tbuckley/cabot-search huggingface dataset:
PWE-159 The effect of natural polymorphism in the promoter of the<i>Helicobacter pylori</i>cytotoxin associated gene,<i>cagA</i>, on<i>cagA</i>transcriptional regulation
Authors: A A Memon, C K Marx, K Robinson, J C Atherton
Journal: Gut (2012)

<h3>Introduction</h3> <i>Helicobacter pylori</i> persistently colonises the gastric mucosa of almost half the human population. It is the main causative agent of peptic ulcer disease and an important risk factor for gastric carcinoma. One of its major virulence determinants is cytotoxin associated gene A, <i>cagA</i>, and high levels of <i>cagA</i> expression are associated with more severe disease. The functional promoter elements of <i>cagA</i> in the 436 bp <i>cagAB</i> intergenic region have been previously analysed but differences in the promoter region and levels of <i>cagA</i> expression between different <i>H pylori</i> strains have not been studied in detail. We aimed to analyse the <i>cagA</i> promoter region to determine whether naturally occurring polymorphic differences within it contribute to differences in <i>cagA</i> expression level. <h3>Methods</h3> Biopsy samples were obtained from 17 patients undergoing routine upper GI endoscopy at the Queen9s Medical Centre Nottingham, UK. RNA was extracted directly from biopsies and <i>cagA</i> expression levels were analysed by real-time qPCR. The <i>cagAB</i> intergenic region of all 17 clinical strains were sequenced and aligned using the ClustalW multiple sequence alignment program and ranked in order of <i>cagA</i> transcript levels. A potentially relevant natural mutation was then created artificially by site-directed mutagenesis to prove its importance. <h3>Results</h3> A potentially important polymorphism was identified within an imperfect inverted repeat where an A was commonly replaced by a T at position -54. Strains possessing T at this position expressed higher <i>cagA</i> mRNA levels than those with an A (p=0.016). To test whether this was a direct determinant of <i>cagA</i> transcription level, a mutation was engineered at position −54 (T to A) in high transcription strain 83. This resulted in a 30% reduction in <i>cagA</i> transcript level when compared to an isogenic control strain without the change (p=0.073). In the complementary experiment, we engineered an A to T mutation in low transcription strain 126 and this led to a 20% increase in the level of <i>cagA</i> mRNA compared to its isogenic control (p=0.002). <h3>Conclusion</h3> Presence of a T at position −54 within the inverted repeat of the <i>cagA</i> promoter region is an important natural determinant of higher levels of <i>cagA</i> transcription. We speculate that this may help explain why only some <i>cagA<sup>+</sup> H pylori</i> strains cause disease. <h3>Competing interests</h3> None declared.
Switching to Anastrozole Versus Continued Tamoxifen Treatment of Early Breast Cancer: Preliminary Results of the Italian Tamoxifen Anastrozole Trial
Authors: Francesco Boccardo, Alessandra Rubagotti, Matteo Puntoni, Pamela Guglielmini, Domenico Amoroso, Angela Fini, Giuseppe Paladini, Mario Mesiti, Domenico Romeo, Michela Rinaldini, Simona Scali, Mauro Porpiglia, Chiara Benedetto, Nunzio Restuccia, Franco Buzzi, Roberto Franchi, Bruno Massidda, Vito Distante, Dino Amadori, Piero Sismondi
Journal: Journal of Clinical Oncology (2005)

Tamoxifen, which is actually the gold standard adjuvant treatment in estrogen receptor-positive early breast cancer, is associated with an increased risk of endometrial cancer and other life-threatening events. Moreover, many women relapse during or after tamoxifen therapy because of the development of resistance. Therefore new approaches are required.We conducted a prospective randomized trial to test the efficacy of switching postmenopausal patients who were already receiving tamoxifen to the aromatase inhibitor anastrozole. After 2 to 3 years of tamoxifen treatment, patients were randomly assigned either to receive anastrozole 1 mg/d or to continue receiving tamoxifen 20 mg/d, for a total duration of treatment of 5 years. Disease-free survival was the primary end point. Event-free survival, overall survival, and safety were secondary end points.Four hundred forty-eight patients were enrolled. All women had node-positive, estrogen receptor-positive tumors. At a median follow-up time of 36 months, 45 events had been reported in the tamoxifen group compared with 17 events in the anastrozole group (P = .0002). Disease-free and local recurrence-free survival were also significantly longer in the anastrozole group (hazard ratio [HR] = 0.35; 95% CI, 0.18 to 0.68; P = .001 and HR = 0.15; 95% CI, 0.03 to 0.65; P = .003, respectively). Overall, more adverse events were recorded in the anastrozole group compared with the tamoxifen group (203 v 150, respectively; P = .04). However, more events were life threatening or required hospitalization in the tamoxifen group than in the anastrozole group (33 of 150 events v 28 of 203 events, P = .04).Switching to anastrozole after the first 2 to 3 years of treatment is well tolerated and significantly improves event-free and recurrence-free survival in postmenopausal patients with early breast cancer.
Influence of relative humidity on prolonged exercise capacity in a warm environment
Authors: P Watson, H Otani, R J Maughan
Journal: British Journal of Sports Medicine (2011)

