tbuckley/cabot-search huggingface dataset:
Transient activation of <i>c-MYC</i> expression is critical for efficient platelet generation from human induced pluripotent stem cells
Authors: Naoya Takayama, Satoshi Nishimura, Sou Nakamura, Takafumi Shimizu, Ryoko Ohnishi, Hiroshi Endo, Tomoyuki Yamaguchi, Makoto Otsu, Ken Nishimura, Mahito Nakanishi, Akira Sawaguchi, Ryozo Nagai, Kazutoshi Takahashi, Shinya Yamanaka, Hiromitsu Nakauchi, Koji Eto
Journal: The Journal of Experimental Medicine (2010)

Human (h) induced pluripotent stem cells (iPSCs) are a potentially abundant source of blood cells, but how best to select iPSC clones suitable for this purpose from among the many clones that can be simultaneously established from an identical source is not clear. Using an in vitro culture system yielding a hematopoietic niche that concentrates hematopoietic progenitors, we show that the pattern of c-MYC reactivation after reprogramming influences platelet generation from hiPSCs. During differentiation, reduction of c-MYC expression after initial reactivation of c-MYC expression in selected hiPSC clones was associated with more efficient in vitro generation of CD41a+CD42b+ platelets. This effect was recapitulated in virus integration-free hiPSCs using a doxycycline-controlled c-MYC expression vector. In vivo imaging revealed that these CD42b+ platelets were present in thrombi after laser-induced vessel wall injury. In contrast, sustained and excessive c-MYC expression in megakaryocytes was accompanied by increased p14 (ARF) and p16 (INK4A) expression, decreased GATA1 expression, and impaired production of functional platelets. These findings suggest that the pattern of c-MYC expression, particularly its later decline, is key to producing functional platelets from selected iPSC clones.
Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome
Authors: A. Meyer-Lindenberg
Journal: Journal of Clinical Investigation (2005)

Williams syndrome (WS), caused by microdeletion of some 21 genes on chromosome 7q11.23, is characterized by dysmorphic features, mental retardation or learning difficulties, elastin arteriopathy, and striking neurocognitive and social-behavioral abnormalities. Recent studies of murine knockouts of key genes in the microdeleted region, LIM kinase 1 (LIMK1) and cytoplasmatic linker protein 2 (CYLN2), demonstrated significant functional and metabolic abnormalities, but grossly normal structure, in the hippocampal formation (HF). Furthermore, deficits in spatial navigation and long-term memory, major cognitive domains dependent on hippocampal function, have been described in WS. We used multimodal neuroimaging to characterize hippocampal structure, function, and metabolic integrity in 12 participants with WS and 12 age-, sex-, and IQ-matched healthy controls. PET and functional MRI studies showed profound reduction in resting blood flow and absent differential response to visual stimuli in the anterior HF in WS. Spectroscopic measures of N-acetyl aspartate, considered a marker of synaptic activity, were reduced. Hippocampal size was preserved, but subtle alterations in shape were present. These data demonstrate abnormalities in HF in WS in agreement with murine models, implicate LIMK1 and CYLN2 in human hippocampal function, and suggest that hippocampal dysfunction may contribute to neurocognitive abnormalities in WS.
Cluster analysis of symptoms and health seeking behaviour differentiates subgroups of patients with severe irritable bowel syndrome
Authors: E Guthrie
Journal: Gut (2003)

Irritable bowel syndrome (IBS) is a heterogeneous condition which is diagnosed according to specific bowel symptom clusters. The aim of the present study was to identify subgroups of IBS subjects using measures of rectal sensitivity and psychological symptoms, in addition to bowel symptoms. Such groupings, which cross conventional diagnostic approaches, may provide greater understanding of the pathogenesis of the condition and its treatment.A K means cluster analysis was used to group 107 clinic patients with IBS according to physiological, physical, and psychological parameters. All patients had severe IBS and had failed to respond to usual medical treatment. Twenty nine patients had diarrhoea predominant IBS, 26 constipation predominant, and 52 had an alternating bowel habit.The clusters were most clearly delineated by two variables: "rectal perceptual threshold (volume)" and "number of doctor visits". Three subgroups were formed. Group I comprised patients with low distension thresholds and high rates of psychiatric morbidity, doctor consultations, interpersonal problems, and sexual abuse. Group II also had low distension thresholds but low rates of childhood abuse and moderate levels of psychiatric disorders. Group III had high distension thresholds, constipation or alternating IBS, and low rates of medical consultations and sexual abuse.The marked differences across the three groups suggest that each may have a different pathogenesis and respond to different treatment approaches. Inclusion of psychosocial factors in the analysis enabled more clinically meaningful groups to be identified than those traditionally determined by bowel symptoms alone or rectal threshold.
Roux-en-Y gastric bypass: effects on feeding behavior and underlying mechanisms
Authors: Sean Manning, Andrea Pucci, Rachel L. Batterham
Journal: Journal of Clinical Investigation (2015)

