tbuckley/cabot-search huggingface dataset:
Physiologic Changes during Chronic Congestive Heart Failure in Dogs with Tricuspid Insufficiency and Pulmonic Stenosis
Authors: NICHOLAS A. YANKOPOULOS, JAMES O. DAVIS, JAMES A. MCFARLAND, JOHN HOLMAN, ALFRED CASPER
Journal: Circulation Research (1959)

chronic congestive heart failure was studied in dogs with surgically-produced tricuspid insufficiency and pulmonic stenosis. Ascites formed in association with an elevation in mean right atrial pressure. The volume of ascitic fluid and the rate of urinary sodium excretion varied greatly in individual dogs during the course of congestive failure and among the different animals. Sodium retention was most common but periods of sodium balance and natriuresis occurred. Comparative data on the right and left ventricles were obtained from determinations of intracardiac pressures, measurements of ventricular muscle mass at the time of sacrifice and studies of the lungs for evidence of chronic passive congestion. There was significant right ventricular hypertrophy but no evidence of left ventricular hypertrophy or failure.
Inactivation of Conditional <i>Rb</i> by <i>Villin-Cre</i> Leads to Aggressive Tumors outside the Gastrointestinal Tract
Authors: Melanie H. Kucherlapati, Andrew A. Nguyen, Roderick T. Bronson, Raju S. Kucherlapati
Journal: Cancer Research (2006)

Abstract We have crossed mice carrying the conditional Rbtm2Brn allele with a constitutive Villin-Cre transgenic mouse. The Villin promoter in these animals is highly expressed in adult intestine and kidney proximal tubules and is expressed in the gut and nephros anlagen during embryogenesis. We report here that these mice develop tumors between 12 and 17 months old outside the gastrointestinal (GI) tract. A high penetrance of pituitary tumors and medullar carcinoma of the thyroid is observed with a lower incidence of hyperplasia of pulmonary neuroendocrine cells and aggressive liver, bile duct, stomach, oral cavity tumors, and lipomas. Rb rearrangement due to ectopic Villin promoter activity in neural crest or neural crest stem cells during embryogenesis is most likely responsible for the medullar carcinoma of the thyroid phenotype. The aggressive nature of the medullar carcinoma of the thyroid and its ability to metastasize to unusual sites make the model suitable for the study of tumor progression and mechanism of metastasis. Observed sites of metastasis include the stomach, small intestine, liver, lung, kidney, pancreas, spleen, bone marrow, salivary gland, fat, lymph nodes, and dorsal root ganglion. Because the Villin promoter is highly active throughout the GI and in the nephros anlagen during development, we find that Rb inactivation is not sufficient to initiate tumorigenesis in the GI or kidneys in mice. (Cancer Res 2006; 66(7): 3576-83)
Scheduled endoscopic surveillance controls secondary cancer after curative endoscopic resection for early gastric cancer: a multicentre retrospective cohort study by Osaka University ESD study group
Authors: Motohiko Kato, Tsutomu Nishida, Katsumi Yamamoto, Shiro Hayashi, Shinji Kitamura, Takamasa Yabuta, Toshiyuki Yoshio, Takeshi Nakamura, Masato Komori, Naoki Kawai, Akihiro Nishihara, Fumihiko Nakanishi, Masanori Nakahara, Hideharu Ogiyama, Kazuo Kinoshita, Takuya Yamada, Hideki Iijima, Masahiko Tsujii, Tetsuo Takehara
Journal: Gut (2012)

<h3>Background</h3> After endoscopic submucosal dissection (ESD) of early gastric cancer (EGC), patients are at high risk for synchronous or metachronous multiple gastric cancers. <h3>Objective</h3> To elucidate the time at which multiple cancers develop and to determine whether scheduled endoscopic surveillance might control their development. <h3>Design</h3> A multicentre retrospective cohort study from 12 hospitals was conducted. Patients with EGC who underwent ESD with en bloc margin-negative curative resection were included. Synchronous cancer was classified as concomitant cancer or missed cancer. The cumulative incidence of metachronous cancers and overall survival rate were calculated using the Kaplan–Meier method. <h3>Results</h3> From April 1999 to December 2010, 1258 patients met the inclusion criteria. Synchronous or metachronous multiple cancers were detected in 175 patients (13.9%) during a mean of 26.8 months. Among the 110 synchronous cancers, 21 were missed at the time of the initial ESD. Many of the missed lesions existed in the upper third of the stomach and the miss rate was associated with the endoscopist9s inexperience (&lt;500 oesophagogastroduodenoscopy cases). The cumulative incidence of metachronous cancers increased linearly and the mean annual incidence rate was 3.5%. The incidence rate did not differ between patients with or without <i>Helicobacter pylori</i> eradication. Four lesions (0.32%) were detected as massively invading cancers during the follow-up. <h3>Conclusions</h3> Nineteen per cent of synchronous cancers were not detected until the initial ESD. The incidence rate of metachronous cancer after ESD was constant. Scheduled endoscopic surveillance showed that almost all recurrent lesions were treatable by endoscopic resection.
Immunoglobulins and dietary protein antibodies in childhood coeliac disease
Authors: K. G. Kenrick, J. A. Walker-Smith
Journal: Gut (1970)

