tbuckley/cabot-search huggingface dataset:
Should we remove all lesions at colonoscopy
Authors: B Rembacken
Journal: Gut (2004)

The study by Hurlstone and colleagues ( Gut 2004; 53 :376–80) is commendable in raising the awareness of flat and depressed colonic neoplasia. However, I am surprised at the high rate of severe dysplasia reported in their study. Of their 170 lesions, 19% harboured high grade dysplasia. This high rate of severe dysplasia is particularly surprising as the study reported on diminutive colorectal lesions.

Large numbers of small adenomas develop as we grow older. According to autopsy studies, over 30% of the population over the age of 50 years have small adenomas.1 With the use of dye spraying and magnification, these lesions can be found in up to 50% of asymptomatic patients attending for colonoscopy.2 As only 5% of the population develop colorectal cancer, clearly the great majority of small adenomas never grow, advance, or turn cancerous. This conclusion is supported by studies reporting a lower than 1% risk of high grade dysplasia in small adenomas.3–5

Further studies have reported on the risk of high grade dysplasia in adenomas of all sizes. In our own series from Leeds,6 high grade dysplasia was found in 9.5% of neoplastic lesions of all size ranges. Similarly, Tsuda and colleagues7 reporting on colorectal adenomas in Sweden found high …
243 Contrast-enhanced sonography in the characterization of small hepatocellular carcinomas in cirrhotic patients: Comparison with contrast-enhanced ultrafast magnetic resonance imaging
Authors: Antonio Giorgio, Giorgio De Stefano, Carmine Coppola, Giovanna Ferraioli, Vincenzo Esposito, Antonella Di Sarno, Valentina Giorgio, Manuela De Stefano, Vincenzo Sangiovanni, Giulia Liorre, Luca Del Viscovo
Journal: Journal of Hepatology (2005)
Transplanted progenitors generate functional enteric neurons in the postnatal colon
Authors: Ryo Hotta, Lincon A. Stamp, Jaime P.P. Foong, Sophie N. McConnell, Annette J. Bergner, Richard B. Anderson, Hideki Enomoto, Donald F. Newgreen, Florian Obermayr, John B. Furness, Heather M. Young
Journal: Journal of Clinical Investigation (2013)

Cell therapy has the potential to treat gastrointestinal motility disorders caused by diseases of the enteric nervous system. Many studies have demonstrated that various stem/progenitor cells can give rise to functional neurons in the embryonic gut; however, it is not yet known whether transplanted neural progenitor cells can migrate, proliferate, and generate functional neurons in the postnatal bowel in vivo. We transplanted neurospheres generated from fetal and postnatal intestinal neural crest–derived cells into the colon of postnatal mice. The neurosphere-derived cells migrated, proliferated, and generated neurons and glial cells that formed ganglion-like clusters within the recipient colon. Graft-derived neurons exhibited morphological, neurochemical, and electrophysiological characteristics similar to those of enteric neurons; they received synaptic inputs; and their neurites projected to muscle layers and the enteric ganglia of the recipient mice. These findings show that transplanted enteric neural progenitor cells can generate functional enteric neurons in the postnatal bowel and advances the notion that cell therapy is a promising strategy for enteric neuropathies.
The Internet-Based MGS2 Control Sample: Self Report of Mental Illness
Authors: Alan R. Sanders, Douglas F. Levinson, Jubao Duan, J. Michael Dennis, Rick Li, Kenneth S. Kendler, John P. Rice, Jianxin Shi, Bryan J. Mowry, Farooq Amin, Jeremy M. Silverman, Nancy G. Buccola, William F. Byerley, Donald W. Black, Robert Freedman, C. Robert Cloninger, Pablo V. Gejman
Journal: American Journal of Psychiatry (2010)

