tbuckley/cabot-search huggingface dataset:
THE ROLE OF HOMOCYSTINE IN PROTECTING PROTEIN-DEPLETED DOGS EXPOSED TO FATAL DOSES OF CHLOROFORM
Authors: George P. Vennart, Frank W. McKee
Journal: The Journal of Experimental Medicine (1955)

In dogs maintained on low protein diets and subjected to phlebotomy over a long period of time, the inhalation of chloroform, for 30 minutes, produced uniform fatality within 48 hours. The histological changes of massive hepato-cellular destruction were observed at autopsy. Homocystine, in the amount of 2.0 gm., given orally 2 hours after or 2 hours prior to the administration of chloroform, protected dogs against the lethal action of the toxin. Inconstant changes in fibrinogen and icteric indices were observed in the protected animals, indicating some mild liver damage, but this was not correlated with the length of the previous depletion period, the phase of the experiment, or any other factor. No evidence was obtained that methyl groups are necessary for the protection of the liver by homocystine.
The Role of Vitamin D in Bone and Intestinal Cell Differentiation
Authors: T Suda, T Shinki, N Takahashi
Journal: Annual Review of Nutrition (1990)

Dans cet article de synthese, il est montre que la capacite du cholecalciferol(dihydro-1,25) a induire la differenciation cellulaire est intimement liee a ses fonctions elastiques dans la regulation du metabolisme du calcium dans les deux organes cibles principaux de la vitamine D: l'intestin et l'os
Human ESCs predisposition to karyotypic instability: Is a matter of culture adaptation or differential vulnerability among hESC lines due to inherent properties?
Authors: Puri Catalina, Rosa Montes, Gertru Ligero, Laura Sanchez, Teresa de la Cueva, Clara Bueno, Paola E Leone, Pablo Menendez
Journal: Molecular Cancer (2008)

Abstract Background The use of human embryonic stem cells (hESCs) in research is increasing and hESCs hold the promise for many biological, clinical and toxicological studies. Human ESCs are expected to be chromosomally stable since karyotypic changes represent a pitfall for potential future applications. Recently, several studies have analysed the genomic stability of several hESC lines maintained after prolonged in vitro culture but controversial data has been reported. Here, we prompted to compare the chromosomal stability of three hESC lines maintained in the same laboratory using identical culture conditions and passaging methods. Results Molecular cytogenetic analyses performed in three different hESC lines maintained in parallel in identical culture conditions revealed significant differences among them in regard to their chromosomal integrity. In feeders, the HS181, SHEF-1 and SHEF-3 hESC lines were chromosomally stable up to 185 passages using either mechanical or enzymatic dissection methods. Despite the three hESC lines were maintained under identical conditions, each hESC line behaved differently upon being transferred to a feeder-free culture system. The two younger hESC lines, HS181 (71 passages) and SHEF-3 (51 passages) became chromosomally unstable shortly after being cultured in feeder-free conditions. The HS181 line gained a chromosome 12 by passage 17 and a marker by passage 21, characterized as a gain of chromosome 20 by SKY. Importantly, the mosaicism for trisomy 12 gradually increased up to 89% by passage 30, suggesting that this karyotypic abnormality provides a selective advantage. Similarly, the SHEF-3 line also acquired a trisomy of chromosome 14 as early as passage 10. However, this karyotypic aberration did not confer selective advantage to the genetically abnormal cells within the bulk culture and the level of mosaicism for the trisomy 14 remained overtime between 15%–36%. Strikingly, however, a much older hESC line, SHEF-1, which was maintained for 185 passages in feeders did not undergo any numerical or structural chromosomal change after 30 passages in feeder-free culture and over 215 passages in total. Conclusion These results support the concept that feeder-free conditions may partially contribute to hESC chromosomal changes but also confirm the hypothesis that regardless of the culture conditions, culture duration or splitting methods, some hESC lines are inherently more prone than others to karyotypic instability.
A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors
Authors: Jhanelle E. Gray, Eric Haura, Alberto Chiappori, Tawee Tanvetyanon, Charles C. Williams, Mary Pinder-Schenck, Julie A. Kish, Jenny Kreahling, Richard Lush, Anthony Neuger, Leticia Tetteh, Angela Akar, Xiuhua Zhao, Michael J. Schell, Gerold Bepler, Soner Altiok
Journal: Clinical Cancer Research (2014)