Twenty-four children with coeliac disease were compared with a control group, comprising 17 children with a variety of gastroenterological disorders, with respect to serum immunoglobulins and dietary protein antibodies. Elevated levels of IgA and abnormally low levels of IgM were demonstrated in one third of the coeliac patients. Antibodies to at least one of eight dietary proteins were found in 50% of coeliac children. Three children with raised levels of serum IgA and two with deficient IgM were re-examined after varying periods on a gluten-free diet. Antibodies to dietary proteins had waned and immunoglobulin levels returned to normal in all cases. The raised IgA was considered to have resulted from an extensive immunological response to antigens of dietary origin which had entered through the abnormal gut mucosa. It is suggested that IgM deficiency was due to specific inhibition of IgM synthesis by dietary components which had also entered through the mucosa.
Breath analysis during one-lung ventilation in cancer patients
Authors: Sabine Kischkel, Wolfram Miekisch, Patricia Fuchs, Jochen K. Schubert
Journal: European Respiratory Journal (2012)

Noninvasive breath analysis may provide valuable information for cancer recognition if disease-specific volatile biomarkers could be identified. In order to compare nondiseased and diseased tissue in vivo , this study took advantage of the special circumstances of one-lung ventilation (OLV) during lung-surgery. 15 cancer patients undergoing lung resection with OLV were enrolled. From each patient, alveolar breath samples were taken separately from healthy and diseased lungs before and after tumour resection. Volatile substances were pre-concentrated by means of solid-phase microextraction, and were separated, identified and quantified by means of gas chromatography–mass spectrometry. Different classes of volatile substances could be identified according to their concentration profiles. Due to prolonged fasting and activation of lipolysis, concentrations of endogenous acetone significantly increased during surgery. Exogenous substances, such as benzene or cyclohexanone, showed typical washout exhalation kinetics. Exhaled concentrations of potentially tumour associated substances, such as butane or pentane, were different for nondiseased and diseased lungs and decreased significantly after surgery. Separate analysis of volatile substances exhaled from healthy and diseased lungs in the same patient, together with thorough consideration of substance origins and exhalation kinetics offers unique opportunities of biomarker recognition and evaluation.
Involvement of the Tubulin Tyrosine Ligase-Like Family Member 4 Polyglutamylase in PELP1 Polyglutamylation and Chromatin Remodeling in Pancreatic Cancer Cells
Authors: Kotoe Kashiwaya, Hidewaki Nakagawa, Masayo Hosokawa, Yasuo Mochizuki, Koji Ueda, Lianhua Piao, Suyoun Chung, Ryuji Hamamoto, Hidetoshi Eguchi, Hiroaki Ohigashi, Osamu Ishikawa, Carsten Janke, Yasuhisa Shinomura, Yusuke Nakamura
Journal: Cancer Research (2010)