Bariatric surgery is the most effective treatment for severe obesity, producing marked sustained weight loss with associated reduced morbidity and mortality. Roux-en-Y gastric bypass surgery (RYGBP), the most commonly performed procedure, was initially viewed as a hybrid restrictive-malabsorptive procedure. However, over the last decade, it has become apparent that alternative physiologic mechanisms underlie its beneficial effects. RYGBP-induced altered feeding behavior, including reduced appetite and changes in taste/food preferences, is now recognized as a key driver of the sustained postoperative weight loss. The brain ultimately determines feeding behavior, and here we review the mechanisms by which RYGBP may affect central appetite-regulating pathways.
An unusual case of ascites
Authors: M J Bahr, B Boozari
Journal: Gut (2007)

This is an introduction to the Gut tutorial “An unusual case of ascites” hosted on BMJ Learning—the best available learning website for medical professionals from the BMJ Group.

A 37-year old woman perceives an increase in her abdominal girth. Initially, she considers being pregnant. After two weeks with persisting …
Mass Cytometry: A High-Throughput Platform to Visualize the Heterogeneity of Acute Myeloid Leukemia
Authors: Priscilla Do, John C. Byrd
Journal: Cancer Discovery (2015)

Behbehani and colleagues use mass cytometry to profile the heterogeneity of acute myeloid leukemia (AML ) as compared with normal hematopoiesis. By using this approach and characterizing leukemic stem cells, important differences in response to chemotherapy between AML subsets can potentially be explained and new targeted approaches considered.
AFM13: a first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy
Authors: Jingjing Wu, Jiaping Fu, Mingzhi Zhang, Delong Liu
Journal: Journal of Hematology & Oncology (2015)

Monoclonal antibodies against CD20 molecule have been leading the revolution of lymphoma treatment. In addition to monoclonal antibodies against CD20 and CD30, novel agents of immunotherapeutics in clinical development are being developed and are rapidly migrating to clinical application. One area of active development is NK cell activators, such as AFM13. This review will highlight the latest development of AFM13 as the first-in-class tetravalent bispecific anti-CD30/CD16A antibody for NK cell-mediated immunotherapy.
Persistent airflow limitation in adult-onset nonatopic asthma is associated with serologic evidence of Chlamydia pneumoniae infection
Authors: Anneke ten Brinke, Jaap T. van Dissel, Peter J. Sterk, Aeilko H. Zwinderman, Klaus F. Rabe, Elisabeth H. Bel
Journal: Journal of Allergy and Clinical Immunology (2001)
A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome
Authors: J Tack
Journal: Gut (2005)

<b>Introduction:</b> Selective serotonin reuptake inhibitors (SSRIs) are frequently used in the treatment of irritable bowel syndrome (IBS) although evidence of their efficacy is scarce. <b>Aim:</b> Twenty three non-depressed IBS patients were recruited from a tertiary care centre and included in a crossover trial comparing six weeks of treatment with the SSRI citalopram (20 mg for three weeks, 40 mg for three weeks) with placebo. IBS symptom severity was the primary outcome measure, and depression and anxiety scores were also measured. The effect of acute administration of citalopram on colonic sensitivity and on colonic response to feeding was investigated as a putative predictor of symptomatic response to the drug. <b>Results:</b> After three and six weeks of treatment, citalopram significantly improved abdominal pain, bloating, impact of symptoms on daily life, and overall well being compared with placebo. There was only a modest effect on stool pattern. Changes in depression or anxiety scores were not related to symptom improvement. The effect of acute administration of citalopram during a colonic barostat study did not predict clinical outcome. Analysis of the first treatment period as a double blind parallel arm study confirmed the benefit of citalopram over placebo. <b>Conclusions:</b> The SSRI citalopram significantly improves IBS symptoms, including abdominal pain, compared with placebo. The therapeutic effect is independent of effects on anxiety, depression, and colonic sensorimotor function.
Rheumatoid arthritis-associated polymorphisms are not protective against Alzheimer's disease
Authors: Christopher R Simmons, Fanggeng Zou, Steven G Younkin, Steven Estus
Journal: Molecular Neurodegeneration (2011)