Objective The Molecular Genetics of Schizophrenia (MGS2) project recruited an adult control sample of non-Hispanic European-ancestry (N=3,364) and African American (N=1,301) subjects. Method Subjects gave consent to deposit phenotypic data and blood samples into a repository for general research use, with full anonymization of the sample. The authors compared the control sample with population census data for demographic data and with previous population surveys for anthropometrics and prevalences of psychiatric disorders as estimated by an Internet-administered questionnaire. Results The full MGS2 control sample includes 4,665 subjects (European-ancestry: N=3,364; African American: N=1,301), of whom 3,626 were included in the MGS2 genome-wide association study (GWAS). The sample is generally demographically representative of the U.S. population, except for being older and more female, educated, and affluent, although all strata are represented. Self-reported ancestry was consistent with genotypic and census data. Lifetime prevalences for depressive, anxiety, and substance use diagnoses were higher than in previous population-based surveys, probably due to use of an abbreviated self-report instrument. However, patterns such as sex ratios, comorbidity, and demographic associations were consistent with previous reports. DNA quality for the Internet collected/evaluated control sample was comparable to that of the face-to-face case sample. Conclusions The Internet-based methods facilitated the rapid collection of large and anonymized non-Hispanic European-ancestry and African American control samples that have been validated as being generally representative for many aspects of demography, ancestry, and morbidity. Utilization of clinical screening data shared with the scientific community may permit investigators to select appropriate controls for some studies.
Overall and Relapse-Free Survival in Oropharyngeal and Hypopharyngeal Squamous Cell Carcinoma Are Associated with Genotypes of T393C Polymorphism of the <i>GNAS1</i> Gene
Authors: Goetz F. Lehnerdt, Peter Franz, Anwar Zaqoul, Klaus J. Schmitz, Sara Grehl, Stephan Lang, Kurt W. Schmid, Winfried Siffert, Klaus Jahnke, Ulrich H. Frey
Journal: Clinical Cancer Research (2008)

Abstract Purpose: In previous studies, we have shown that the T allele of a specific single-nucleotide polymorphism (SNP) in the Gαs gene (T393C) correlates with increased Gαs expression and hence apoptosis. The T allele was associated with a favorable outcome in a variety of human cancers, e.g., carcinoma of the urinary bladder, kidney, and colorectum. Experimental Design: The prognostic value of the T393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival. Results: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death. Conclusion: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.
Inhibition of p53-Murine Double Minute 2 Interaction by Nutlin-3A Stabilizes p53 and Induces Cell Cycle Arrest and Apoptosis in Hodgkin Lymphoma
Authors: Elias Drakos, Athanasios Thomaides, L. Jeffrey Medeiros, Jiang Li, Vasiliki Leventaki, Marina Konopleva, Michael Andreeff, George Z. Rassidakis
Journal: Clinical Cancer Research (2007)

p53 is frequently expressed but rarely mutated in Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's lymphoma (HL). p53 protein levels are regulated by murine double minute 2 (MDM2) through a well-established autoregulatory feedback loop. In this study, we investigated the effects of nutlin-3A, a recently developed small molecule that antagonizes MDM2 and disrupts the p53-MDM2 interaction, on p53-dependent cell cycle arrest and apoptosis in cultured HRS cells.HL cell lines carrying wild-type (wt) or mutated p53 gene were treated with the potent MDM2 inhibitor nutlin-3A or a 150-fold less active enantiomer, nutlin-3B.We show that nutlin-3A, but not nutlin-3B, stabilizes p53 in cultured HRS cells carrying wt p53 gene resulting in p53-dependent cell cycle arrest and apoptosis. Cell cycle arrest was associated with up-regulation of the cyclin-dependent kinase inhibitor p21. Nutlin-3A-induced apoptotic cell death was accompanied by Bax and Puma up-regulation and caspase-3 cleavage and was abrogated, in part, by inhibition of caspase-9 and caspase-3 activity. By contrast, no effects on cell cycle or apoptosis were found in HL cell lines harboring mutated p53 gene. Furthermore, combined treatment with nutlin-3A and doxorubicin revealed enhanced cytotoxicity in HRS cells with wt p53 gene. Blocking of nuclear export by leptomycin B, or inhibition of proteasome by MG132, stabilized p53 at a level comparable with that of nutlin-3A treatment in HRS cells with wt p53.These data suggest that nutlin-3A stabilized p53 by preventing MDM2-mediated p53 degradation in HRS cells. wt p53 stabilization and activation by nutlin-3A may be a novel therapeutic approach for patients with HL.
A Drosophila In Vivo Screen Identifies Store-Operated Calcium Entry as a Key Regulator of Adiposity
Authors: Jens Baumbach, Petra Hummel, Iris Bickmeyer, Katarzyna M Kowalczyk, Martina Frank, Konstantin Knorr, Anja Hildebrandt, Dietmar Riedel, Herbert Jäckle, Ronald P Kühnlein
Journal: Cell Metabolism (2014)
Comparative in vitro performance of the new drug aclidinium in a novel multidose dry powder inhaler
Authors: Doetie Gjaltema, Paul Hagedoorn, Floris Grasmeijer, Bernardus G. Huijbers, Henderik W. Frijlink, Anne H. De Boer
Journal: European Respiratory Journal (2013)