Polyglutamylation is a new class of posttranslational modification in which glutamate side chains are formed in proteins, although its biological significance is not well known. Through our genome-wide gene expression profile analyses of pancreatic ductal adenocarcinoma (PDAC) cells, we identified the overexpression of tubulin tyrosine ligase-like family member 4 (TTLL4) in PDAC cells. Subsequent reverse transcription-PCR and Northern blot analyses confirmed its upregulation in several PDACs. TTLL4 belongs to the TTLL family which was reported to have polyglutamylase activity. Knockdown of TTLL4 by short hairpin RNA in PDAC cells attenuated the growth of PDAC cells and exogenous introduction of TTLL4 enhanced cell growth. We also found that TTLL4 expression was correlated with polyglutamylation levels of a glutamate stretch region of the proline, glutamate, and leucine-rich protein 1 (PELP1) that was shown to interact with various proteins such as histone H3, and was involved in several signaling pathways through its function as a scaffold protein. PELP1 polyglutamylation could influence its interaction with histone H3 and affect histone H3 acetylation. We also identified the interaction of PELP1 with LAS1L and SENP3, components of the MLL1-WDR5 supercomplex involving chromatin remodeling. Our findings imply that TTLL4 could play important roles in pancreatic carcinogenesis through its polyglutamylase activity and subsequent coordination of chromatin remodeling, and might be a good molecular candidate for the development of new therapeutic strategies for pancreatic cancer.
In Vivo Therapeutic Success of MicroRNA‐155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage
Authors: Shiyu Zhou, Yan Wang, Yao Meng, Chunyuan Xiao, Zheng Liu, Philip Brohawn, Brandon W. Higgs, Bahija Jallal, Qian Jia, Bo Qu, Xinfang Huang, Yuanjia Tang, Yihong Yao, John B. Harley, Nan Shen
Journal: Arthritis & Rheumatology (2015)

Objective Diffuse alveolar hemorrhage (DAH) is a rare but life‐threatening complication of systemic lupus erythematosus (SLE). Pristane‐treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA‐155 (miR‐155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. Recent studies have revealed a pathogenic role of miR‐155 in various autoimmune disorders. The purpose of this study was to examine the role of miR‐155 in the development of DAH in pristane‐induced lupus using miR‐155–knockout (miR‐155 −/− ) mice and miR‐155 antagomir to silence miR‐155. Methods DAH was induced by an intraperitoneal injection of 0.5 ml of pristane. MicroRNA‐155 antagomir was administered intravenously to silence miR‐155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real‐time quantitative polymerase chain reaction analysis was used for single‐gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation. Results MicroRNA‐155 expression was significantly increased during the development of DAH. Disease progression was reduced in miR‐155 −/− mice as well as by in vivo silencing of miR‐155 using a miR‐155 antagomir. MicroRNA‐155 silencing dampened pristane‐induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF‐κB signaling were inhibited by pristane and were reactivated in miR‐155 −/− mice. In particular, the antiinflammatory factor peroxisome proliferator–activated receptor α was identified as a direct target of miR‐155. Conclusion MicroRNA‐155 promotes pristane‐induced lung inflammation. It contributes to ectopic activation of NF‐κB signaling pathways by targeting multiple negative regulators. MicroRNA‐155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.
Creatine Kinase Activity Is Associated With Blood Pressure
Authors: Lizzy M. Brewster, Gideon Mairuhu, Navin R. Bindraban, Richard P. Koopmans, Joseph F. Clark, Gert A. van Montfrans
Journal: Circulation (2006)

Background— We previously hypothesized that high activity of creatine kinase, the central regulatory enzyme of energy metabolism, facilitates the development of high blood pressure. Creatine kinase rapidly provides adenosine triphosphate to highly energy-demanding processes, including cardiovascular contraction, and antagonizes nitric oxide–mediated functions. Relatively high activity of the enzyme, particularly in resistance arteries, is thought to enhance pressor responses and increase blood pressure. Tissue creatine kinase activity is reported to be high in black people, a population subgroup with greater hypertension risk; the proposed effects of high creatine kinase activity, however, are not “race dependent.” We therefore assessed whether creatine kinase is associated with blood pressure in a multiethnic population. Methods and Results— We analyzed a stratified random sample of the population of Amsterdam, the Netherlands, consisting of 1444 citizens (503 white European, 292 South Asian, 580 black, and 69 of other ethnicity) aged 34 to 60 years. We used linear regression analysis to investigate the association between blood pressure and normal serum creatine kinase after rest, as a substitute measure of tissue activity. Creatine kinase was independently associated with blood pressure, with an increase in systolic and diastolic pressure, respectively, of 8.0 (95% CI, 3.3 to 12.7) and 4.7 (95% CI, 1.9 to 7.5) mm Hg per log creatine kinase increase after adjustment for age, sex, body mass index, and ethnicity. Conclusions— Creatine kinase is associated with blood pressure. Further studies are needed to explore the nature of this association, including how variation in cardiovascular creatine kinase activity may affect pressor responses.
New Fibrate Use and Acute Renal Outcomes in Elderly Adults
Authors: Ying Y. Zhao
Journal: Annals of Internal Medicine (2012)

