tbuckley/cabot-search huggingface dataset:
Obesity, Bisphosphonates, and Colorectal Cancer
Authors: Ibrahim Halil Sahin
Journal: Journal of Clinical Oncology (2013)

fourstudiesinvestigatingtherelationshipbetweenbisphosphonate use and colorectal cancer risk and concluded that the use of oral bisphosphonates,whentheyareprescribed10ormoretimesinthe course of a year, is associated with a decreased risk of developing colorectal cancer. However, some confounding factors in the study may weaken this conclusion. Obesity (body mass index [BMI] 30) has been showntobeariskfactorforcolorectalcancer, 2 andhavingaBMImore than 26 to 28 is associated with a decreased risk of osteoporosis. 3 Therefore, obese patients included in this meta-analysis, who already hadanincreasedriskofdevelopingcolorectalcancer,mighthavebeen exposed less frequently to bisphosphonates. TheriskofcolorectalcancerwasadjustedforBMIinonlytwoof four studies examined in the meta-analysis (Rennert et al 4 and Green et al 5 ). Moreover, a recent study reported no association between exposuretobisphosphonatesandriskofcolorectalcancerafteradjusting for BMI. 6 Thus, the protective effects of oral bisphoshonates against colorectal cancer observed in the meta-analysis by Thosani et al 1 may have been related to the more frequent use of bisphosphonates in nonobese patients than the bisphosphonate use in
Recurrence up to 3.5 years after antibiotic treatment of acute otitis media in very young Dutch children: survey of trial participants
Authors: N. Bezakova, R. A M J Damoiseaux, A. W Hoes, A. G M Schilder, M. M Rovers
Journal: BMJ (2009)

<b>Objective</b> To determine the long term effects of antibiotic treatment for acute otitis media in young children. <b>Design</b> Prospective three year follow-up study within the framework of a primary care based, double blind, randomised, placebo controlled trial. <b>Setting</b> 53 general practices in the Netherlands. <b>Participants</b> 168 children aged 6 months to 2 years with acute otitis media. <b>Interventions</b> Amoxicillin 40 mg/kg/day in three doses compared with placebo. <b>Main outcome measures</b> Recurrence of acute otitis media; referral to secondary care; ear, nose, and throat surgery. <b>Results</b> Acute otitis media recurred in 63% (47/75) of children in the amoxicillin group and in 43% (37/86) of the placebo group (risk difference 20%, 95% confidence interval 5% to 35%); 30% (24/78 amoxicillin; 27/89 placebo) of children in both groups were referred to secondary care, and 21% (16/78) of the amoxicillin group compared with 30% (27/90) of the placebo group had ear, nose, and throat surgery (risk difference −9%, −23% to 4%). <b>Conclusion</b> Recurrent acute otitis media occurred more often in the children originally treated with amoxicillin. This is another argument for judicious use of antibiotics in children with acute otitis media. <b>Trial registration</b> Netherlands Trial Register NTR1426.
Nebulized Glutathione Induces Bronchoconstriction in Patients with Mild Asthma
Authors: RAMON M. MARRADES, JOSEP ROCA, JOAN ALBERT BARBERÁ, LLUÍS de JOVER, WILLIAM MacNEE, ROBERT RODRIGUEZ-ROISIN
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

To assess the effects on bronchial responsiveness of nebulized glutathione (GSH), one of the most efficient scavengers of oxidant substances in the airways, we studied eight patients with mild asthma (FEV1, 88 ± 11% predicted [SD]) in a randomized, double-blind, cross-over, placebo-controlled fashion. Bronchial challenge was measured using both FEV1 and total pulmonary resistance (Rrs) by the forced oscillation technique. Patients received nebulized GSH (600 mg with 4 ml of 0.9% sodium chloride) or placebo (identical saline solution) over a period of 25 min, 1 wk apart. Placebo provoked subclinical mild bronchoconstriction (changes from baseline: FEV1, − 1%; Rrs, + 17%); by contrast, GSH caused major airway narrowing (changes from baseline: FEV1, − 19%; Rrs, + 61%) and induced cough (four patients) or breathlessness (three patients). Differences between placebo and GSH after challenge were also noticeable in both FEV1 (p = 0.03) and Rrs (p = 0.02). Neither osmolarity (660 mosm · kg− 1) nor pH (3.0) of the GSH solution accounted for these effects. Nebulized salbutamol (5.0 mg) given before the GSH challenge blocked GSH-induced bronchoconstriction. Furthermore, GSH-induced FEV1 falls were inversely correlated with metabisulfite bronchoprovocation (provocative dose [PD20], 1.49 ± 1.83 μ mol) but not with methacholine challenge. The detrimental effects of nebulized GSH on the airway bronchial tone in patients with mild asthma strongly suggests bronchoconstriction provoked by sulfite formation.
Prediction of the acute mountain sickness using SaO2 indices at rest and exercise in hypoxic conditions
Authors: Akpay Sarybaev, Almaz Akunov
Journal: European Respiratory Journal (2011)