Background:  With new inhalation products, lack of knowledge of how much drug is deposited at the site of action in the lungs plus variation in performance of inhalation devices can lead to inaccurate conclusions about drug efficacy.   Aim:  To compare the consistency of delivered dose (DD) and fine particle dose (FPD) from four inhalation devices.   Methods:  This in vitro study compared inhalers used for delivery of: aclidinium 400 µg (Genuair®); tiotropium 18 and 2.5 µg (HandiHaler®, Respimat®); and indacaterol 150 µg (Breezhaler®) at three different inhalation flow rates. Measurements included airflow resistance, consistency of DD, FPD and dose emission times.   Results:  Airflow resistance was highest with HandiHaler, medium with Genuair and lowest with Respimat and Breezhaler. Flow rates corresponding to a 4 kPa pressure drop across the dry powder inhalers were: 38.8 L/min, HandiHaler; 64.5 L/min, Genuair; and 105.3 L/min Breezhaler. Generally, mean DDs were independent of flow rate and consistent over labelled contents. FP mass fractions of 1–3 µm and 3–6 µm differed among devices. Genuair delivered the finest particles within the FPD  :  2.4 µm) followed by Breezhaler (2.9 µm); HandiHaler and Respimat delivered the coarsest particles (3.5 and 3.3 µm, respectively). However, Respimat delivered the highest very fine particle mass fraction    Conclusions:  Based on known in vitro in vivo correlations 1  it can be assumed that different inhalation systems will have significantly different lung depositions.   1 Usmani et al. AJRCCM 2005;172:1497-1504.
Proteinuria Impairs Podocyte Regeneration by Sequestering Retinoic Acid
Authors: Anna Peired, Maria Lucia Angelotti, Elisa Ronconi, Giancarlo la Marca, Benedetta Mazzinghi, Alessandro Sisti, Duccio Lombardi, Elisa Giocaliere, Marialuisa Della Bona, Fabio Villanelli, Eliana Parente, Lara Ballerini, Costanza Sagrinati, Nicola Wanner, Tobias B. Huber, Helen Liapis, Elena Lazzeri, Laura Lasagni, Paola Romagnani
Journal: Journal of the American Society of Nephrology (2013)

