tbuckley/cabot-search huggingface dataset:
Epigenetic inactivation of<i>BCL6B</i>, a novel functional tumour suppressor for gastric cancer, is associated with poor survival
Authors: Lixia Xu, Xiaoxing Li, Eagle S H Chu, Guijun Zhao, Minnie Y Y Go, Qian Tao, Hongchuan Jin, Zhirong Zeng, Joseph J Y Sung, Jun Yu
Journal: Gut (2011)

<h3>Objective</h3> Using genome-wide promoter methylation assay, B cell CLL/lymphoma 6 member B <i>(BCL6B)</i> was found to be preferentially methylated in cancer. A study was undertaken to examine the epigenetic regulation, biological function and clinical significance of <i>BCL6B</i> in gastric cancer (GC). <h3>Methods</h3> <i>BCL6B</i> promoter methylation was evaluated by combined bisulfite restriction analysis and sequencing. The biological functions of BCL6B were determined by cell viability, colony formation, flow cytometry and in vivo tumorigenicity assays. The molecular targets of <i>BCL6B</i> were identified by cDNA expression array. <h3>Results</h3> <i>BCL6B</i> was silenced or downregulated in all nine GC cell lines and readily expressed in normal gastric tissues. Loss of <i>BCL6B</i> expression was regulated by promoter hypermethylation. Re-expression of <i>BCL6B</i> in GC cell lines inhibited colony formation, suppressed cell viability, induced apoptosis and restrained the tumorigenecity in nude mice. These effects were associated with upregulation of the pro-apoptosis genes tumour necrosis factor receptor superfamily member 1A, caspase-8, caspase-9, caspase-3 and caspase-7 and nuclear enzyme poly (ADP-ribose) polymerase, downregulation of the pro-proliferation genes S100 calcium binding protein A4 and vascular endothelial growth factor A, and induction of the tumour suppressor genes ataxia telangiectasia mutated homologue and p53. <i>BCL6B</i> hypermethylation was detected in 49.0% (102/208) and 66.3% (67/101) of two independent cohorts of patients with GC, respectively. <i>BCL6B</i> methylation was an independent factor for the survival of patients with GC (p=0.001 for cohort I, p=0.02 for cohort II). <h3>Conclusions</h3> <i>BCL6B</i> plays a pivotal role as a potential tumour suppressor in GC. Detection of methylated <i>BCL6B</i> may serve as an independent biomarker for the prognosis of GC.
1α,25-Dihydroxyvitamin D <sub>3</sub> Inhibits Angiogenesis In Vitro and In Vivo
Authors: D. J. Mantell, P. E. Owens, N. J. Bundred, E. B. Mawer, A. E. Canfield
Journal: Circulation Research (2000)

Abstract —Modulation of angiogenesis is now a recognized strategy for the prevention and treatment of pathologies categorized by their reliance on a vascular supply. The purpose of this study was to evaluate the effect of 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], the active metabolite of vitamin D 3 , on angiogenesis by using well-characterized in vitro and in vivo model systems. 1,25(OH) 2 D 3 (1×10 − 9 to 1×10 − 7 mol/L) significantly inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell sprouting and elongation in vitro in a dose-dependent manner and had a small, but significant, inhibitory effect on VEGF-induced endothelial cell proliferation. 1,25(OH) 2 D 3 also inhibited the formation of networks of elongated endothelial cells within 3D collagen gels. The addition of 1,25(OH) 2 D 3 to endothelial cell cultures containing sprouting elongated cells induced the regression of these cells, in the absence of any effect on cells present in the cobblestone monolayer. Analysis of nuclear morphology, DNA integrity, and enzymatic in situ labeling of apoptosis-induced strand breaks demonstrated that this regression was due to the induction of apoptosis specifically within the sprouting cell population. The effect of 1,25(OH) 2 D 3 on angiogenesis in vivo was investigated by using a model in which MCF-7 breast carcinoma cells, which had been induced to overexpress VEGF, were xenografted subcutaneously together with MDA-435S breast carcinoma cells into nude mice. Treatment with 1,25(OH) 2 D 3 (12.5 pmol/d for 8 weeks) produced tumors that were less well vascularized than tumors formed in mice treated with vehicle alone. These results highlight the potential use of 1,25(OH) 2 D 3 in both the prevention and regression of conditions characterized by pathological angiogenesis.
Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23
Authors: Nelson B. Freimer, Victor I. Reus, Michael A. Escamilla, L. Alison Mclnnes, Mitzi Spesny, Pedro Leon, Susan K. Service, Lauren B. Smith, Sandra Silva, Eugenia Rojas, Alvaro Gallegos, Luis Meza, Eduardo Fournier, Siamak Baharloo, Kathleen Blankenship, David J. Tyler, Steven Batki, Sophia Vinogradov, Jean Weissenbach, Samuel H. Barondes, Lodewijk A. Sandkuijl
Journal: Nature Genetics (1996)
Milburn is to head initiative to widen entry to medical training
Authors: A. O'Dowd
Journal: BMJ (2009)

