS structures within TLR4 receptor complex interactions were generated using the automated docking program AutoDock v4. <h3>Results</h3> <i>H pylori</i> LPS was not altered by subculturing, although purified laboratory and clinical strains were shown to have compositional differences. Fatty acids of carbon length 14 and 16 (indicative of hexa-acylated lipid A) were absent from laboratory strain <i>H pylori</i> lipid A following purification, but remained in the lipid A purified from clinical strains. Unpurified laboratory strain LPS induced greatest levels of cytokine production in monocyte/LPS challenge experiments followed by purified clinical strain LPS, with purified laboratory strain LPS inducing the lowest levels (Abstract 053). Modelling analysis confirmed that the tetra-acylated species was less effective than the hexa-acylated species at interacting with the TLR4 signalling complex. <h3>Conclusion</h3> Purification of <i>H pylori</i> LPS had a dramatic effect on inflammatory cytokine production indicating that contaminating lipoprotein and or capsular polysaccharide can impact the immune response. However, LPS derived from clinical isolates is significantly more immunogenic than laboratory strains. This further strengthens the evidence that TLR4-mediated immune responses are important in <i>H pylori</i> infections.
Rituximab Plus Hypercvad (R-HCVAD) Alternating with Rituximab Plus High-Dose Methotrexate-Cytarabine (R-M/A) in Untreated Mantle Cell Lymphoma (MCL): Prolonged Follow-Up Confirms High Rates of Failure-Free Survival (FFS) and Overall Survival (OS).
Authors: Jorge Enrique Romaguera, Luis Fayad, Maria A. Rodriguez, Fredrick B. Hagemeister, Barbara Pro, Peter McLaughlin, Anas Younes, Felipe Samaniego, Andre Goy, Andreas H. Sarris, Nam H. Dang, L. Jeffrey Medeiros, Ruth Katz, Harish Gagneja, Barry I. Samuels, Fernando Cabanillas
Journal: Blood (2004)
Pulmonary valve incompetence: II. Application of electromagnetic flow velocity catheters in children
Authors: J. ROHMER, F. V. D. MARK, W. G. ZIJLSTRA
Journal: Cardiovascular Research (1976)

During cardiac catheterization in 49 children regurgitant flow through competent and incompetent pulmonary valves was evaluated with electromagnetic flow velocity catheters using the ratio of the separately integrated backward and forward flow velocity signals (vb/vf). When the pulmonary valve was normal, vb/vf was less than or equal to 0.10. After operation for pulmonary valve stenosis or tetralogy of Fallot larger values were often found. In patients with an outflow patch across the pulmonary valve ring vb/vf values of up to 0.54 were found.
Reducing Risk of Dementia in Older Age
Authors: Behnam Sabayan, Farzaneh Sorond
Journal: JAMA (2017)

There is no cure for dementia (including Alzheimer disease), but there may be ways to lower the chance of developing it.

Dementia is a disease that is more common in older people. Alzheimer disease is the most common form of dementia and affects more than 5 million people in the United States. Alzheimer disease starts with memory loss, language problems, and difficulty with logical thinking. For now, there is no curative treatment for patients with Alzheimer disease. However, studies suggest that individuals may be able to lower their chances of developing it. Recent reports show that the number of people with new dementia diagnoses is decreasing in the United States. There are currently 3 main areas of focus in prevention of dementia: lifestyle habits, medical conditions, and mental and social well-being.
Selective killing of tumor cells by RNAi-Silencing of BORIS
Authors: Christopher Dougherty, Thomas Ichim, Greg Maguire, Grigor Mamikonyan, Aramayis Kocharyan, Anahit Ghochikyan, Michael Agadjanyan, Boris Reznik
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2700 