In CKD, the risk of kidney failure and death depends on the severity of proteinuria, which correlates with the extent of podocyte loss and glomerular scarring. We investigated whether proteinuria contributes directly to progressive glomerulosclerosis through the suppression of podocyte regeneration and found that individual components of proteinuria exert distinct effects on renal progenitor survival and differentiation toward a podocyte lineage. In particular, albumin prevented podocyte differentiation from human renal progenitors in vitro by sequestering retinoic acid, thus impairing retinoic acid response element (RARE)-mediated transcription of podocyte-specific genes. In mice with Adriamycin nephropathy, a model of human FSGS, blocking endogenous retinoic acid synthesis increased proteinuria and exacerbated glomerulosclerosis. This effect was related to a reduction in podocyte number, as validated through genetic podocyte labeling in NPHS2.Cre;mT/mG transgenic mice. In RARE-lacZ transgenic mice, albuminuria reduced retinoic acid bioavailability and impaired RARE activation in renal progenitors, inhibiting their differentiation into podocytes. Treatment with retinoic acid restored RARE activity and induced the expression of podocyte markers in renal progenitors, decreasing proteinuria and increasing podocyte number, as demonstrated in serial biopsy specimens. These results suggest that albumin loss through the damaged filtration barrier impairs podocyte regeneration by sequestering retinoic acid and promotes the generation of FSGS lesions. Our findings may explain why reducing proteinuria delays CKD progression and provide a biologic rationale for the clinical use of pharmacologic modulators to induce regression of glomerular diseases.
Phase I and Pharmacokinetic Study of Pemetrexed plus Cisplatin in Chemonaive Patients with Locally Advanced or Metastatic Malignant Pleural Mesothelioma or Non–Small Cell Lung Cancer
Authors: Nicolas J. Dickgreber, Thomas H. Fink, Jane E. Latz, Anwar M. Hossain, Luna C. Musib, Michael Thomas
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Pemetrexed is approved as monotherapy and in combination with cisplatin. The established combination dose was identified before the addition of folic acid and vitamin B12 to the treatment regimen. We evaluated the toxicity and pharmacokinetics (PK) of higher pemetrexed doses with cisplatin and vitamin supplementation. Experimental Design: Patients with malignant pleural mesothelioma or non–small cell lung cancer received pemetrexed doses from 500 to 900 mg/m2 + 75 mg/m2 cisplatin once every 21 days. Folic acid and vitamin B12 were administered per label recommendations. Results: Twenty-one patients received a combined total of 84 cycles. The maximum tolerated dose was 900 mg/m2 pemetrexed + 75 mg/m2 cisplatin. Dose-limiting toxicities at this dose included grade 3 anemia, bronchopneumonia, and neutropenia, and 1 death from sepsis secondary to grade 4 febrile neutropenia, considered possibly related to study drugs. The recommended dose was 800 mg/m2 pemetrexed + 75 mg/m2 cisplatin. Pemetrexed PK were consistent across doses; pemetrexed did not seem to affect total or free platinum PK. Conclusions: Pemetrexed with vitamin supplementation was safe and well tolerated at higher doses than the currently established 500 mg/m2 + 75 mg/m2 cisplatin. Based on this study, the recommended dose would be 800 mg/m2 pemetrexed + 75 mg/m2 cisplatin. However, recent studies showed a lack of improved efficacy for 900 or 1,000 mg/m2 single-agent pemetrexed versus 500 mg/m2 and a lack of PK/pharmacodynamic exposure-response relationship for the pemetrexed/cisplatin combination across pemetrexed exposures corresponding to this dose range. Based on currently available evidence, we recommend retaining the established dose.
Dietary antioxidant intake, allergic sensitization and allergic diseases in young children
Authors: S. Patel, C. S. Murray, A. Woodcock, A. Simpson, A. Custovic
Journal: Allergy (2009)

Allergic diseases have risen in prevalence over recent decades. The aetiology remains unclear but is likely to be a result of changing lifestyle and/or environment. A reduction in antioxidant intake, consequent to reduced intake of fresh fruits and vegetables, has been suggested as a possible cause.To investigate whether dietary antioxidant intake at age 5 was related to atopy at 5 and 8 years of age amongst children in an unselected birth cohort.Children were followed from birth. Parents completed a validated respiratory questionnaire and children were skin prick tested at 5 and 8 years of age. Serum IgE levels were measured at age 5. At age 5, antioxidant intake was assessed using a semi-quantitative food frequency questionnaire (FFQ). A nutrient analysis program computed nutrient intake, and frequency counts of foods high in the antioxidant vitamins A, C and E were assessed.Eight hundred and sixty-one children completed both the respiratory and FFQ. Beta-carotene intake was associated with reduced risk of allergic sensitization at age 5 [0.80 (0.68-0.93)] and 8 [0.81 (0.70-0.94)]. In addition, beta-carotene intake was negatively associated with total IgE levels (P = 0.002). Vitamin E intake was associated with an increased risk of allergic sensitization [1.19 (1.02-1.39)], only at age 5. There was no association between antioxidant intakes and wheeze or eczema.Increased beta-carotene intake was associated with a reduced risk of allergic sensitization and lower IgE levels, in 5- and 8-year-old children. Dietary antioxidants may play a role in the development of allergic sensitization.
Pneumococcal spherical pneumonia multiply distributed in one lung
Authors: Y Katsumura, K Shirakami, S Satoh
Journal: European Respiratory Journal (1997)