The aim of the study was to compare the oxygen saturation at rest and exercise during the simulated high altitude ascent in subjects who had suffered from acute mountain sickness (AMS) as well as healthy subjects. Ninety seven subjects were divided into three groups depending on the Lake Louise score during the previous staying at high altitude (3800 m above sea level). The 1st, control, group consisted of 62 people without AMS symptoms; the 2nd group included 18 patients with mild AMS (3-4 points in LL score) and 17 subjects with moderate to severe AMS made the 3rd group (5 or more points in LL score). SaO2 indices were taken at rest and after 5 minute of strenuous bicycle test both at normoxia (760 m) and inside the hypobaric chamber (4500 m above sea level, 30 minutes).

Results: It was revealed that rest oxygen desaturation rate was significantly higher in the 2nd and 3rd group compared with the 1st, control, group (rest ΔSaO2 – 16,0±0,5% and 16,5±7% compared with 14,2%, p>0,05) while the exercise oxygen desaturation rate was significantly higher in the 3rd group compared with 1st and 2nd group (exercise ΔSaO2 – 24,7±0,8% compared with 18,5±0,8% and 21,7%, p>0,05).

Conclusion: Both rest and exercise indices of oxygen saturation during the simulated ascent to high altitude may be used as prediction markers for acute mountain sickness.
Efficacy, tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials
Authors: J. J Deeks
Journal: BMJ (2002)

To determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis.Systematic review of randomised trials that compared at least 12 weeks' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis.15 187 patients with osteoarthritis or rheumatoid arthritis.Western Ontario and McMaster universities osteoarthritis index; American College of Rheumatology responder index and joint scores for rheumatoid arthritis. Tolerability: withdrawal rates for adverse effects. Gastrointestinal safety: incidence of ulcers, bleeds, perforations, and obstructions.Nine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin.Celecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.
Leptin Enhances the Recruitment of Endothelial Progenitor Cells Into Neointimal Lesions After Vascular Injury by Promoting Integrin-Mediated Adhesion
Authors: Marco R. Schroeter, Maren Leifheit, Philipp Sudholt, Nana-Maria Heida, Claudia Dellas, Ilonka Rohm, Frauke Alves, Marta Zientkowska, Stavros Rafail, Miriam Puls, Gerd Hasenfuss, Stavros Konstantinides, Katrin Schäfer
Journal: Circulation Research (2008)

The adipocytokine leptin modulates vascular remodeling and neointima formation. Because endothelial progenitor cells (EPCs) participate in vascular repair, we analyzed the effects of leptin on human EPC function in vitro and in vivo. After 7 days in culture, EPCs expressed the leptin receptor and responded to leptin stimulation with increased STAT3 phosphorylation. Incubation of EPCs with leptin (at concentrations between 1 and 100 ng/mL) increased the number of EPCs adhering to vitronectin and fibronectin in a receptor-specific manner. It also enhanced the capacity of EPCs to incorporate into a monolayer of human endothelial cells and the adherence of these cells to activated platelets. Leptin upregulated alphavbeta5 and alpha4 integrin expression in EPCs, and the effects of leptin on EPC function could be prevented, at least in part, by RGD peptides and function-blocking antibodies. Intravenous injection of fluorescently labeled human EPCs into athymic nude mice shortly after vascular injury revealed that preincubation of EPCs with leptin augmented their accumulation within intimal lesions, accelerating reendothelialization and decreasing neointima formation in an alphavbeta5 and alpha4 integrin-dependent manner. Our findings suggest that leptin specifically modulates the adhesive properties and the homing potential of EPCs and may thus enhance their capacity to promote vascular regeneration in vivo.
Phylogenetic Relationsghip, Divergence Times, and Rates of Molecular Evolution for Camarodent Sea Urchins
Authors: Andrew B. Smith
Journal: Molecular Biology and Evolution (1988)