Background: Brother of the Regulator of Imprinted Sites (BORIS) is an epigenetically acting transcription factor that displaces the tumor suppressor protein CTCF in cancer cells resulting in upregulation of numerous proteins associated with oncogenesis. Previous studies have demonstrated vaccination against BORIS results in the generation of cytolytic immune responses against histologically-diverse tumors. In this study, RNAi induction was assessed as an alternative approach to induction of selective tumor cell killing.    Materials and Methods: Short interfering RNA nucleotides targeting either specific zinc finger or non-zinc finger portions of BORIS, as well as scrambled control siRNA, were generated and administered to non-malignant epithelial and endothelial cells, and to several tumor cell lines representing breast cancer, glioma, and hepatoma. BORIS expression, and silencing thereof, was assessed by Western Blot analysis. TUNEL, MTT and Caspase 3/7 assays were performed to ascertain the effects of the siRNAs on proliferation and apoptosis of non-malignant and cancer cells.    Results: BORIS expression was found in all cancer cell lines tested, but not control non-malignant cells, with highest expression in the MDA-231 breast cancer cell line. Treatment with 1.7nM of BORIS-specific siRNA, but not scrambled control siRNA, led to a significant reduction in BORIS expression and a profound induction of cell death in MDA-231 cells. Cell death was concentration dependent and peaked between 48 to 72 hours post treatment. Apoptosis was confirmed as the mechanism of cell death by TUNEL staining and Caspase 3/7 activation.    Conclusion: This is the first unequivocal validation that the BORIS transcription factor represents an important target in the development of cancer therapeutics.
<i>Circulation: Cardiovascular Genetics</i> 2013 Editors’ Picks
Journal: Circulation (2014)

Hypertrophic cardiomyopathy (HCM) is characterized by excessive thickening and enlargement of the heart muscle, causing heart failure, syncope, and death.HCM is caused by rare mutations that change the peptide sequence of proteins in the cardiac sarcomere.We asked whether genetic polymorphisms common in the general population might also be found more frequently in HCM as has been recently shown for dilated cardiomyopathy.To address this question, we performed a case-control genomewide association study in the Tufts HCM cohort, and we validated our findings in the Mayo Clinic HCM cohort.These studies identified a peptide-altering variant in the FHOD3 gene associated with HCM.Although HCM patients were more likely to carry the FHOD3 polymorphism, carriers had similar HCM phenotypes as noncarriers.We found that the FHOD3 protein is expressed in the heart, and its expression was increased in the setting of HCM.To answer whether this family of genes is important in muscle function, as might be expected of a gene associated with HCM, we studied the fruit fly whose homolog of FHOD3 is called fhos.Genetic knockdown of the fhos transcript specifically in the fly heart caused a decrease in heart contractile function.In summary, these studies have identified a new gene associated with HCM that is common in the general population and likely required for normal heart contractile function.Future studies will define the role of FHOD3 in cardiac function and cardiomyopathy.Conclusions-Here we demonstrate the association of a common nonsynonymous FHOD3 genetic variant with HCM.This discovery further strengthens the potential role of gene mutations and polymorphisms that alter the amino acid sequence of sarcomere proteins and HCM. 1
Taxanes can enhance immunotherapy of cancer - importance of timing
Authors: Birgit Schultes, Fuxiang Hou, Graham Daley, Lin Wang, L. Smith, Christopher Nicodemus
Journal: Cancer Research (2008)

