tbuckley/cabot-search huggingface dataset:
Role of Aortic Root Motion in the Pathogenesis of Aortic Dissection
Authors: Carsten J. Beller, Michel R. Labrosse, Mano J. Thubrikar, Francis Robicsek
Journal: Circulation (2004)

The downward movement of the aortic root during the cardiac cycle may be responsible for producing the circumferential tear observed in aortic dissections.Contrast injections were investigated in 40 cardiac patients, and a finite element model of the aortic root, arch, and branches of the arch was built to assess the influence of aortic root displacement and pressure on the aortic wall stress. The axial displacement of the aortic root ranged from 0 to 14 mm. It was increased in patients with aortic insufficiency (22+/-13% of the sino-tubular junction diameter versus 12+/-9%) and reduced in patients with hypokinesis of the left ventricle (10+/-9% of sino-tubular junction versus 17+/-12%). The largest stress increase due to aortic root displacement was found approximately 2 cm above the sino-tubular junction, where the longitudinal stress increased by 50% to 0.32 Nmm(-2) when 8.9-mm axial displacement was applied in addition to 120-mm Hg luminal pressure. A similar result was observed when the pressure load was increased to 180 mm Hg without axial displacement.Both aortic root displacement and hypertension significantly increase the longitudinal stress in the ascending aorta. For patients with hypertension who are at risk of dissection, aortic root movement may be monitored as an important risk factor.
Metal carcinogenesis: Mechanistic implications
Authors: Elizabeth T. Snow
Journal: Pharmacology & Therapeutics (1992)

Cancer epidemiology has identified several metal compounds as human carcinogens. Recent evidence suggests that carcinogenic metals induce genotoxicity in a multiplicity of ways, either alone or by enhancing the effects of other agents. This review summarizes current information on the genotoxicity of arsenic, chromium, nickel, beryllium and cadmium compounds and their possible roles in carcinogenesis. Each of these metals is distinct in its primary modes of action; yet there are several mechanisms induced by more than one metal, including: the induction of cellular immunity and oxidative stress, the inhibition of DNA metabolism and repair and the formation of DNA- and/or protein-crosslinks.
Treatment Failure and Dietary Habits in Women With Breast Cancer
Authors: L.-E. Holm, E. Nordevang, M.-L. Hjalmar, E. Lidbrink, E. Callmer, B. Nilsson
Journal: JNCI Journal of the National Cancer Institute (1993)

Background : Epidemiological and experimental evidence suggests that breast cancer risk can be reduced by dietary measures. Study of the relationships between dietary habits and prognosis in patients with breast cancer is essential to the design of diet intervention trials. Purpose : Our purpose was to determine whether dietary habits are associated with disease-free survival in patients with breast cancer who have undergone treatment. Methods : We interviewed 240 women about their dietary histories. These women were 50–65 years old and had pathological stage I-II breast cancer with subsequent follow-up for 4 years; 209 of these women were postmenopausal. Differences in dietary variables between groups of patients were analyzed with bivariate and multivariate statistical methods. Results : Cancers were classified as estrogen receptor (ER) rich (≥0.10 fmol/μg of DNA) in 149 patients and as ER poor (<0.10 fmol/μg of DNA) in 71 patients. Fifty-two patients had treatment failure during follow-up. The 30 patients with ER-rich tumors who had treatment failure reported higher intakes of total fat, saturated fatty acids, and polyunsaturated fatty acids than did the 119 patients with ER-rich tumors who did not have treatment failure. The multiple-odds ratio (OR) for treatment failure in these women was 1.08 for each 1% increment in percentage of total energy (E%) from total fat. For treatment failure within the frist 2 years, the OR was 1.19 for each 1-mg increase in vitamin E intake per 10 megajoules of energy. In women with treatment failure 2–4 years after diagnosis, ORs were 1.13 and 1.23 for each E% increment in total fat or saturated fatty acids, respectively. No association between dietary habits and treatment failure was found for women with ER-poor cancers. There was a tendency to a does-response relationship (in quartiles) between intake of saturated fatty acids and disease-free survival, but the observed differences were not statistically significant. Conclusions : Dietary habits at the time of diagnosis may affect prognosis, at least for patients with ER-rich breast cancers. Dietary fat may have an effect on growth or spread of breast cancer, both of which may vary according to type of fat. Total fat and saturated fatty acids were the dietary parameters most strongly associated with risk for treatment failure. Implications : Dietary intervention might serve as an adjuvant treatment to improve breast cancer prognosis. [J Natl Cancer Inst 85: 32–36, 1993]
The role of the nuclear receptor constitutive androstane receptor in the pathogenesis of non-alcoholic steatohepatitis
Authors: Y. Yamazaki, S. Kakizaki, N. Horiguchi, N. Sohara, K. Sato, H. Takagi, M. Mori, M. Negishi
Journal: Gut (2006)