Panobinostat, a histone deacetylase (HDAC) inhibitor, enhances antiproliferative activity in non-small cell lung cancer (NSCLC) cell lines when combined with erlotinib. We evaluated this combination in patients with advanced NSCLC and head and neck cancer.Eligible patients were enrolled in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of twice weekly panobinostat plus daily erlotinib at four planned dose levels (DL). Pharmacokinetics, blood, fat pad biopsies (FPB) for histone acetylation, and paired pre and posttherapy tumor biopsies for checkpoint kinase 1 (CHK1) expression were assessed.Of 42 enrolled patients, 33 were evaluable for efficacy. Dose-limiting toxicities were prolonged-QTc and nausea at DL3. Adverse events included fatigue and nausea (grades 1-3), and rash and anorexia (grades 1-2). Disease control rates were 54% for NSCLC (n = 26) and 43% for head and neck cancer (n = 7). Of 7 patients with NSCLC with EGF receptor (EGFR) mutations, 3 had partial response, 3 had stable disease, and 1 progressed. For EGFR-mutant versus EGFR wild-type patients, progression-free survival (PFS) was 4.7 versus 1.9 months (P = 0.43) and overall survival was 41 (estimated) versus 5.2 months (P = 0.39). Erlotinib pharmacokinetics was not significantly affected. Correlative studies confirmed panobinostat's pharmacodynamic effect in blood, FPB, and tumor samples. Low CHK1 expression levels correlated with PFS (P = 0.006) and response (P = 0.02).We determined MTD at 30 mg (panobinostat) and 100 mg (erlotinib). Further studies are needed to further explore the benefits of HDAC inhibitors in patients with EGFR-mutant NSCLC, investigate FPB as a potential surrogate source for biomarker investigations, and validate CHK1's predictive role.
Comparative Analyses of DNA Methylation and Sequence Evolution Using Nasonia Genomes
Authors: J. Park, Z. Peng, J. Zeng, N. Elango, T. Park, D. Wheeler, J. H. Werren, S. V. Yi
Journal: Molecular Biology and Evolution (2011)

The functional and evolutionary significance of DNA methylation in insect genomes remains to be resolved. Nasonia is well situated for comparative analyses of DNA methylation and genome evolution, since the genomes of a moderately distant outgroup species as well as closely related sibling species are available. Using direct sequencing of bisulfite-converted DNA, we uncovered a substantial level of DNA methylation in 17 of 18 Nasonia vitripennis genes and a strong correlation between methylation level and CpG depletion. Notably, in the sex-determining locus transformer, the exon that is alternatively spliced between the sexes is heavily methylated in both males and females, whereas other exons are only sparsely methylated. Orthologous genes of the honeybee and Nasonia show highly similar relative levels of CpG depletion, despite ∼190 My divergence. Densely and sparsely methylated genes in these species also exhibit similar functional enrichments. We found that the degree of CpG depletion is negatively correlated with substitution rates between closely related Nasonia species for synonymous, nonsynonymous, and intron sites. This suggests that mutation rates increase with decreasing levels of germ line methylation. Thus, DNA methylation is prevalent in the Nasonia genome, may participate in regulatory processes such as sex determination and alternative splicing, and is correlated with several aspects of genome and sequence evolution.
Improvement of Mild Sleep-disordered Breathing with CPAP Compared with Conservative Therapy
Authors: SUSAN REDLINE, NANCY ADAMS, MILTON E. STRAUSS, THERESA ROEBUCK, MARY WINTERS, CARL ROSENBERG
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The aim of this randomized controlled trial was to assess the effects of treatment with continuous positive airway pressure versus conservative therapy (CT) on well-being, mood, and functional status in subjects with mild sleep-disordered breathing (SDB). One hundred and eleven subjects, aged 25 to 65 yr, with a respiratory disturbance index (RDI) of 5 to 30 and without subjective pathologic sleepiness, were randomized to nasal CPAP or to CT. Ninety-seven subjects were followed-up after 8 wk. Treatment response was assessed from changes between baseline and follow-up measures of mood, energy/fatigue, and functional status/general health. Of the 51 subjects randomized to CPAP, 25 (49%) experienced an improved outcome, as compared with 12 of 46 of subjects (26%) randomized to CT (p < 0.05). The odds of experiencing a treatment response in the CPAP as compared with the CT group were 2.72 (OR: 1.18 to 6.58, 95% CI). A beneficial effect of CPAP over CT was most evident among individuals without sinus problems and among subjects with hypertension or diabetes. Differential treatment responses were not related to degree of baseline sleepiness or SDB. This suggests that middle-aged snorers with relatively low levels of SDB (RDI < 30) may benefit more from nasal CPAP than from less specific therapy directed at improving breathing during sleep. CPAP therapy may be beneficial to a broader group of subjects than previously appreciated.
Myocardial Strain by Doppler Echocardiography
Authors: Stig Urheim, Thor Edvardsen, Hans Torp, Bjørn Angelsen, Otto A. Smiseth
Journal: Circulation (2000)