2068  The taxanes, paclitaxel and docetaxel are widely used in the treatment of ovarian, breast and prostate cancer. Immunotherapy of cancer is extensively being studied with limited success in patients with large disease burden. As taxanes reduce tumor burden and potentially also the associated immune suppressive pathways, combination taxane-immunotherapy is intriguing. However, more insight into the immune suppressive effects of taxanes and the optimum timing of co-administration is needed. The present study evaluated the feasibility and scheduling of taxane-based chemo-immunotherapy with the immune modulating antibodies MAb-B43.13 (anti-CA125, oregovomab) and AR47.47 (anti-PSA). Upon injection, the MAbs form immune complexes with their respective circulating antigens, leading to enhanced processing and T cell activation. To assess the effects of taxanes on immune cells and antigen processing, two parallel approaches were conducted: a) an in vitro co-culture system of immature DC, tumor and T cells; and b) a time course study of docetaxel (15 mg/kg) in CT26 tumor bearing mice. In vitro, paclitaxel and docetaxel did not affect T cell or DC survival at concentrations ≤ 25 µg/mL. Interestingly, both taxanes enhanced maturation of DC (increased CD86 and CD83 expression), decreased the percentage of FoxP3+CD4+CD25+ T reg cells and enhanced T cell proliferation to non-specific stimuli (anti-CD3/CD28) as well as to the co-cultured tumor cells. The in vivo time course study confirmed minor effects of docetaxel on T and B cell survival. DC migration to the tumor, including about 30% expressing CD83 and CD80, increased by Day 7-10 compared to non-treated tumor-bearing control mice. Further, the taxane significantly reduced T regs and myeloid derived suppressor cells (MDSC) in the draining LN, tumor, PBMC and spleen (Day 3-5); however, reduction was transient with recovery to baseline levels noted by Day 10. The reduction in T reg and MDSC correlated with a sharp increase in T and B cell responsiveness at Day 3-5. Further, we observed a more than 3-fold increase in T cell infiltrate to the tumor at Day 5-7 and in B cell infiltrate at Day 3. A Phase II combination chemo-immunotherapy study of oregovomab with front-line paclitaxel/carboplatin in stage III/IV ovarian cancer patients revealed that the immune response to oregovomab was not abrogated by concurrent administration of chemotherapy but in fact had an immune-adjuvant effect on both humoral and cellular responses. The data favored a simultaneous over a 1-week delayed administration schedule with regard to immune induction and possibly clinical outcome. The immune modulating effects of taxanes appear to synergize with immunotherapy, particularly as reduction in T reg and MDSC paired with recruitment of T cells and mature DC to the tumor could render immunotherapy-induced T cells more effective within the tumor microenvironment.
The effects of non-invasive radiofrequency electric field hyperthermia on biotransport and biodistribution of fluorescent [60]fullerene derivative in a murine orthotopic model of breast adenocarcinoma
Authors: Norman A. Lapin, Martyna Krzykawska-Serda, Sean Dilliard, Yuri Mackeyev, Maciej Serda, Lon J. Wilson, Steven A. Curley, Stuart J. Corr
Journal: Journal of Controlled Release (2017)
Abstract P342: Mitochondria-Targeted Antioxidant Therapy Prevents Angiotensin II--Mediated Connexin43 Remodeling and Sudden Arrhythmic Death
Authors: Ali A Sovari, Shadi Zandieh, Shahriar Iravanian, Lianzhi Gu, Euy-Myong Jeong, Marcelo G Bonini, Samuel C Dudley
Journal: Circulation Research (2011)

Introduction: Angiotensin II activation and associated elevation in ROS have been implicated in pathogenesis of arrhythmia. Nevertheless commonly used antioxidants have been ineffective in clinical trials. We created a transgenic mouse model of cardiac restricted overexpression of ACE (ACE8/8). These mice show spontaneous VT/ VF, SCD, and a reduction in Cx43 level, which impairs conduction and predisposes to arrhythmia. We sought to determine the role and the major source of ROS by angiotensin II in VT/ VF and Cx43 remodeling. Method: Wild type and ACE8/8 mice with and without 2 weeks of treatment with a NOS inhibitor (L-NIO, 25mg/Kg IP injections daily), a mitochondria-targeted antioxidant (Mito-TEMPO, 0.7mg/Kg IP injections daily), a NADPH oxidase inhibitor (Apocynin 80mg/L in drinking water), and ACE8/8 crossed with P67DN were studied. Western blotting (with derivatization to dinitrophenylhydrozone to detect oxidized protein levels), detection of superoxide production in mitochondria by red mitochondrial superoxide indicator and immunohistochemistry staining for Cx43 were performed. EP study was performed by a 1.1F octapolar catheter through pacing the right ventricle using a burst pacing protocol. Results: Proteins were more oxidized (increased protein-carbonyl detection), and Cx43 was reduced in ACE8/8 to 33% of control. Treatment with Mito-TEMPO prevented SCD and improved survival in ACE8/8 mice (p=0.0005, hazard ratio 4.76 with 95% CI of 1.96 to 11.53). Inducibility of VT/VF was higher in ACE8/8 mice compare to WT (87.5% vs. 2.3%) and VT inducibility was reduced with Mito-TEMPO treatment (50% in treatment group). Cx43 level was increased by 1.7 fold with Mito-TEMPO treatment. Treatments with L-NIO, Apocynin and crossing with P67DN mice did not prevent VT/VF and SCD in ACE8/8 mice. Conclusion: In a model of angiotensin II activation mitochondria-targeted antioxidant, prevents VT/VF/SCD and Cx43 remodeling. Suppression of NADPH oxidase activity by Apocynin and crossing the ACE8/8 mice with P67DN or inhibition of NOS by L-NIO did not prevent the arrhythmic deaths in ACE8/8 mice. This result suggests that mitochondria are the major source of ROS by angiotensin II and mitochondria-targeted antioxidants may be effective antiarrhythmic drugs.
Social nature of eating could explain missing link between food insecurity and childhood obesity
Authors: Jutta Mata, Mattea Dallacker, Ralph Hertwig
Journal: Behavioral and Brain Sciences (2017)