The phylogenetic relationships of 21 relatively common and well-studied genera of camarodont echinoids were established using a numerical cladistic approach.This combines data about test morphology, pedicellarial structure, tooth ultrastructure, and larval morphology.The fossil record of the group was reappraised in the light of this analysis, and times of divergence for taxa were estimated.Camarodont families are considered to have diverged much more recently than has previously been suggested, and all except the paraphyletic Temnopleuridae have originated between 65 and 35 Myr ago.Estimates of rates of molecular evolution established on the basis of both thermal stability of heterologous single-copy DNA duplexes and gene sequence data were recalculated using the revised divergence times.Rate of nucleotide divergence, as measured by thermal stability of single-copy DNA heteroduplexes, was calculated to be 0.65-0.85degrees C/Myr, while sequence data on histone genes indicated a rate of silent substitution of 0.70%-0.85%/Myr.Times of divergence estimated from the fossil record remain too poorly constrained to prove whether molecular evolution proceeds at a stochastically constant rate, but the results are wholly consistent with such a model.1.
Schedule-dependent Inhibition of Hypoxia-inducible Factor-1α Protein Accumulation, Angiogenesis, and Tumor Growth by Topotecan in U251-HRE Glioblastoma Xenografts
Authors: Annamaria Rapisarda, Jessica Zalek, Melinda Hollingshead, Till Braunschweig, Badarch Uranchimeg, Carrie A. Bonomi, Suzanne D. Borgel, John P. Carter, Stephen M. Hewitt, Robert H. Shoemaker, Giovanni Melillo
Journal: Cancer Research (2004)

Abstract We have previously shown that topotecan, a topoisomerase I poison, inhibits hypoxia-inducible factor (HIF)-1α protein accumulation by a DNA damage-independent mechanism. Here, we report that daily administration of topotecan inhibits HIF-1α protein expression in U251-HRE glioblastoma xenografts. Concomitant with HIF-1α inhibition, topotecan caused a significant tumor growth inhibition associated with a marked decrease of angiogenesis and expression of HIF-1 target genes in tumor tissue. These results provide a compelling rationale for testing topotecan in clinical trials to target HIF-1 in cancer patients.
Differential Regulation of Dopamine Transporter Function and Location by Low Concentrations of Environmental Estrogens and 17β-Estradiol
Authors: Rebecca A. Alyea, Cheryl S. Watson
Journal: Environmental Health Perspectives (2009)

The effects of 17beta-estradiol (E2) and xenoestrogens (XEs) on dopamine transport may have important implications for the increased incidence of neurologic disorders, especially in women during life stages characterized by frequent hormonal fluctuations.
Tobacco smoking and hand eczema: a population-based study
Authors: B. Meding, M. Alderling, K. Wrangsjö
Journal: British Journal of Dermatology (2010)

Background Tobacco smoking has been proposed to promote hand eczema. Objectives To examine the association between tobacco smoking and hand eczema and to investigate a possible dose-response relation. Methods A national environmental health survey was performed in 2007. A questionnaire was mailed to 43 905 individuals and responses were obtained from 25 851 (59%). Questions on 1-year prevalence of hand eczema and on previous and current smoking were included. Respondents were asked to report number of cigarettes per day and to provide information on history of atopy and frequency of hand exposure to water. Results In total, answers regarding smoking and hand eczema were obtained from 25 428 individuals. Of regular daily smokers, 10·0% reported hand eczema vs. 9·1% of nonsmokers (P = 0·0951). A history of atopy showed the strongest influence on the occurrence of hand eczema: prevalence proportion ratio (PPR) 3·46. The PPR for hand eczema among individuals smoking > 15 cigarettes per day was 1·25 and 1·40 in uni- and multivariate analysis, respectively. Age, history of atopy, sex and water exposure were found to be confounders but not effect modifiers. A dose-response relation between level of smoking and 1-year prevalence of hand eczema was revealed with a PPR of 1·05 (P < 0·001) for the continuous variable of smoking habits, indicating a significantly increased prevalence of hand eczema among individuals with higher consumption of tobacco. Conclusions An association between heavy smoking and hand eczema was confirmed. It is important to consider the level of exposure, as a dose-response relation was revealed, and to be aware of confounding factors.
SPARC Is Associated with Gastric Cancer Progression and Poor Survival of Patients
Authors: Zhong-Sheng Zhao, Yuan-Yu Wang, Yong-Quan Chu, Zai-Yuan Ye, Hou-Quan Tao
Journal: Clinical Cancer Research (2009)