Non-alcoholic fatty liver disease is a common liver injury, but the pathophysiological mechanisms leading to the development of non-alcoholic steatohepatitis (NASH) remain unclear. The pathological roles of the nuclear receptor constitutive androstane receptor (CAR), a key regulator of drug-metabolising enzymes, in the development of NASH were investigated.CAR(+/+) and CAR(-/-) mice were given a methionine and choline-deficient (MCD) diet to establish a dietary model of NASH. Increases in serum alanine aminotransferase (ALT) and in infiltration of inflammatory cells were dominant in CAR(+/+) mice at 8 weeks. There was no significant difference in the lipid concentration of the liver - namely, the first hit between CAR(+/+) and CAR(-/-) mice. The index of lipid peroxidation increased in liver of the CAR(+/+) mice, as demonstrated by 8-iso-prostaglandin F2alpha (F2-isoprostanes). Western blotting analysis showed that nuclear translocation of CAR occurred in CAR(+/+) mice fed the MCD diet. As a result, the CAR activation caused the lipid peroxidation - namely, the second hit. The expressions of cytochrome P450 (CYP)2B10, 2C29, 3A11 all increased considerably in the CAR(+/+) mice. Furthermore, alpha smooth muscle actin immunohistochemistry and Sirius red staining showed an increase in the degree of fibrosis in CAR(+/+) mice fed the MCD diet at 16 weeks. The mRNA expressions of collagen alpha1(1) and the tissue inhibitor of metalloproteinase-1 were found to be elevated in CAR(+/+) mice.CAR caused the worsening of the hepatic injury and fibrosis in the dietary model of NASH. Our results suggest that the CAR nuclear receptor may thus play a critical role in the pathogenesis of NASH.
Phase I and Pharmacokinetic Study of Sequences of the Rebeccamycin Analogue NSC 655649 and Cisplatin in Patients with Advanced Solid Tumors
Authors: Alejandro D. Ricart, Lisa A. Hammond, John G. Kuhn, Chris H. Takimoto, Andrew Goetz, Bahram Forouzesh, Leonardo Forero, Jose L. Ochoa-Bayona, Kristin Berg, Anthony W. Tolcher, Eric K. Rowinsky
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin (CDDP) in adults with solid malignancies. Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed. Experimental Design: NSC 655649 was administered as a 60-minute i.v. infusion; CDDP was given i.v. before or after NSC 655649 on day 1. Each patient was treated with alternating drug sequences every 3 weeks; doses of each drug were escalated in separate cohorts of new patients. Sequential dose escalation of NSC 655649 or CDDP resulted in three dosage permutations of NSC 655649/CDDP: 440/50, 550/50, and 440/75 mg/m2. After the maximum tolerated dose level was determined, the feasibility of using granulocyte colony-stimulating factor to permit further dose escalation was explored. Results: Twenty patients were treated with 70 courses of NSC 655649/CDDP. Myelosuppression was the principal toxicity. The incidence of severe neutropenia, often associated with severe thrombocytopenia, was unacceptably high in minimally pretreated patients at the NSC 655649/CDDP dose level of 550/50 mg/m2 without and with granulocyte colony-stimulating factor. Major pharmacokinetic interactions between NSC 655649 and CDDP were not apparent. No relevant sequence-dependent differences in toxicity or pharmacokinetic variables occurred. Three patients had partial responses. Conclusions: NSC 655649 and CDDP were well tolerated by minimally pretreated subjects at 440 and 50 mg/m2, respectively. Neither pharmacokinetic interactions between the agents nor sequence-dependent toxicologic or pharmacokinetic effects were apparent. The tolerance and preliminary activity observed with this combination suggest that disease-directed evaluations of the regimen are warranted.
Association of<i>GSK-3β</i>Genetic Variation With GSK-3β Expression, Prefrontal Cortical Thickness, Prefrontal Physiology, and Schizophrenia
Authors: Giuseppe Blasi, Francesco Napolitano, Gianluca Ursini, Annabella Di Giorgio, Grazia Caforio, Paolo Taurisano, Leonardo Fazio, Barbara Gelao, Maria Teresa Attrotto, Lucia Colagiorgio, Giovanna Todarello, Francesco Piva, Apostolos Papazacharias, Rita Masellis, Marina Mancini, Annamaria Porcelli, Raffaella Romano, Antonio Rampino, Tiziana Quarto, Matteo Giulietti, Barbara K. Lipska, Joel E. Kleinman, Teresa Popolizio, Daniel R. Weinberger, Alessandro Usiello, Alessandro Bertolino
Journal: American Journal of Psychiatry (2013)