Abstract We suggest that social factors are key to explain the missing link between food insecurity and obesity in children. Parents and public institutions are children's nutritional gatekeepers. They protect children from food insecurity by trimming down their consumption or by institutional support. To gauge children's food insecurity, evaluations across the different nutritional gatekeepers need to be integrated.
Comparison of three longitudinal analysis models for the health-related quality of life in oncology: A simulation study.
Authors: Amelie Anota, Antoine Barbieri, Marion Savina, Alhousseiny Pam, Marc Ychou, Sophie Gourgou, Franck Bonnetain, Caroline Mollevi
Journal: Journal of Clinical Oncology (2014)

e17639 Background: Most clinical trials now integrate Health-related Quality of Life (HRQoL) as one of the major endpoints to investigate the clinical benefit of new therapeutic strategies for the patient and the health system. However, longitudinal analysis of HRQoL remains complex and unstandardized. Moreover, it is necessary to propose accessible statistical methods and meaningful results for the clinician. The objective was to compare three strategies of longitudinal analyses for HRQoL data in oncology clinical trials through a simulation study. Methods: The methods proposed were the score and mixed model (SM), the longitudinal partial credit model (LPCM) and survival analysis approach based on the time to HRQoL score deterioration (TTD). Simulations compared the methods regarding the type I error and statistical power of the test of an interaction effect between treatment arm and time. Longitudinal HRQoL data were performed using a LPCM considering that the latent trait (HRQoL) follows a multivariate normal distribution with a first-order autoregressive covariance matrix. Several scenarios of simulations were explored based on the EORTC HRQoL questionnaires and varying the number of patients (100, 200 or 300), items (1, 2 or 4) and response category per item (4 or 7). Five or 10 measurement times were considered with a low to high correlation between each measure. The impact of informative missing data on these methods was also studied to reflect most of clinical trials. Results: With complete data, type I error rate were closed to the expected value (5%) for all methods and SM method was the most powerful method. The power of the TTD is low for uni-item dimension because only four possible values exist for the score. When the number of items increases, the power of TTD method increases while the power of LPCM and SM remains stable. For 10 measurement times, the LPCM is less efficient. With informative missing data, the results for SM and LPCM are similar whereas the power of TTD method increases. Conclusions: To conclude, SM method is as efficient as LPCM. Moreover, the TTD approach, which began to be used extensively in HRQoL data analysis, could be optimal for phase III clinical trials with a multi-item scale.
Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression after Myocardial Infarction
Journal: New England Journal of Medicine (1989)