The present study investigated the clinical significance of secreted protein, acidic and rich in cysteine (SPARC), in the development and progression of gastric cancer.Immunohistochemistry was used to analyze SPARC, integrin beta1, and matrix metalloproteinase (MMP)-2 expression in 436 clinicopathologically characterized gastric cancer cases.SPARC, integrin beta1, and MMP-2 protein levels were upregulated in gastric cancer lesions compared with adjacent noncancerous tissues. SPARC protein was detected in 334 of 436 human gastric cancer cases and was highly expressed in 239 tumors. We also found a positive correlation between expression of SPARC and MMP2, and SPARC and integrin beta1. In stages I, II, and III, the 5-year survival rate of patients with a high expression of SPARC was significantly lower than those in patients with low expression. In stage IV, SPARC expression did not correlate with the 5-year survival rate. Further multivariate analysis suggested that the depth of invasion; lymph node and distant metastasis; tumor-node-metastasis stage; and upregulation of SPARC, MMP-2, and integrin beta1, were independent prognostic indicators for the disease.Our study provided a basis for the development of a novel biomarker for diagnosis and prognosis of gastric cancer. Expression of SPARC in gastric cancer is significantly associated with lymph node and distant metastasis, high MMP2 expression, high intergrin beta1 expression, and poor prognosis. SPARC, intergrin beta1, and MMP-2 protein could be useful markers to predict tumor progression.
Protein catabolic rate in patients with acute renal failure on continuous arteriovenous hemofiltration and total parenteral nutrition.
Authors: C S Chima, L Meyer, A C Hummell, C Bosworth, R Heyka, E P Paganini, A Werynski
Journal: Journal of the American Society of Nephrology (1993)

Continuous arteriovenous hemofiltration (CAVH) has been used to provide nutrition support to critically ill patients in acute renal failure (ARF). Limited information exists regarding protein needs of these patients. Nineteen postoperative patients in ARF and on CAVH and total parenteral nutrition (TPN) were studied (10 men; 9 women; mean age, 65 yr) to determine protein needs (protein catabolic rate; PCR), urea nitrogen appearance (UNA), and total nitrogen appearance (TNA). TPN was adjusted to meet the needs estimated by the Harris-Benedict and Long equations. A total of 38 24-h studies were conducted on the 19 subjects. TNA, UNA, and PCR were determined by direct measurement of body losses and calculation of body pool nitrogen changes. Patients received an average of 93.9 +/- 30.5 g of protein (1.4 g/kg) and 2,600 +/- 534 kcal/day in TPN. Mean PCR was 117.5 +/- 42.8 g/day; UNA was 18.3 +/- 6.9 g/day. TNA and UNA were strongly correlated (r = 0.99; P < 0.001). PCR was less strongly correlated with estimated protein needs (r = 0.35; P = 0.03). A regression equation was developed describing the relationship between TNA and UNA as follows: TNA = 1.895 + 0.9444 (UNA) or UNA = 0.1602 (PCR) - 0.916. On the basis of this study, CAVH permits the provision of adequate nutrition support to critically ill, unstable patients. It appears that the protein needs of patients in ARF on CAVH can be accurately estimated by determining UNA through the measurement of urea losses and urea body pool changes and by regression equations to calculate PCR.(ABSTRACT TRUNCATED AT 250 WORDS)
Involvement of RNA Helicases p68 and p72 in Colon Cancer
Authors: Sook Shin, Kari L. Rossow, Joseph P. Grande, Ralf Janknecht
Journal: Cancer Research (2007)