Major sports championships are often scheduled in warm/dry and warm/humid environments, so it is important to be able to quantify the influence of these environmental extremes on work capacity. The aim of the present study was to examine the influence of relative humidity on endurance exercise performance in a warm environment. Eight male volunteers (mean ± SD age 26 ± 4 years; height 1.80 ± 0.03 m; body mass 72.0 ± 7.0 kg; VO 2 max 4.38 ± 0.65 l/min) performed four cycle exercise trials at 70% maximum oxygen uptake until volitional exhaustion in an environmental chamber maintained at 30.2 ± 0.2°C. Volunteers were tested under four relative humidity (rh) conditions: 24%, 40%, 60% and 80%. Core and weighted mean skin temperature, heart rate, skin blood flow, and cutaneous vascular conductance (CVC) were recorded at rest and at regular intervals during exercise. Mean (SD) time to exhaustion was 68 ± 19, 60 ± 17, 54 ± 17, and 46 ± 14 min at 24, 40, 60, and 80% rh, respectively (P &lt; 0.001); exercise time was significantly less at 60 (P = 0.013) and 80% (P = 0.005) rh than recorded at 24% rh. There were no differences in core temperature (P = 0.480) and heart rate (P = 0.097) between trials. Core temperature at exhaustion was 39.0 ± 0.3°C at 24, 40, and 60% rh and 39.1 ± 0.3°C at 80% rh (P = 0.159). Mean skin temperature at the point of exhaustion was higher at 80% rh than at 24% rh (P &lt; 0.001). Total sweat loss was similar between trials (P = 0.345), but sweating rate was higher at 60 and 80% rh than at 24% rh (P &lt; 0.001). The results suggest that exercise capacity at moderate intensity in a warm environment is progressively impaired as the relative humidity increases. Early fatigue in the higher humidity trials was accompanied by a faster rate of rise in core temperature and a greater weighted mean skin temperature, with no differences in heart rate, skin blood flow or the metabolic response to exercise.
Precision and Accuracy of Divergence Time Estimates from STR and SNPSTR Variation
Authors: U. Ramakrishnan
Journal: Molecular Biology and Evolution (2004)

Inference of intraspecific population divergence patterns typically requires genetic data for molecular markers with relatively high mutation rates. Microsatellites, or short tandem repeat (STR) polymorphisms, have proven informative in many such investigations. These markers are characterized, however, by high levels of homoplasy and varying mutational properties, often leading to inaccurate inference of population divergence. A SNPSTR is a genetic system that consists of an STR polymorphism closely linked (typically < 500 bp) to one or more single-nucleotide polymorphisms (SNPs). SNPSTR systems are characterized by lower levels of homoplasy than are STR loci. Divergence time estimates based on STR variation (on the derived SNP allele background) should, therefore, be more accurate and precise. We use coalescent-based simulations in the context of several models of demographic history to compare divergence time estimates based on SNPSTR haplotype frequencies and STR allele frequencies. We demonstrate that estimates of divergence time based on STR variation on the background of a derived SNP allele are more accurate (3% to 7% bias for SNPSTR versus 11% to 20% bias for STR) and more precise than STR-based estimates, conditional on a recent SNP mutation. These results hold even for models involving complex demographic scenarios with gene flow, population expansion, and population bottlenecks. Varying the timing of the mutation event generating the SNP revealed that estimates of divergence time are sensitive to SNP age, with more recent SNPs giving more accurate and precise estimates of divergence time. However, varying both mutational properties of STR loci and SNP age demonstrated that multiple independent SNPSTR systems provide less biased estimates of divergence time. Furthermore, the combination of estimates based separately on STR and SNPSTR variation provides insight into the age of the derived SNP alleles. In light of our simulations, we interpret estimates from data for human populations.
Permanent iodine 125 brachytherapy in patients with progressive or recurrent glioblastoma multiforme
Authors: David A. Larson, Jeffrey M. Suplica, Susan M. Chang, Kathleen R. Lamborn, Michael W. McDermott, Penny K. Sneed, Michael D Prados, William M. Wara, M. Kelly Nicholas, Mitchel S. Berger
Journal: Neuro-Oncology (2004)