Abstract Background Rheumatoid arthritis (RA) and Alzheimer's disease (AD) are inversely associated. To test the hypothesis that genetic elements associated with increased RA risk are associated with decreased AD risk, we evaluated RA genetic risk factors recently identified in genome-wide association studies (GWAS) for their association with AD in a two-stage, case-control analysis. Results In our Stage 1 analysis of ~800 AD and ~1,200 non-AD individuals, three of seventeen RA-associated SNPs were nominally associated with AD (p &lt; 0.05) with one SNP, rs2837960, retaining significance after correction for multiple testing (p = 0.03). The rs2837960_G (minor) allele, which is associated with increased RA risk, was associated with increased AD risk. Analysis of these three SNPs in a Stage 2 population, consisting of ~1,100 AD and ~2,600 non-AD individuals, did not confirm their association with AD. Analysis of Stage 1 and 2 combined suggested that rs2837960 shows a trend for association with AD. When the Stage 2 population was age-matched for the Stage 1 population, rs2837960 exhibited a non-significant trend with AD. Combined analysis of Stage 1 and the age-matched Stage 2 subset showed a significant association of rs2837960 with AD (p = 0.002, OR 1.24) that retained significance following correction for age, sex and APOE (p = 0.02, OR = 1.20). Rs2837960 is near BACE2 , which encodes an aspartic protease capable of processing the AD-associated amyloid precursor protein. Testing for an association between rs2837960 and the expression of BACE2 isoforms in human brain, we observed a trend between rs2837960 and the total expression of BACE2 and the expression of a BACE2 transcript lacking exon 7 (p = 0.07 and 0.10, respectively). Conclusions RA-associated SNPs are generally not associated with AD. Moreover, rs2837960_G is associated with increased risk of both RA and, in individuals less than 80 years of age, with AD. Overall, these results contest the hypothesis that genetic variants associated with RA confer protection against AD. Further investigation of rs2837960 is necessary to elucidate the mechanism by which rs2837960 contributes to both AD and RA risk, likely via modulation of BACE2 expression.
The prognostic implications of further renal function deterioration within 48 h of interventional coronary procedures in patients with pre-existent chronic renal insufficiency
Authors: Luis Gruberg, Gary S Mintz, Roxana Mehran, George Dangas, Alexandra J Lansky, Kenneth M Kent, Augusto D Pichard, Lowell F Satler, Martin B Leon
Journal: Journal of the American College of Cardiology (2000)
LP13 : Effect of long term viral suppression with sofosbuvir + ribavirin on hepatic venous pressure gradient in HCV-infected patients with cirrhosis and portal hypertension
Authors: N. Afdhal, G.T. Everson, J.L Calleja, G. McCaughan, J. Bosch, J. Denning, D.M. Brainard, J.G. McHutchison, T. Brandt-Sarif, D. An, M. Charlton, K.R. Reddy, T. Asselah, E. Gane, X. Forns
Journal: Journal of Hepatology (2015)
EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab
Authors: S. Gori, A. Sidoni, M. Colozza, I. Ferri, M.G. Mameli, D. Fenocchio, L. Stocchi, J. Foglietta, V. Ludovini, E. Minenza, V. De Angelis, L. Crinò
Journal: Annals of Oncology (2009)
Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly
Authors: Karine Poirier, Nicolas Lebrun, Loic Broix, Guoling Tian, Yoann Saillour, Cécile Boscheron, Elena Parrini, Stephanie Valence, Benjamin Saint Pierre, Madison Oger, Didier Lacombe, David Geneviève, Elena Fontana, Franscesca Darra, Claude Cances, Magalie Barth, Dominique Bonneau, Bernardo Dalla Bernadina, Sylvie N'Guyen, Cyril Gitiaux, Philippe Parent, Vincent des Portes, Jean Michel Pedespan, Victoire Legrez, Laetitia Castelnau-Ptakine, Patrick Nitschke, Thierry Hieu, Cecile Masson, Diana Zelenika, Annie Andrieux, Fiona Francis, Renzo Guerrini, Nicholas J Cowan, Nadia Bahi-Buisson, Jamel Chelly
Journal: Nature Genetics (2013)
0pen-heart palliative surgery for pulmonary atresia with ventricular septal defect and hypoplastic pulmonary arteries.
Authors: G Crupi, G Locatelli, M Villani, R Tiraboschi, L Parenzan
Journal: Thorax (1978)