The former health secretary Alan Milburn has been chosen to head a new commission for social mobility that will aim to widen access to people from all backgrounds to professions such as medicine.

The need to widen the field for future doctors was underlined in a report commissioned by the Liberal Democrat party and published on 12 January by the children’s charity Barnardo’s. It showed that a child’s life chances still depend largely on background and parents’ earnings.

Prime Minister Gordon Brown announced at the weekend that Alan Milburn, Labour MP for Darlington and the health secretary from 1999 to 2003, would head …
The Microculture-Kinetic (MiCK) Assay: The Role of a Drug-Induced Apoptosis Assay in Drug Development and Clinical Care
Authors: Linda Bosserman, Franklyn Prendergast, Roy Herbst, Martin Fleisher, Emery Salom, Steven Strickland, Anastasios Raptis, Allan Hallquist, Mathieu Perree, Swapnil Rajurkar, Misagh Karimi, Karl Rogers, Dirk Davidson, Carl Willis, Manuel Penalver, Howard Homesley, Matthew Burrell, Audrey Garrett, James Rutledge, Michael Chernick, Cary A. Presant
Journal: Cancer Research (2012)

A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development.
Reciprocal In Vivo Regulation of Myocardial G Protein–Coupled Receptor Kinase Expression by β-Adrenergic Receptor Stimulation and Blockade
Authors: Guido Iaccarino, Eric D. Tomhave, Robert J. Lefkowitz, Walter J. Koch
Journal: Circulation (1998)