Myocardial strain is a measure of regional deformation, and by definition, negative strain means shortening and positive strain, elongation. This study investigates whether myocardial strain can be measured by Doppler echocardiography as the time integral of regional velocity gradients, using sonomicrometry as reference method.In 13 anesthetized dogs, myocardial longitudinal strain was measured on apical images as the time integral of regional Doppler velocity gradients. Ultrasonic segment-length crystals were placed near the left ventricular (LV) apex and near the base. Apical ischemia was induced by occluding the left anterior descending coronary artery (LAD), and preload was increased by saline. Percentage systolic strain by Doppler correlated well with strain by sonomicrometry (y=0.82x-1.79, r=0.92, P<0.01). During LAD occlusion, apical myocardium became dyskinetic, as indicated by positive strain values and negative Doppler velocities. At the LV base, myocardial strain by Doppler, strain by sonomicrometry, and velocity of shortening by sonomicrometry (dL/dt) were unchanged during apical ischemia. However, myocardial Doppler velocities at the base decreased from 4.2+/-0.7 (+/-SEM) to 2.7+/-0. 4 cm/s (P<0.05), probably reflecting loss of motion caused by tethering to apical segments. Volume loading increased myocardial Doppler velocities from 2.2+/-0.3 to 4.1+/-0.8 cm/s (P<0.05) and Doppler-derived strain from -12+/-1% to -22+/-2% (P<0.05), whereas peak LV elastance remained unchanged.Myocardial strain by Doppler echocardiography may represent a new, powerful method for quantifying regional myocardial function and is less influenced by tethering effects than Doppler tissue imaging. Like myocardial Doppler velocities, strain is markedly load-dependent.
Postpolypectomy Colonoscopy Surveillance Guidelines: Predictive Accuracy for Advanced Adenoma at 4 Years
Authors: Adeyinka O Laiyemo, Gwen Murphy, Paul S Albert, Leah B Sansbury, Zhuoqiao Wang, Amanda J Cross, Pamela M Marcus, Bette Caan, James R Marshall, Peter Lance, Electra D Paskett, Joel Weissfeld, Martha L Slattery, Randall Burt, Frank Iber, Moshe Shike, J Walter Kikendall, Elaine Lanza, Arthur Schatzkin
Journal: Annals of Internal Medicine (2008)

Background: Lack of confidence in postpolypectomy surveillance guidelines may be a factor in the observed low adherence rates among providers. Objective: To assess the 2006 postpolypectomy colonoscopy surveillance guidelines, which recommend 3-year follow-up colonoscopy for individuals with high-risk adenomas (defined as ≥3 adenomas or any advanced adenomas) and 5- to 10-year follow-up for patients with 2 or fewer nonadvanced adenomas, who are considered to be at low risk. Design: Analysis of prospective data from the Polyp Prevention Trial. Setting: United States. Participants: 1905 patients who had colorectal adenomas removed at baseline screening or diagnostic colonoscopy and completed the trial. Measurements: Baseline adenoma characteristics, risk-stratified according to definitions used in the guidelines, were examined as predictors for advanced adenoma recurrence. Results: 125 patients (6.6%) had advanced and 629 (33.0%) had nonadvanced adenoma recurrence; 1151 (60.4%) had no recurrence within 4 years of follow-up. The probability of advanced adenoma recurrence was 0.09 (95% CI, 0.07 to 0.11) among patients with high-risk adenomas at baseline and 0.05 (CI, 0.04 to 0.06) among those with low-risk adenomas at baseline. The relative risk for advanced adenoma recurrence for patients with high-risk adenomas versus those with low-risk adenomas at baseline was 1.68 (CI, 1.19 to 2.38) when advanced adenoma recurrence was compared with no advanced adenoma recurrence and 1.76 (CI, 1.26 to 2.46) when advanced adenoma recurrence was compared with no adenoma recurrence. The c-statistics for these 2 comparisons were 0.68 and 0.72, respectively. Limitation: Participants were self-selected and had restrictions on the degree of obesity. Conclusion: Although the risk for recurrence of advanced adenoma within 4 years is greater for patients with high-risk adenomas at baseline than for those with low-risk adenomas, the discrimination of this risk stratification scheme is relatively low.
Genetic association between EPHX1 and Crohn's disease: population stratification, genotyping error, or random chance?
Authors: A P Cuthbert
Journal: Gut (2004)