The occurrence of ventricular premature depolarizations in survivors of myocardial infarction is a risk factor for subsequent sudden death, but whether antiarrhythmic therapy reduces the risk is not known. The Cardiac Arrhythmia Suppression Trial (CAST) is evaluating the effect of antiarrhythmic therapy (encainide, flecainide, or moricizine) in patients with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more ventricular premature beats per hour) after myocardial infarction. As of March 30, 1989, 2309 patients had been recruited for the initial drug-titration phase of the study: 1727 (75 percent) had initial suppression of their arrhythmia (as assessed by Holter recording) through the use of one of the three study drugs and had been randomly assigned to receive active drug or placebo. During an average of 10 months of follow-up, the patients treated with active drug had a higher rate of death from arrhythmia than the patients assigned to placebo. Encainide and flecainide accounted for the excess of deaths from arrhythmia and nonfatal cardiac arrests (33 of 730 patients taking encainide or flecainide [4.5 percent]; 9 of 725 taking placebo [1.2 percent]; relative risk, 3.6; 95 percent confidence interval, 1.7 to 8.5). They also accounted for the higher total mortality (56 of 730 [7.7 percent] and 22 of 725 [3.0 percent], respectively; relative risk, 2.5; 95 percent confidence interval, 1.6 to 4.5). Because of these results, the part of the trial involving encainide and flecainide has been discontinued. We conclude that neither encainide nor flecainide should be used in the treatment of patients with asymptomatic or minimally symptomatic ventricular arrhythmia after myocardial infarction, even though these drugs may be effective initially in suppressing ventricular arrhythmia. Whether these results apply to other patients who might be candidates for antiarrhythmic therapy is unknown.
PTH-176 Predicting histological remission in patients with coeliac disease on a gluten free diet: Abstract PTH-176 Table 1
Authors: PD Mooney, S Wong, M Kurien, M Burden, DS Sanders
Journal: Gut (2015)

<h3>Introduction</h3> Up to 30% of patients with celiac disease (CD) will have persistent symptoms despite the introduction of a gluten free diet (GFD). Assess­ment of adherence in celiac disease can involve any combination of patient self-reporting adherence, dietetic assessment, serol­ogy and biopsy with histology. Histology is considered to be the ‘gold standard’ but this requires a repeat endoscopic exam­ination with its associated risks and problems with tolerance. As a result surrogate markers of persistent gluten exposure and histological changes such as serology are frequently used but the relationship between serology and persistent histological changes is not linear. A structured interview with a dietician has been shown to be the most accurate method of assessing GFD adherence however this is time consuming and requires extra clinic visits. The aim of this study was to assess the useful­ness of two novel options. Firstly a previously internally validated scoring system for assessing GFD adherence (which has never been externally validated) and secondly a rapid deami­dated gliadin peptide based point of care test (POCT, Simtomax) for the prediction of persistent villous atrophy (VA). <h3>Method</h3> All patients with known CD and persistent symptoms coming to a specialist CD endoscopy list for the re-assessment of histology were invited to take part. All patients were tested for Endomysial Antibody (EMA), tissue transglutaminase (tTG), immunoglobulins and the POCT. They were also asked to complete a questionnaire to calculate a 5 point score (0–4) with a high score representative of improved adherence to a gluten free diet. All patients underwent gastroscopy with at least 4 biopsies from the second part of the duodenum and 1 to 2 biopsies from the bulb. <h3>Results</h3> 94 patients (77% female, mean age 52.6) were recruited between April 2013 and December 2014. Median duration of GFD was 84 months (range 6–768). 36 (38.3%) patients had persistent VA on duodenal biopsy. The POCT was the most sensitive marker with 63.4% of patients with VA having a positive test. EMA was the most specific surrogate marker at 82.8% although it was highly insensitive with only 33.0% of patients with VA having a positive EMA. The adherence score could not be reliably used to predict VA with a sensitivity of only 30.6%. <h3>Conclusion</h3> An accurate surrogate marker for VA could reduce the number of endoscopies required. In this cohort the POCT had the best sensitivity, detect­ing 23/36 (63.4%) cases of villous atrophy, however this is pilot data and further work is required. It may be that additive methods for assessing adherence could achieve 100% sensitivity. <h3>Disclosure of interest</h3> P. Mooney: None Declared, S. Wong: None Declared, M. Kurien: None Declared, M. Burden: None Declared, D. Sanders Grant/ Research Support from: Received research grants from BHR Pharmaceuticals and Tillotts Pharma for investigator led studies into coeliac disease.