Impaired myocardial beta-adrenergic receptor (betaAR) signaling, including desensitization and functional uncoupling, is a characteristic of congestive heart failure. A contributing mechanism for this impairment may involve enhanced myocardial beta-adrenergic receptor kinase (betaARK1) activity because levels of this betaAR-desensitizing G protein-coupled receptor kinase (GRK) are increased in heart failure. An hypothesis has emerged that increased sympathetic nervous system activity associated with heart failure might be the initial stimulus for betaAR signaling alterations, including desensitization. We have chronically treated mice with drugs that either activate or antagonize betaARs to study the dynamic relationship between betaAR activation and myocardial levels of betaARK1.Long-term in vivo stimulation of betaARs results in the impairment of cardiac +betaAR signaling and increases the level of expression (mRNA and protein) and activity of +betaARK1 but not that of GRK5, a second GRK abundantly expressed in the myocardium. Long-term beta-blocker treatment, including the use of carvedilol, improves myocardial betaAR signaling and reduces betaARK1 levels in a specific and dose-dependent manner. Identical results were obtained in vitro in cultured cells, demonstrating that the regulation of GRK expression is directly linked to betaAR signaling.This report demonstrates, for the first time, that betaAR stimulation can significantly increase the expression of betaARK1 , whereas beta-blockade decreases expression. This reciprocal regulation of betaARK1 documents a novel mechanism of ligand-induced betaAR regulation and provides important insights into the potential mechanisms responsible for the effectiveness of beta-blockers, such as carvedilol, in the treatment of heart failure.
Correlation of serum level of high mobility group box 1 with the burden of granulomatous inflammation in granulomatosis with polyangiitis (Wegener's)
Authors: F. O. Henes, Y. Chen, T. Bley, M. Fabel, M. Both, K. Herrmann, E. Csernok, W. Gross, F. Moosig
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objectives</h3> To investigate the correlation of serum levels of high mobility group box 1 (HMGB1) with the extent of granulomatous inflammation in granulomatosis with polyangiitis (GPA). <h3>Methods</h3> From 169 patients with GPA, 17 patients with granulomatous inflammation, without evidence of vasculitis were identified and 36 patients without measurable 'granuloma' formation. HMGB1 serum levels were determined and compared between the two groups, using a Mann–Whitney U test. Serum levels of 26 healthy individuals served as controls. In a further 21 patients with GPA with a pulmonary granulomatous manifestation from the study population, CT volumetry of 'granuloma' was performed. Volumes were compared with serum levels of HMGB1 (Spearman rank order test). <h3>Results</h3> Serum levels of HMGB1 were significantly higher in patients with predominant granulomatous disease than in patients without measurable 'granuloma' manifestations (6.44±4.53 ng/ml vs 3.85±2.88 ng/ml; p=0.0107). In both groups, levels of HMGB1 were significantly higher than in controls (2.34±2.01 ng/ml; p&lt;0.01). A positive correlation of HMGB1 serum levels with volumes of pulmonary 'granuloma' (r=0.761, p&lt;0.0017) was seen. <h3>Conclusions</h3> HMGB1 serum levels are significantly higher in GPA with predominant granulomatous manifestations and correlate with volumes of pulmonary 'granuloma'. HMGB1 may be used as a marker of the burden of granulomatous inflammation in GPA.
Morphometric Analysis of Explant Lungs in Cystic Fibrosis
Authors: Mieke Boon, Stijn E. Verleden, Barbara Bosch, Elise J. Lammertyn, John E. McDonough, Cindy Mai, Johny Verschakelen, Mariette Kemner-van de Corput, Harm A. W. Tiddens, Marijke Proesmans, François L. Vermeulen, Erik K. Verbeken, Joel Cooper, Dirk E. Van Raemdonck, Marc Decramer, Geert M. Verleden, James C. Hogg, Lieven J. Dupont, Bart M. Vanaudenaerde, Kris De Boeck
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

After repeated cycles of lung infection and inflammation, patients with cystic fibrosis (CF) evolve to respiratory insufficiency. Although histology and imaging have provided descriptive information, a thorough morphometric analysis of end-stage CF lung disease is lacking.To quantify the involvement of small and large airways in end-stage CF.Multidetector computed tomography (MDCT) and micro-CT were applied to 11 air-inflated CF explanted lungs and 7 control lungs to measure, count, and describe the airway and parenchymal abnormalities in end-stage CF lungs. Selected abnormalities were further investigated with thin section histology.On MDCT, CF explanted lungs showed an increased median (interquartile range) number (631 [511-710] vs. 344 [277-349]; P = 0.003) and size of visible airways (cumulative airway diameter 217 cm [209-250] vs. 91 cm [80-105]; P < 0.001) compared with controls. Airway obstruction was seen, starting from generation 6 and increasing to 40 to 50% of airways from generation 9 onward. Micro-CT showed that the total number of terminal bronchioles was decreased (2.9/ml [2.6-4.4] vs. 5.3/ml [4.8-5.7]; P < 0.001); 49% were obstructed, and the cross-sectional area of the open terminal bronchioles was reduced (0.093 mm(2) [0.084-0.123] vs. 0.179 mm(2) [0.140-0.196]; P < 0.001). On micro-CT, 41% of the obstructed airways reopened more distally. This remodeling was confirmed on histological analysis. Parenchymal changes were also seen, mostly in a patchy and peribronchiolar distribution.Extensive changes of dilatation and obstruction in nearly all airway generations were observed in end-stage CF lung disease.
Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury
Authors: Tamás Dolinay, Young Sam Kim, Judie Howrylak, Gary M. Hunninghake, Chang Hyeok An, Laura Fredenburgh, Anthony F. Massaro, Angela Rogers, Lee Gazourian, Kiichi Nakahira, Jeffrey A. Haspel, Roberto Landazury, Sabitha Eppanapally, Jason D. Christie, Nuala J. Meyer, Lorraine B. Ware, David C. Christiani, Stefan W. Ryter, Rebecca M. Baron, Augustine M. K. Choi
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation.We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS.We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid.In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18-neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality.The inflammasome pathway and its downstream cytokines play critical roles in ARDS development.
Management of Antiphospholipid Antibody Syndrome
Authors: Wendy Lim, Mark A Crowther, John W Eikelboom
Journal: JAMA (2006)