This study reports the initial experience at the University of California San Francisco (UCSF) with tumor resection and permanent, low-activity iodine 125 (125I) brachytherapy in patients with progressive or recurrent glioblastoma multiforme (GM) and compares these results to those of similar patients treated previously at UCSF with temporary brachytherapy without tumor resection. Thirtyeight patients with progressive or recurrent GM were treated at UCSF with repeat craniotomy, tumor resection, and permanent, low-activity 125I brachytherapy between June 1997 and May 1998. Selection criteria were Karnofsky performance score ≥60, unifocal, contrast-enhancing, well-circumscribed progressive or recurrent GM that was judged to be completely resectable, and no evidence of leptomeningeal or subependymal spread. The median brachytherapy dose 5 mm exterior to the resection cavity was 300 Gy (range, 150-500 Gy). One patient was excluded from analysis. Median survival was 52 weeks from the date of brachytherapy. Age, Karnofsky performance score, and preimplant tumor volume were all statistically significant on univariate analyses. Multivariate analysis for survival showed only age to be significant. Median time to progression was 16 weeks. Both univariate and multivariate analysis of freedom from progression showed only preoperative tumor volume to be significant. Comparison to temporary brachytherapy patients showed no apparent difference in survival time. Chronic steroid requirements were low in patients with minimal postoperative residual tumor. We conclude that permanent 125I brachytherapy for recurrent or progressive GM is well tolerated. Survival time was comparable to that of a similar group of patients treated with temporary brachytherapy.
Maternally Transmitted and Food-Derived Glycotoxins
Authors: Veronica Mericq, Cecilia Piccardo, Weijing Cai, Xue Chen, Li Zhu, Gary E. Striker, Helen Vlassara, Jaime Uribarri
Journal: Diabetes Care (2010)

OBJECTIVE Proinflammatory advanced glycation end products (AGEs) found in thermally processed foods correlate with serum AGEs (sAGEs) and promote type 1 and type 2 diabetes in mice. Herein we assess the relationship of maternal blood and food AGEs to circulating glycoxidants, inflammatory markers, and insulin levels in infants up to age 1 year. RESEARCH DESIGN AND METHODS AGEs (Nε-carboxymethyllysine [CML] and methylglyoxal derivatives) were tested in sera of healthy mothers in labor (n = 60), their infants, and infant foods. Plasma 8-isoprostane, fasting glucose, insulin, leptin, and adiponectin levels were assessed in 12-month-old infants. RESULTS Significant correlations were found between newborn and maternal serum CML (sCML) (r = 0.734, P = 0.001) serum methylglyoxal derivatives (sMGs) (r = 0.593, P = 0.001), and 8-isoprostanes (r = 0.644, P = 0.001). Infant adiponectin at 12 months negatively correlated with maternal sCML (r = −0.467, P = 0.011), whereas high maternal sMGs predicted higher infant insulin or homeostasis model assessment (P = 0.027). Infant sAGEs significantly increased with the initiation of processed infant food intake, raising daily AGE consumption by ∼7.5-fold in year 1. CONCLUSIONS Maternal blood and food-derived AGEs prematurely raise AGEs in children to adult norms, preconditioning them to abnormally high oxidant stress and inflammation and thus possibly to early onset of disease, such as diabetes.
Treating Achalasia
Authors: Anita E. Spiess, Peter J. Kahrilas
Journal: JAMA (1998)

To review the pathophysiology and management of achalasia.Peer-reviewed publications located via MEDLINE using the search term esophageal achalasia (subheadings: complications, drug therapy, epidemiology, etiology, physiopathology, surgery, and therapy) published in English from 1966 to December 1997.Of 2632 citations identified, 4.5% were selected for inclusion by authors' blinded review of the abstracts. New developments in the understanding of achalasia or reports of therapeutic efficacy in either controlled trials or uncontrolled consecutive series involving 10 patients or more observed for a year or longer were reviewed in detail.All 6 controlled therapeutic trials were included, and therapeutic efficacy in uncontrolled series was assessed by the authors extracting the patients with a good-to-excellent response from each study and calculating a pooled estimate of response rate with individual studies weighted proportionally to sample size.Achalasia results from irreversible destruction of esophageal myenteric plexus neurons causing aperistalsis and failed lower sphincter relaxation. The only therapies that adequately compensate for this dysfunction for a sustained time are pneumatic dilation and Heller myotomy. The single controlled trial comparing these treatments found surgery superior to dilation (95% vs 51% nearly complete symptom resolution, P<.01). In uncontrolled trials pneumatic dilation (weighted mean [SD]) is 72% (26%) effective vs 84% (20%) for Heller myotomy. The limitation of dilation is a 3% risk of perforation; thoracotomy morbidity has been the major limitation of myotomy. Surgical morbidity has been sharply reduced by laparoscopic techniques.Both pneumatic dilation and surgical myotomy are effective therapies for achalasia; laparoscopic Heller myotomy is emerging as the optimal surgical therapy.
Compensatory Uptake of I-123 MIBG in the Contralateral Adrenal Gland After Removal of a Pheochromocytoma
Authors: HENDRIKUS H. BOERSMA, JOHANNA W. WENSING, LIANG T. KHO, MAURITS L. DE BRAUW, ING HAN LIEM, MARINUS J. P. G. VAN KROONENBURGH
Journal: Clinical Nuclear Medicine (2002)