Background: Fibric acid derivatives (fibrates) have been shown to increase serum creatinine level in randomized trials. Objective: To assess renal outcomes in elderly adults within 90 days of a new fibrate prescription. Design: Population-based cohort study. Setting: Ontario, Canada. Patients: Patients aged 66 years or older with a new outpatient prescription for a fibrate or ezetimibe (comparator drug) between January 2004 and December 2008. Measurements: Hospitalization for an increase in serum creatinine level (primary outcome) and consultation with a nephrologist, receipt of dialysis for severe acute kidney injury, all-cause mortality, and increases in serum creatinine level (secondary outcomes). All outcomes were assessed within 90 days of a new prescription for ezetimibe or a fibrate. Results: Compared with ezetimibe users (n = 61 831), fibrate users (n = 19 072) were more likely to be hospitalized for an increase in serum creatinine level (adjusted odds ratio, 2.4 [95% CI, 1.7 to 3.3]) and were more likely to consult a nephrologist (absolute risk difference, 0.15% [CI, 0.01% to 0.29%]; adjusted odds ratio, 1.3 [CI, 1.0 to 1.6]). There were no differences between groups in the risk for all-cause mortality or receiving dialysis for severe acute kidney injury. In a subpopulation of 1110 patients (fibrates, n = 220; ezetimibe, n = 890), 9.1% of fibrate users and 0.3% of ezetimibe users had an increase in serum creatinine level of 50% or more (absolute difference, 8.8% [CI, 4.5% to 13.1%]; odds ratio, 29.6 [CI, 8.7 to 100.5]). Risks were greater among fibrate users with chronic kidney disease. Limitations: Because hospitalizations for an increase in serum creatinine level were underestimated, absolute differences may be misleading. Most patients (91%) were prescribed fenofibrate. Serum creatinine levels were measured as part of routine care and were not available for everyone or at predefined times. Conclusion: New fibrate use in elderly adults was associated with an increase in serum creatinine level and a small 90-day absolute increase in hospitalizations and nephrologist consultations. There was no detectable effect on dialysis for severe acute kidney injury or on mortality. The mechanism and clinical significance of the increase in serum creatinine level with fibrates is unclear. Primary Funding Source: Ontario Ministry of Health and Long-Term Care Drug Innovation Fund.
Thenar oxygen saturation during weaning from mechanical ventilation: an observational study
Authors: Guillem Gruartmoner, Jaume Mesquida, Jordi Masip, Maria L. Martínez, Ana Villagra, Francisco Baigorri, Michael R. Pinsky, Antonio Artigas
Journal: European Respiratory Journal (2013)

Our aim was to determine whether thenar tissue oxygen saturation ( S tO 2 ), measured by noninvasive near-infrared spectroscopy, and its changes derived from an ischaemic challenge are associated with weaning outcome. Our study comprised a prospective observational study in a 26-bed medical–surgical intensive care unit. Patients receiving mechanical ventilation for &gt;48 h, and considered ready to wean by their physicians underwent a 30-min weaning trial. S tO 2 was measured continuously on the thenar eminence. A transient vascular occlusion test was performed prior to and at the end of the 30-min weaning trial, in order to obtain S tO 2 deoxygenation and reoxygenation rates, and estimated local oxygen consumption. 37 patients were studied. Patients were classified as weaning success (n=24) or weaning failure (n=13). No significant demographic, respiratory or haemodynamic differences were observed between the groups at inclusion. Patients who failed the overall weaning process showed a significant increase in deoxygenation and in local oxygen consumption from baseline to 30 min of weaning trial, whereas no significant changes were observed in the weaning success group. Failure to wean from mechanical ventilation was associated with higher relative increases in deoxygenation after 30 min of spontaneous ventilation.
Skeletal Complications in Patients with Bone Metastases from Renal Cell Carcinoma and Therapeutic Benefits of Zoledronic Acid
Authors: Allan Lipton, Alejandro Colombo-Berra, Ronald M. Bukowski, Lee Rosen, Ming Zheng, Gladys Urbanowitz
Journal: Clinical Cancer Research (2004)