Antiphospholipid antibodies are autoantibodies directed against proteins that bind to phospholipid. Antiphospholipid antibody syndrome (APS) refers to the association between antiphospholipid antibodies and thrombosis risk or pregnancy morbidity. Patients with APS may be at increased risk of recurrent arterial or venous thrombosis or pregnancy loss.To systematically review the evidence for treatment of thrombosis risk in patients with antiphospholipid antibodies or APS.Search of MEDLINE (1966 to November 2005) and Cochrane Library electronic databases (2005) and reference lists for randomized trials, meta-analyses of randomized trials, and prospective cohort studies of the treatment of thrombosis risk in patients with antiphospholipid antibodies or APS. Studies were selected on the basis of clinical relevance.Among patients with antiphospholipid antibodies, the absolute risk of developing new thrombosis is low (<1% per year) in otherwise healthy patients without prior thrombotic events, may be moderately increased (up to 10% per year) in women with recurrent fetal loss without prior thrombosis, and is highest (>10% in the first year) in patients with a history of venous thrombosis who have discontinued anticoagulant drugs within 6 months. Compared with placebo or untreated control, anticoagulation with moderate-intensity warfarin (adjusted to a target international normalized ratio [INR] of 2.0-3.0) reduces the risk of recurrent venous thrombosis by 80% to 90% irrespective of the presence of antiphospholipid antibodies and may be effective for preventing recurrent arterial thrombosis. No evidence exists that high-intensity warfarin (target INR, >3.0) is more effective than moderate-intensity warfarin. For patients with a single positive antiphospholipid antibody test result and prior stroke, aspirin and moderate-intensity warfarin appear equally effective for preventing recurrent stroke. Treatment issues that have not been addressed in clinical trials, or for which the evidence is conflicting, include the role of antithrombotic prophylaxis in patients with antiphospholipid antibodies without prior thrombosis, the optimal treatment of noncerebrovascular arterial thrombosis, recurrent thrombosis despite warfarin therapy, and treatment of women with antiphospholipid antibodies and recurrent fetal loss.In patients with APS, moderate-intensity warfarin is effective for preventing recurrent venous thrombosis and perhaps also arterial thrombosis. Aspirin appears to be as effective as moderate-intensity warfarin for preventing recurrent stroke in patients with prior stroke and a single positive test result for antiphospholipid antibody. The optimal treatment of other thrombotic aspects of APS needs to be addressed in well-designed prospective studies.
Cognitive therapy for people with schizophrenia spectrum disorders not taking antipsychotic drugs: a single-blind randomised controlled trial
Authors: Anthony P Morrison, Douglas Turkington, Melissa Pyle, Helen Spencer, Alison Brabban, Graham Dunn, Tom Christodoulides, Rob Dudley, Nicola Chapman, Pauline Callcott, Tim Grace, Victoria Lumley, Laura Drage, Sarah Tully, Kerry Irving, Anna Cummings, Rory Byrne, Linda M Davies, Paul Hutton
Journal: The Lancet (2014)
Expansion of natural killer cells but not T cells in human interleukin 2/interleukin 2 receptor (Tac) transgenic mice.
Authors: Y Ishida, M Nishi, O Taguchi, K Inaba, M Hattori, N Minato, M Kawaichi, T Honjo
Journal: The Journal of Experimental Medicine (1989)