Abstract The homologous proteins p68 and p72 are members of the DEAD box family of RNA helicases. Here, we show that expression of both of these helicases strongly increases during the polyp→adenoma→adenocarcinoma transition in the colon. Furthermore, p68 and p72 form complexes with β-catenin and promote the ability of β-catenin to activate gene transcription. Conversely, simultaneous knockdown of p68 and p72 leads to reduced expression of the β-catenin–regulated genes, c-Myc, cyclin D1, c-jun, and fra-1, all of which are proto-oncogenes. Moreover, transcription of the cell cycle inhibitor p21WAF1/CIP1, whose expression is suppressed by c-Myc, is enhanced on p68/p72 knockdown. Thus, p68/p72 may contribute to colon cancer formation by directly up-regulating proto-oncogenes and indirectly by down-regulating the growth suppressor p21WAF1/CIP1. Accordingly, knockdown of p68 and p72 in colon cancer cells inhibits their proliferation and diminishes their ability to form tumors in vivo. Altogether, these results suggest that p68/p72 overexpression is not only a potential marker of colon cancer but is also causally linked to this disease. Therefore, p68 and p72 may be novel targets in the combat against colon cancer. [Cancer Res 2007;67(16):7572–8]
Inhibition of submandibular and lacrimal gland infiltration in nonobese diabetic mice by transgenic expression of soluble TNF-receptor p55.
Authors: R E Hunger, S Müller, J A Laissue, M W Hess, C Carnaud, I Garcia, C Mueller
Journal: Journal of Clinical Investigation (1996)

Besides a prominent mononuclear cell infiltration of the islets of Langerhans, nonobese diabetic (NOD) mice also show massive cellular infiltrates of the submandibular and lacrimal glands concomitant with histological signs of tissue damage. To obtain insights into the mechanisms operative during the initiation and progression of tissue damage, we followed by in situ hybridization the appearance of cells containing mRNA of the gene encoding the proinflammatory cytokine TNF-alpha in the cellular infiltrates. Cells expressing TNF-alpha are mainly located in infiltrates, are absent in nonaffected glands, and are preferentially found among CD4 T cells. Secretion of TNF-alpha by gland-infiltrating cells was confirmed by an ELISPOT procedure. Direct evidence for an instrumental role of TNF-alpha in initiation and progression of submandibular and lacrimal gland infiltration is provided by the observed significant reduction in the extent of infiltration in nonobese diabetic mice transgenic for a soluble TNF receptor p55 fused to the Fc part of human IgG3. This protection from infiltration is paralleled by decreased expression of the adhesion molecules ICAM-1 and VCAM-1 in submandibular and lacrimal glands. These data suggest a central role of TNF-alpha in the initiation and progression of autoimmune tissue destruction of salivary glands and indicate beneficial effects of soluble TNF receptors in the treatment of organ-specific autoimmune diseases.
Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation
Authors: Samira Alliouachene, Robyn L. Tuttle, Stephanie Boumard, Thomas Lapointe, Sophie Berissi, Stephane Germain, Francis Jaubert, David Tosh, Morris J. Birnbaum, Mario Pende
Journal: Journal of Clinical Investigation (2008)

Factors that promote pancreatic β cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate β cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling cascades, but how the interplay between these proteins controls β cell growth and function has not been determined. Here, we found that although transgenic mice overexpressing the constitutively active form of Akt1 under the rat insulin promoter (RIP-MyrAkt1 mice) had enlarged β cells and high plasma insulin levels, leading to improved glucose tolerance, a substantial proportion of the mice developed insulinomas later in life, which caused decreased viability. This oncogenic transformation tightly correlated with nuclear exclusion of the tumor suppressor PTEN. To address the role of the mammalian target of rapamycin (mTOR) substrate S6K1 in the MyrAkt1-mediated phenotype, we crossed RIP-MyrAkt1 and S6K1-deficient mice. The resulting mice displayed reduced insulinemia and glycemia compared with RIP-MyrAkt1 mice due to a combined effect of improved insulin secretion and insulin sensitivity. Importantly, although the increase in β cell size in RIP-MyrAkt1 mice was not affected by S6K1 deficiency, the hyperplastic transformation required S6K1. Our results therefore identify S6K1 as a critical element for MyrAkt1-induced tumor formation and suggest that it may represent a useful target for anticancer therapy downstream of mTOR.