We read with interest the article by de Jong and colleagues ( Gut 2003; 52 :547–51) reporting studies of genetic associations between DNA polymorphisms in xenobiotic metabolising genes and Crohn’s disease (CD). The authors employed a case control study design to test seven polymorphisms in five candidate genes for disease association. Evidence was found for a significant association of a single nucleotide polymorphism (SNP), Tyr113His (348T>C), in the microsomal epoxide hydrolase 1 gene ( EPHX1 ), with CD. Homozygosity for the T (Tyr 113) allele was significantly higher in cases than in healthy controls (χ2 = 23.7, p<0.0001, odds ratio 2.9). The observed frequency of the T allele in controls was 41%, which is outside the range of frequencies (58–94%) reported in other control populations (reviewed in de Jong et al ). Its frequency in CD cases was 67%. In view of the strength of reported association, we sought to replicate …
Frequency of voice problems and cough in patients using pressurized aerosol inhaled steroid preparations
Authors: IJ Williamson, SP Matusiewicz, PH Brown, AP Greening, GK Crompton
Journal: European Respiratory Journal (1995)

The aim of the study was to assess the prevalence of throat and voice symptoms in asthma patients using pressurized aerosol, metered-dose, inhaled corticosteroid preparations. A questionnaire was administered to hospital out-patients in an asthma clinic and to a control group attending a diabetic clinic. Two hundred and fifty five consecutive out-patients using pressurized aerosol inhaled corticosteroids and 100 controls were surveyed. One hundred and forty seven (58%) patients taking inhaled steroids reported voice dysphonia or throat symptoms compared with 13% of control patients. Women admitted to symptoms more frequently than men. Throat symptoms were more prevalent in patients using higher doses of inhaled steroid. Aerosol inhaler-induced cough was reported by 87 (34%) patients. Local side-effects were equally prevalent both with beclomethasone dipropionate and budesonide aerosol inhalers. The use of a large volume spacing device with either steroid aerosol did not appear to protect against these symptoms. Local side-effects are common in asthmatics taking pressurized aerosol, metered-dose, inhaled steroids.
Incidence of Type 2 Diabetes Using Proposed HbA1c Diagnostic Criteria in the European Prospective Investigation of Cancer–Norfolk Cohort
Authors: Parinya Chamnan, Rebecca K. Simmons, Nita G. Forouhi, Robert N. Luben, Kay-Tee Khaw, Nicholas J. Wareham, Simon J. Griffin
Journal: Diabetes Care (2010)

To evaluate the incidence and relative risk of type 2 diabetes defined by the newly proposed HbA(1c) diagnostic criteria in groups categorized by different baseline HbA(1c) levels.Using data from the European Prospective Investigation of Cancer (EPIC)-Norfolk cohort with repeat HbA(1c) measurements, we estimated the prevalence of known and previously undiagnosed diabetes at baseline (baseline HbA(1c) ≥6.5%) and the incidence of diabetes over 3 years. We also examined the incidence and corresponding odds ratios (ORs) by different levels of baseline HbA(1c). Incident diabetes was defined clinically (self-report at follow-up, prescribed diabetes medication, or inclusion on a diabetes register) or biochemically (HbA(1c) ≥6.5% at the second health assessment), or both.The overall prevalence of diabetes was 4.7%; 41% of prevalent cases were previously undiagnosed. Among 5,735 participants without diabetes at baseline (identified clinically or using HbA(1c) criteria, or both), 72 developed diabetes over 3 years (1.3% [95% CI 1.0-1.5]), of which 49% were identified using the HbA(1c) criteria. In 6% of the total population, the baseline HbA(1c) was 6.0-6.4%; 36% of incident cases arose in this group. The incidence of diabetes in this group was 15 times higher than in those with a baseline HbA(1c) of <5.0% (OR 15.5 [95% CI 7.2-33.3]).The cumulative incidence of diabetes defined using a newly proposed HbA(1c) threshold in this middle-aged British cohort was 1.3% over 3 years. Targeting interventions to individuals with an HbA(1c) of 6.0-6.4% might represent a feasible preventive strategy, although complementary population-based preventive strategies are also needed to reduce the growing burden of diabetes.
Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development
Authors: Robert L Wilensky, Yi Shi, Emile R Mohler, Damir Hamamdzic, Mark E Burgert, Jun Li, Anthony Postle, Robert S Fenning, James G Bollinger, Bryan E Hoffman, Daniel J Pelchovitz, Jisheng Yang, Rosanna C Mirabile, Christine L Webb, LeFeng Zhang, Ping Zhang, Michael H Gelb, Max C Walker, Andrew Zalewski, Colin H Macphee
Journal: Nature Medicine (2008)
Reversibility of T helper 1 and 2 populations is lost after long-term stimulation.
Authors: E Murphy, K Shibuya, N Hosken, P Openshaw, V Maino, K Davis, K Murphy, A O'Garra
Journal: The Journal of Experimental Medicine (1996)