The surgical management of pulmonary atresia with ventricular septal defect (VSD) and hypoplastic pulmonary arteries poses difficult problems. Adequate palliation was achieved in two such patients by restoring continuity between the right ventricle and the pulmonary arteries by means of a woven Dacron patch. The VSD was left unrepaired. Angiography performed one month after operation showed the reconstructed pulmonary outflow tract to be widely patent and the pulmonary arteries to be enlarged. This approach may allow subsequent total correction by closure of the VSD in these hopeless patients.
Interleukin production in juvenile chronic arthritis.
Authors: G R Burgio, A Martini
Journal: Annals of the Rheumatic Diseases (1985)

Interleukin production in juvenile chronic arthritis SIR, We read with interest the paper by Gilman and coworkers who showed that in rats with adjuvant-induced arthritis peritoneal macrophages produce higher amounts of interleukin 1 (IL-1), while splenic T cells produce less interleukin 2 (IL-2) than controls.'We found comparable results when studying interleukin production by peripheral blood mononuclear cells in children with juvenile chronic arthritis (JCA) (unpublished data).We investigated a total of 28 children with JCA ranging in age from 3 to 16 years.Ten presented a systemic form, six a polyarticular, and twelve a pauciarticular form.Patients were divided accord- ing to clinical activity of the disease into three groups: active disease, partial remission, and remission.Twenty- one age matched healthy children served as controls.Peripheral blood monocytes were isolated by adherence and stimulated in vitro with lipopolysaccharide: IL-1 in the supernatants was assessed by a thymocyte coproliferation assay.Peripheral blood lymphocytes were stimulated in vitro with phytohaemagglutinin, and IL-2 in the super- natants was quantified by an IL-2-dependent cell line.Monocytes from patients with JCA produced significantly more IL-1 than controls (17-1±11-1 (SD) v 10-6±8-9 (SD), p<0-05).while lymphocytes from the same patients produced significantly less IL-2 than controls (40-6±31.2(SD) v 69-8±40 9 (SD), p<0-01).These
Multiphoton Imaging Reveals Differences in Mitochondrial Function between Nephron Segments
Authors: Andrew M. Hall, Robert J. Unwin, Nadeene Parker, Michael R. Duchen
Journal: Journal of the American Society of Nephrology (2009)

Mitochondrial dysfunction may play a role in the pathogenesis of several renal diseases. Although functional roles and metabolic demands differ among tubule segments, relatively little is known about the properties of mitochondria in different parts of the nephron. Clinically, the proximal tubule seems particularly vulnerable to mitochondrial toxicity. In this study, we used multiphoton imaging of live rat kidney slices to investigate differences in mitochondrial function along the nephron. The mitochondrial membrane potential was markedly higher in distal than proximal tubules. Inhibition of respiration rapidly collapsed the membrane potential in proximal tubules, but potential was better maintained in distal tubules. Inhibition of the F1F(o)-ATPase abolished this difference, suggesting that maintenance of potential via ATPase activity is more effective in distal than proximal tubules. Immunostaining revealed that the ratio of the expression of ATPase to IF1, an endogenous inhibitor of the mitochondrial ATPase, was lower in proximal tubules than in distal tubules. Production of reactive oxygen species was higher in proximal than distal cells, but inhibition of NADPH oxidase eliminated this difference. Glutathione levels were higher in proximal tubules. Overall, mitochondria in the proximal tubules were in a more oxidized state than those in the distal tubules. In summary, there are axial differences in mitochondrial function along the nephron, which may contribute to the pattern and pathophysiology of some forms of renal injury.
The Lymphotoxin-β Receptor Induces Different Patterns of Gene Expression via Two NF-κB Pathways
Authors: Emmanuel Dejardin, Nathalie M Droin, Mireille Delhase, Elvira Haas, Yixue Cao, Constantin Makris, Zhi-Wei Li, Michael Karin, Carl F Ware, Douglas R Green
Journal: Immunity (2002)
Cryptic messages in FAP
Authors: A WATSON, R N DuBOIS
Journal: Gut (1999)

See article on page 822 

A series of remarkable clinical, epidemiological, and laboratory studies has shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac, can prevent the development of colorectal cancer and cause regression of pre-existing adenomas.1 Aspirin is one of the most potent chemopreventive agents against colorectal cancer. However, its mechanism for causing a reduction in colorectal cancer risk and mortality is unknown.2 The anti-inflammatory properties of NSAIDs are thought to reside in their ability to inhibit prostaglandin production at sites of inflammation.