The identification of recurrent or residual tumor tissue is sometimes complicated. The authors describe a 53-year-old woman in whom I-123 metaiodobenzylguanidine (MIBG) scintigraphy revealed a pheochromocytoma in the right adrenal gland. After the tumor was removed, the patient's catecholamine levels normalized. At the 3-month follow-up examination, I-123 MIBG scintigraphy did not reveal uptake in the right adrenal region but rather showed uptake in the left adrenal region. The patient's blood pressure remained in the normal range. A third scintigram, obtained 1 year after tumor resection, no longer detected I-123 MIBG accumulation in the left adrenal gland. These findings suggest that compensatory hyperplasia of the left adrenal gland led to enhanced uptake of I-123 MIBG. They also highlight the need for careful follow-up of such patients to distinguish between physiologic and pathologic processes.
α‐interferon therapy for severe chronic idiopathic thrombocytopenic purpura in children
Authors: Richard J. Cohn, Rosemarie Schwyzer, Janet E. Poole, Peter B. Hesseling, Joan Naidoo, Corrieta Van Heerden
Journal: American Journal of Hematology (1993)

Abstract We report the use of α 2b ‐interferon in 15 children with symptomatic, chronic idiopathic thrombocytopenic purpura, who did not respond to standard therapy. The platelet count increased in nine children during therapy. In six children the increase lasted less than 6 weeks. An increased platelet count was seen when a higher dose was used in two of four initial nonresponders. One responder who relapsed had an identical response when retreated with the same dose. No significant side effects were documented. Further studies are required to establish the optimal dose and administration schedule of α 2b ‐interferon for use in children with chronic idiopathic thrombocytopenic purpura.
CXCL11-dependent induction of FOXP3-negative regulatory T cells suppresses autoimmune encephalomyelitis
Authors: Yaniv Zohar, Gizi Wildbaum, Rostislav Novak, Andrew L. Salzman, Marcus Thelen, Ronen Alon, Yiftah Barsheshet, Christopher L. Karp, Nathan Karin
Journal: Journal of Clinical Investigation (2014)

A single G protein-coupled receptor (GPCR) can activate multiple signaling cascades based on the binding of different ligands. The biological relevance of this feature in immune regulation has not been evaluated. The chemokine-binding GPCR CXCR3 is preferentially expressed on CD4+ T cells, and canonically binds 3 structurally related chemokines: CXCL9, CXCL10, and CXCL11. Here we have shown that CXCL10/CXCR3 interactions drive effector Th1 polarization via STAT1, STAT4, and STAT5 phosphorylation, while CXCL11/CXCR3 binding induces an immunotolerizing state that is characterized by IL-10(hi) (Tr1) and IL-4(hi) (Th2) cells, mediated via p70 kinase/mTOR in STAT3- and STAT6-dependent pathways. CXCL11 binds CXCR3 with a higher affinity than CXCL10, suggesting that CXCL11 has the potential to restrain inflammatory autoimmunity. We generated a CXCL11-Ig fusion molecule and evaluated its use in the EAE model of inflammatory autoimmune disease. Administration of CXCL11-Ig during the first episode of relapsing EAE in SJL/J mice not only led to rapid remission, but also prevented subsequent relapse. Using GFP-expressing effector CD4+ T cells, we observed that successful therapy was associated with reduced accumulation of these cells at the autoimmune site. Finally, we showed that very low doses of CXCL11 rapidly suppress signs of EAE in C57BL/6 mice lacking functional CXCL11.
Suppression of Tak1 Promotes Prostate Tumorigenesis
Authors: Min Wu, Lihong Shi, Adela Cimic, Lina Romero, Guangchao Sui, Cynthia J. Lees, J. Mark Cline, Darren F. Seals, Joseph S. Sirintrapun, Thomas P. McCoy, Wennuan Liu, Jin Woo Kim, Gregory A. Hawkins, Donna M. Peehl, Jianfeng Xu, Scott D. Cramer
Journal: Cancer Research (2012)