Transgenic mice expressing both human IL-2 and the L chain of IL-2-R constitutively had an unusual expansion of Thy-1+/CD3-4-8- large granular lymphocytes, which bore the elevated NK activity. Unexpectedly, the transgenic mice had neither T cell expansion nor autoreactive antibodies. The increase in number and activity of NK cells seems to be responsible for both the severe interstitial pneumonia and lymphocyte depletion in the spleen that we found in these transgenic mice. In addition, we found the selective loss of Purkinje cells in the cerebellum of the mice, which gave rise to their disturbed gait. All the transgenic mice died by 4 wk of age.
Genes and epigenetic processes as prospective pain targets
Authors: Megan Crow, Franziska Denk, Stephen B McMahon
Journal: Genome Medicine (2013)

Chronic pain affects approximately one in five adults, resulting in a greatly reduced quality of life and a higher risk of developing co-morbidities such as depression. Available treatments often provide inadequate pain relief, but it is hoped that through deeper understanding of the molecular mechanisms underlying chronic pain states we can discover new and improved therapies. Although genetic research has flourished over the past decade and has identified many key genes in pain processing, the budding field of epigenetics promises to provide new insights and a more dynamic view of pain regulation. This review gives an overview of basic mechanisms and current therapies to treat pain, and discusses the clinical and preclinical evidence for the contribution of genetic and epigenetic factors, with a focus on how this knowledge can affect drug development.
Laser microdissection expression profiling of marginal edges of colorectal tumours reveals evidence of increased lactate metabolism in the aggressive phenotype
Authors: C C Thorn, T C Freeman, N Scott, P J Guillou, D G Jayne
Journal: Gut (2008)

<h3>Background:</h3> The morphology of the invasive margin in colorectal cancer can be described as either pushing or infiltrative. These phenotypes carry prognostic significance, particularly in node negative disease, and provide an excellent model for the study of invasive behaviour in vivo. <h3>Methods:</h3> The marginal edges of 16 stage-matched tumours exhibiting these contrasting growth patterns were microdissected. The extracted mRNA was amplified and hybridised to a 9546 feature oligonucleotide array. Selected differentials were validated using real-time polymerase chain reaction and the protein product was interrogated by using immunohistochemistry. <h3>Results:</h3> After stringent quality control and filtering of data generated, 39 genes were identified as being significantly differentially expressed between the two types of marginal edge. Several genes involved in cellular metabolism were identified as differentials including lactate dehydrogenase B (LDHB) and modulators of glucose transport. <h3>Conclusions:</h3> The <i>LDH</i> expression profile differs between the invasive phenotypes. A hypothesis is proposed in which altered metabolism is a cause of contrasting invasive behaviour independent of the hypoxia-inducible factor mediated hypoxic response, consistent with the Warburg phenomenon.
Flat adenomas exist in asymptomatic people: important implications for colorectal cancer screening programmes
Authors: A R Hart, S Kudo, E H Mackay, J F Mayberry, W S Atkin
Journal: Gut (1998)

Flat adenomas are non-exophytic with a flat top or central depression and histologically the depth of dysplastic tissue is never more than twice the mucosal thickness. Flat adenomas frequently contain severely dysplastic tissue, and may progress rapidly through the adenoma-carcinoma sequence. Flat lesions have never been described in a British asymptomatic population.To determine whether flat adenomas exist in an asymptomatic population participating in a large randomised controlled trial of flexible sigmoidoscopy screening.A total of 3000 subjects (aged 55-64 years) underwent screening by flexible sigmoidoscopy.All polyps were removed and sent for histology. The number of polyps with endoscopic and histological features of flat adenomas was recorded.Three subjects had a total of four flat lesions--that is, one per 1000 people screened. Three contained severely dysplastic tissue, one a focus of adenocarcinoma. Three of the four lesions were less than 5 mm in size and the fourth was 15 mm in diameter.Flat lesions with severe dysplasia exist in the asymptomatic population. This has major implications for gastroenterologists who should be trained to identify them. Their existence is of importance to molecular biologists and epidemiologists investigating the aetiology of colorectal cancer.