Cyclooxygenase (COX) is a key enzyme in the production of prostaglandins, and aspirin can inhibit its activity directly. Initially, COX was thought to be a single enzyme, but in 1991 a second COX isoform was discovered (COX-2) which is induced by cytokines, growth factors, and tumour promoters.3 COX-1 is expressed constitutively in many tissues …
Tumour necrosis factor blockade in treatment resistant pigmented villonodular synovitis
Authors: E-J A Kroot
Journal: Annals of the Rheumatic Diseases (2004)

<b>Background:</b> Pigmented villonodular synovitis (PVNS) is considered to be a neoplastic-like disorder of the synovium histologically characterised by villonodular hyperplasia, resulting in dense fibrosis and haemosiderin deposition. The pathogenesis of the disease is still unknown. <b>Case report:</b> A patient presented with severe treatment resistant PVNS of the right knee joint. Several conventional treatment regimens, including open surgical synovectomy and intra-articular injections of yttrium-90 (<sup>90</sup>Y) failed to control the disease. After finding marked tumour necrosis factor α (TNFα) expression in arthroscopic synovial tissue samples, treatment with an anti-TNFα monoclonal antibody (infliximab) at a dose of 5 mg/kg was started. Additional courses with the same dose given 2, 6, 14, and 20 weeks later, and bimonthly thereafter up to 54 weeks, controlled the signs and symptoms. Immunohistological analysis at follow up identified a marked reduction in macrophage numbers and TNFα expression in the synovium. <b>Discussion:</b> This is probably the first case which describes treatment with TNFα blockade of PVNS in a patient who is refractory to conventional treatment. It provides the rationale for larger controlled studies to elucidate further the efficacy of TNFα blockade treatment in refractory PVNS.
An Oncolytic HSV-1 Mutant Expressing ICP34.5 under Control of a Nestin Promoter Increases Survival of Animals even when Symptomatic from a Brain Tumor
Authors: Hirokazu Kambara, Hideyuki Okano, E. Antonio Chiocca, Yoshinaga Saeki
Journal: Cancer Research (2005)

Abstract Oncolytic herpes simplex virus-1 (HSV-1) mutants possessing mutations in the ICP34.5 and ICP6 genes have proven safe through clinical trials. However, ICP34.5-null viruses may grow poorly in cells due to their inability to prevent host-cell shut-off of protein synthesis caused by hyperphosphorylation of eukaryotic initiation factor 2α. To increase tumor selectivity, glioma-selective expression of ICP34.5 in the context of oncolysis may be useful. Malignant gliomas remain an incurable disease. One molecular marker of malignant gliomas is expression of the intermediate filament nestin. Expression of nestin mRNA was confirmed in 6 of 6 human glioma lines and in 3 of 4 primary glioma cells. Normal human astrocytes were negative. A novel glioma-selective HSV-1 mutant (rQNestin34.5) was thus engineered by expressing ICP34.5 under control of a synthetic nestin promoter. Replication, cellular propagation, and cytotoxicity of rQNestin34.5 were significantly enhanced in cultured and primary human glioma cell lines compared with control virus. However, replication, cellular propagation, and cytotoxicity of rQNestin34.5 in normal human astrocytes remained quantitatively similar to that of control virus. In glioma cell lines infected with rQNestin34.5, the level of phospho-eukaryotic initiation factor 2α was lower than that of cells infected by control rHsvQ1, confirming selective ICP34.5 expression in glioma cells. In vivo, rQNestin34.5 showed significantly more potent inhibition of tumor growth compared with control virus. Treatment in the brain tumor model was instituted on animal's display of neurologic symptoms, which usually led to rapid demise. rQNestin34.5 treatment doubled the life span of these animals. These results show that rQNestin34.5 could be a potent agent for the treatment of malignant glioma.