More than 30% of primary prostate cancers contain a consensus deletion of an approximately 800 kb locus on chromosome 6q15.1. The MAP3K7 gene, which encodes TGF-β activated kinase-1 (Tak1), is a putative prostate tumor suppressor gene within this region whose precise function remains obscure. In this study, we investigated the role of Tak1 in human and murine prostate cancers. In 50 well-characterized human cancer specimens, we found that Tak1 expression was progressively lost with increasing Gleason grade, both within each cancer and across all cancers. In murine prostate stem cells and Tak1-deficient prostatic epithelial cells, Tak1 loss increased proliferation, migration, and invasion. When prostate stem cells attenuated for Tak1 were engrafted with fetal urogenital mesenchyme, the histopathology of the grafts reflected the natural history of prostate cancer leading from prostatic intraepithelial neoplasia to invasive carcinoma. In the grafts containing Tak1-suppressed prostate stem cells, p38 and c-jun-NH(2)-kinase activity was attenuated and proliferation was increased. Together, our findings functionally validate the proposed tumor suppressor role of Tak1 in prostate cancer.
Glucose intolerance, as reflected by hemoglobin a1clevel, is associated with the incidence and severity of transplant coronary artery disease
Authors: Tomoko Kato, Michael C.Y Chan, Shao-Zhou Gao, John S Schroeder, Mitsuhiro Yokota, Toyoaki Murohara, Mitsunori Iwase, Akiko Noda, Sharon A Hunt, Hannah A Valantine
Journal: Journal of the American College of Cardiology (2004)
Cardiac Sympathetic Rejuvenation
Authors: Kensuke Kimura, Masaki Ieda, Hideaki Kanazawa, Takashi Yagi, Makoto Tsunoda, Shin-ichi Ninomiya, Hiroyuki Kurosawa, Kenji Yoshimi, Hideki Mochizuki, Kazuto Yamazaki, Satoshi Ogawa, Keiichi Fukuda
Journal: Circulation Research (2007)

Neuronal function and innervation density is regulated by target organ-derived neurotrophic factors. Although cardiac hypertrophy drastically alternates the expression of various growth factors such as endothelin-1, angiotensin II, and leukemia inhibitory factor, little is known about nerve growth factor expression and its effect on the cardiac sympathetic nerves. This study investigated the impact of pressure overload-induced cardiac hypertrophy on the innervation density and cellular function of cardiac sympathetic nerves, including kinetics of norepinephrine synthesis and reuptake, and neuronal gene expression. Right ventricular hypertrophy was induced by monocrotaline treatment in Wistar rats. Newly developed cardiac sympathetic nerves expressing beta(3)-tubulin (axonal marker), GAP43 (growth-associated cone marker), and tyrosine hydroxylase were markedly increased only in the right ventricle, in parallel with nerve growth factor upregulation. However, norepinephrine and dopamine content was paradoxically attenuated, and the protein and kinase activity of tyrosine hydroxylase were markedly downregulated in the right ventricle. The reuptake of [(125)I]-metaiodobenzylguanidine and [(3)H]-norepinephrine were also significantly diminished in the right ventricle, indicating functional downregulation in cardiac sympathetic nerves. Interestingly, we found cardiac sympathetic nerves in hypertrophic right ventricles strongly expressed highly polysialylated neural cell adhesion molecule (PSA-NCAM) (an immature neuron marker) as well as neonatal heart. Taken together, pressure overload induced anatomical sympathetic hyperinnervation but simultaneously caused deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves as well as the hypertrophic cardiomyocytes, which also showed the fetal form gene expression.
Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome
Authors: Cornelis A Albers, Dirk S Paul, Harald Schulze, Kathleen Freson, Jonathan C Stephens, Peter A Smethurst, Jennifer D Jolley, Ana Cvejic, Myrto Kostadima, Paul Bertone, Martijn H Breuning, Najet Debili, Panos Deloukas, Rémi Favier, Janine Fiedler, Catherine M Hobbs, Ni Huang, Matthew E Hurles, Graham Kiddle, Ingrid Krapels, Paquita Nurden, Claudia A L Ruivenkamp, Jennifer G Sambrook, Kenneth Smith, Derek L Stemple, Gabriele Strauss, Chantal Thys, Chris van Geet, Ruth Newbury-Ecob, Willem H Ouwehand, Cedric Ghevaert
Journal: Nature Genetics (2012)