Abstract Bone metastases in patients with renal cell carcinoma are associated with a high risk of skeletal complications. Therefore, a subset analysis of a larger clinical trial was performed to determine the efficacy of zoledronic acid in renal cell carcinoma patients. Patients with bone metastases from solid tumors other than breast or prostate cancer (n = 773) were randomized to receive zoledronic acid or placebo via 15-minute infusion every 3 weeks for 9 months. Patients were monitored for skeletal-related events, which were defined as pathological fracture, spinal cord compression, radiotherapy, or surgery to bone. Among the subset of 74 patients with renal cell carcinoma, 46 patients were treated with 4 mg of zoledronic acid or placebo. Significantly fewer patients treated with 4 mg zoledronic acid had a skeletal-related event (37% versus 74% for placebo, P = 0.015), and zoledronic acid significantly prolonged the time to first skeletal-related event (median not reached at 9 months versus 72 days for placebo; P = 0.006). Zoledronic acid significantly reduced the annual incidence of skeletal-related events by ∼21% (mean 2.68 versus 3.38 events per year for placebo, P = 0.014) and significantly reduced the risk of developing a skeletal-related event by 61% compared with placebo (risk ratio = 0.394, P = 0.008) by multiple event analysis. Median time to progression of bone lesions was also significantly extended with zoledronic acid treatment (P = 0.014). Zoledronic acid is the first bisphosphonate to significantly reduce skeletal morbidity and significantly prolong time to bone lesion progression in patients with bone metastases from renal cell carcinoma.
Pharmacokinetic/Pharmacodynamic Modeling Identifies SN30000 and SN29751 as Tirapazamine Analogues with Improved Tissue Penetration and Hypoxic Cell Killing in Tumors
Authors: Kevin O. Hicks, Bronwyn G. Siim, Jagdish K. Jaiswal, Frederik B. Pruijn, Annie M. Fraser, Rita Patel, Alison Hogg, H.D. Sarath Liyanage, Mary Jo Dorie, J. Martin Brown, William A. Denny, Michael P. Hay, William R. Wilson
Journal: Clinical Cancer Research (2010)

Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization.The SR-PKPD model was used to guide the progression of 281 TPZ analogues through a hierarchical screen. For compounds exceeding hypoxic selectivity thresholds in single-cell cultures, SR-PKPD model parameters (kinetics of bioreductive metabolism, clonogenic cell killing potency, diffusion coefficients in multicellular layers, and plasma pharmacokinetics at well tolerated doses in mice) were measured to prioritize testing in xenograft models in combination with radiation.SR-PKPD-guided lead optimization identified SN29751 and SN30000 as the most promising hypoxic cytotoxins from two different structural subseries. Both were reduced to the corresponding 1-oxide selectively under hypoxia by HT29 cells, with an oxygen dependence quantitatively similar to that of TPZ. SN30000, in particular, showed higher hypoxic potency and selectivity than TPZ in tumor cell cultures and faster diffusion through HT29 and SiHa multicellular layers. Both compounds also provided superior plasma PK in mice and rats at equivalent toxicity. In agreement with SR-PKPD predictions, both were more active than TPZ with single dose or fractionated radiation against multiple human tumor xenografts.SN30000 and SN29751 are improved TPZ analogues with potential for targeting tumor hypoxia in humans. Novel SR-PKPD modeling approaches can be used for lead optimization during anticancer drug development.
A Career in Toxicology
Authors: R A Neal
Journal: The Annual Review of Pharmacology and Toxicology (1996)

Heme oxygenases (HO) catabolize free heme, that is, iron (Fe) protoporphyrin (IX), into equimolar amounts of Fe2+, carbon monoxide (CO), and biliverdin. The stress-responsive HO-1 isoenzyme affords protection against programmed cell death. The mechanism ...Read More
Epithelial–mesenchymal transition in lung development and disease: does it exist and is it important?
Authors: Domokos Bartis, Nikica Mise, Rahul Y Mahida, Oliver Eickelberg, David R Thickett
Journal: Thorax (2013)

Epithelial–mesenchymal transition (EMT) is a process when epithelial cells gradually transform into mesenchymal-like cells losing their epithelial functionality and characteristics. EMT is thought to be involved in the pathogenesis of numerous lung diseases ranging from developmental disorders, fibrotic tissue remodelling to lung cancer. The most important question—namely what is the importance and contribution of EMT in the pathogenesis of several chronic lung conditions (asthma, COPD, bronchiolitis obliterans syndrome and lung fibrosis)—is currently intensely debated. This review gives a brief insight into the mechanism and assessment methods of EMT in various pulmonary diseases and summarises the recent literature highlighting the controversial experimental data and conclusions.