Commitment of T helper 1 (Th1) or Th2 populations developing during an immune response to a pathogen, or an inappropriate immune response to an allergen or autoantigen, may determine the difference between health and chronic disease. We show that strongly polarized Th1 and Th2 populations assessed by immunoassay are heterogeneous using flow cytometry to detect single cells producing interferon gamma (IFN-gamma) and interleukin 4 (IL-4). Th1 populations arising after 1 wk of stimulation in IL-12 plus anti-IL-4 antibodies could convert to Th2 cells when restimulated in IL-4. Th2 populations resulting from stimulation for 1 wk in IL-4 could give rise to Th1 cells upon restimulation in IL-12 plus anti-IL-4. In contrast, the cytokine profiles of long-term Th1 and Th2 populations arising originally from repeated stimulation in IL-12 or IL-4 appeared more homogeneous and were not reversible, although IL-4 dramatically reduced the number of IFN-gamma-producing Th1 cells. This may explain previous reports that Th1 cells can be converted to Th2 cells.
Acute liver failure of unknown pathogenesis: The hidden agenda
Authors: Elizabeth Ann Fagan
Journal: Hepatology (1994)

A major proportion of sporadic cases of ALF remain of uncertain cause (formerly termed NANB hepatitis). The application of sensitive molecular biology techniques such as PCR indicates that a few cases may be due to cryptic infections with one or more known hepatotropic agents, such as HBV and HCV. Evidence continues to accumulate to incriminate at least one potentially novel and transmissible agent (candidate hepatitis F). In ALF of unknown pathogenesis, survival without transplantation remains less than 20% despite recent improvements in medical management. Close study of recurrent hepatitis after grafting may provide further clues to the possible causes of ALF and the interaction between infectious agent and host. The continued pursuit of potential causes seems justified to allow stratification according to possible pathogeneses. This scientific approach should provide a rational basis for future therapeutic options.
Triketocholanoic (Dehydrocholic) Acid. HEPATIC METABOLISM AND EFFECT ON BILE FLOW AND BILIARY LIPID SECRETION IN MAN
Authors: Roger D. Soloway, Alan F. Hofmann, Paul J. Thomas, Leslie J. Schoenfield, Peter D. Klein
Journal: Journal of Clinical Investigation (1973)

[24-(14)C]Dehydrocholic acid (triketo-5-beta-cholanoic acid) was synthesized from [24-(14)C]cholic acid, mixed with 200 mg of carrier, and administered intravenously to two patients with indwelling T tubes designed to permit bile sampling without interruption of the enterohepatic circulation. More than 80% of infused radioactivity was excreted rapidly in bile as glycine- and taurine-conjugated bile acids. Radioactive products were identified, after deconjugation, as partially or completely reduced derivatives of dehydrocholic acid. By mass spectrometry, as well as chromatography, the major metabolite (about 70%) was a dihydroxy monoketo bile acid (3alpha,7alpha-dihydroxy-12-keto-5beta-cholanoic acid); a second metabolite (about 20%) was a monohydroxy diketo acid (3alpha-hydroxy-7,12-di-keto-5beta-cholanoic acid); and about 10% of radioactivity was present as cholic acid. Reduction appeared to have been sequential (3 position, then 7 position, and then 12 position) and stereospecific (only alpha epimers were recovered). Bile flow, expressed as the ratio of bile flow to bile acid excretion, was increased after dehydrocholic acid administration. It was speculated that the hydroxy keto metabolites are hydrocholeretics. The proportion of cholesterol to lecithin and bile acids did not change significantly after dehydrocholic acid administration. In vitro studies showed that the hydroxy keto metabolites dispersed lecithin poorly compared to cholate; however, mixtures of cholate and either metabolite had dispersant properties similar to those of cholate alone, provided the ratio of metabolite to cholate remained below a value characteristic for each metabolite. These experiments disclose a new metabolic pathway in man, provide further insight into the hydrocholeresis induced by keto bile acids, and indicate the striking change in pharmacologic and physical properties caused by replacement of hydroxyl by a keto substituent in the bile acid molecule.