Spherical pneumonia, which is seen more frequently in children than in adults, is usually manifested as a solitary nodule. We report the case of a middle-aged man with small spherical pneumonia, with multiple distribution in the right lung, caused by Streptococcus pneumoniae. This type of pneumonia is very unusual and should be included in the differential diagnosis of multiple nodular densities of the lung.
Glucagonoma syndrome demonstrating giant duodenal villi.
Authors: F M Stevens, R W Flanagan, D O'Gorman, K D Buchanan
Journal: Gut (1984)

A 39 year old man developed an itchy bullous rash in the perineum and on the extremities. Six years later, after giant intestinal villi had been noted at endoscopy, a diagnosis of the glucagonoma syndrome was made. Investigation revealed a large tumour of the pancreatic body and tail. The molecular species of glucagon secreted by the tumour were characterised using the combined purification procedures of immunoaffinity chromatography followed by gel filtration.
Neutrophil Elastase in Human Atherosclerotic Plaques
Authors: Clare M. Dollery, Caroline A. Owen, Galina K. Sukhova, Alexandra Krettek, Steven D. Shapiro, Peter Libby
Journal: Circulation (2003)

Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease. Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheroma-related cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity.Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (n=7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1beta, TNF-alpha, or IFN-gamma but released it when stimulated by CD40 ligand, a cytokine found in atheroma.These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.
Cytokine-induced glucocorticoid resistance: Effect on GILZ expression and reversal by formoterol
Authors: Christopher Rider, Joanna Chivers, Anna Miller-Larsson, Mark Giembycz, Robert Newton
Journal: European Respiratory Journal (2013)

The most effective treatment for asthma is inhaled glucocorticoid (GC), whose anti-inflammatory activity can be synergistically enhanced by addition of a long-acting β2-adrenoceptor agonist (LABA), e.g. formoterol. However, in severe asthma enhanced production of cytokines, such as interleukin (IL)-1β and tumor necrosis factor α (TNF), appears to contribute to GC resistance. We therefore examined cytokine-induced resistance to the GC dexamethasone (Dex) in human pulmonary cells and evaluated the effects of formoterol.

METHODS: Type II A549 epithelial cells were pre-treated for 2 h with IL-1β (1 ng/ml), before Dex (1 µM) addition, and harvested 2 or 4 h later for microarray analysis. Primary human airway smooth muscle (ASM) and bronchial epithelial (HBE) cells, or BEAS-2B and A549 cells with 2×glucocorticoid response element (GRE) reporter, were pre-treated with TNF (10 ng/ml) or IL-1β for 1 h prior to 6 h Dex and/or formoterol (10 nM) treatment, followed by RT-PCR analysis of GILZ and GAPDH expression or luciferase assay.

RESULTS: Expression of a majority of Dex-induced genes on the microarray was repressed by IL-1β. Both IL-1β and TNF repressed 2×GRE reporter activation in A549 cells, while formoterol functionally reversed TNF-induced repression in BEAS-2B 2×GRE cells. Expression of GILZ, a GC inducible gene, was significantly repressed in BEAS-2B, ASM and HBE cells. However, this repression was modestly reversed by formoterol addition in ASM and BEAS-2B cells.

CONCLUSIONS: IL-1β and TNF induce GC resistance in multiple lung cells relevant to asthma, in a manner that is reversed by formoterol. This provides support for the use of GC/LABA combinations in severe asthma.