OBJECTIVE Glycogen synthase kinase 3β (GSK-3β) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3β gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. METHOD Based on computer predictions, the authors investigated in humans the association of GSK-3β functional variation with 1) GSK-3β mRNA expression from postmortem prefrontal cortex, 2) GSK-3β and β-catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. RESULTS Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3β (rs12630592) was associated with reduced GSK-3β mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3β protein expression and kinase activity, as well as with downstream effects on β-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. CONCLUSIONS These results suggest that GSK-3β variation is implicated in multiple phenotypes relevant to schizophrenia.
Serum high–molecular weight adiponectin decreases abruptly after an oral glucose load in subjects with normal glucose tolerance or impaired fasting glucose, but not those with impaired glucose tolerance or diabetes mellitus
Authors: Noriyuki Ozeki, Kenji Hara, Chikako Yatsuka, Tomoki Nakano, Sachiko Matsumoto, Mariko Suetsugu, Takafumi Nakamachi, Kohzo Takebayashi, Toshihiko Inukai, Kohsuke Haruki, Yoshimasa Aso
Journal: Metabolism (2009)
Lipid peroxidation and electrogenic ion transport in the jejunum of the vitamin E deficient rat.
Authors: K J Lindley, M A Goss-Sampson, D P Muller, P J Milla
Journal: Gut (1994)

Increased concentrations of reactive oxygen species in children with depleted antioxidant defences have been implicated in a cycle of malnutrition, malabsorption, and infection leading to protracted diarrhoea. A rat model of chronic vitamin E deficiency has been used to study the effects of antioxidant depletion on jejunal structure and function in vitro. Basal intestinal short circuit current (Isc), a measure of net electrogenic ion movement across the intestinal epithelium, was greater in chronically vitamin E deficient jejuna than controls, as was the electrogenic secretory response to aminophylline and Escherichia coli STa but not to bethanechol. The galactose stimulated current was also greater in vitamin E deficient jejuna. Indices of lipid peroxidation (concentrations of thiobarbituric acid reactive substances and malondialdehyde) were increased in the vitamin E deficient small bowel. Small intestinal brush border membranes from vitamin E deficient animals displayed changes in both static and dynamic components of membrane fluidity measured by steady state fluorescence polarography. The results of these studies support the hypothesis that oxidative stress in subjects with compromised antioxidant defences results in small intestinal hypersecretion, which could predispose to or perpetuate protracted diarrhoea.
Promotion and Prescribing of Hormone Therapy After Report of Harm by the Women’s Health Initiative
Authors: Sumit R. Majumdar
Journal: JAMA (2004)

Little is known about how the pharmaceutical industry responds to evidence of harm associated with its products, such as the publication in July 2002 of the Women's Health Initiative Estrogen Plus Progestin Trial (WHI E+P) report demonstrating that standard-dose Prempro produced significant harm and lacked net benefits.To examine pharmaceutical industry response to the WHI E+P results by analyzing promotional expenditures for hormone therapy before and after July 2002.Nationally representative and prospectively collected longitudinal data (January 2001 through December 2003) on prescribing and promotion of hormone therapies were obtained from IMS Health and Consumer Media Reports.Trends in quarterly prescriptions for hormone therapy and expenditures on 5 modes of drug promotion: samples, office-based detailing, hospital-based promotion, journal advertisements, and direct-to-consumer advertising.Prior to the WHI E+P report, prescribing rates and promotional spending for hormone therapy were stable. In the quarter before the WHI E+P report (April-June 2002), 22.4 million prescriptions for hormone therapy were dispensed and 71 million dollars was spent on promotion (in annual terms, 350 dollars per year per US physician). Within 9 months of the report's publication (quarter 1 of 2003), there was a 32% decrease in hormone therapy prescriptions, and a nadir had been reached for promotional spending (37% decrease compared with pre-WHI E+P levels). Spending decreased for all promotional activities and most hormone therapies. Overall, the greatest declines were for samples (36% decrease as of quarter 1 of 2003) and direct-to-consumer advertising (100% decrease). The greatest declines in promotion occurred for standard-dose Prempro (61% decrease as of quarter 1 of 2003), the agent implicated by the WHI E+P report. More recently, promotional efforts have increased, particularly for lower-dose Prempro, a resurgence associated with modestly increased prescriptions for this newer agent.Concordant with its widespread use, hormone therapy was among the most heavily promoted medications prior to the WHI E+P report. Following reporting of the evidence of harm from this trial, there was a substantial decline in promotional spending for hormone therapy, particularly for the agents most directly implicated in the trial. Interrelated with the impact of the trial results themselves and the ensuing media coverage, reduced promotion may have contributed to a substantial decline in hormone therapy prescriptions.
Evidence for a causal relationship between the structure, size, and load of calcium pyrophosphate dihydrate crystals, and attacks of pseudogout.
Authors: A Swan, B Heywood, B Chapman, H Seward, P Dieppe
Journal: Annals of the Rheumatic Diseases (1995)

OBJECTIVE--To investigate any relationship between the nature, size, and numbers of synovial fluid (SF) calcium pyrophosphate dihydrate (CPPD) crystals, and attacks of pseudogout. METHODS--Knee SF was aspirated from nine selected patients, first during an attack of pseudogout (acute sample) and again later when the attack had subsided (interval sample). CPPD crystals were extracted, weighed, examined by high resolution transmission electron microscopy (HRTEM), and characterised by size and crystal habit (monoclinic or triclinic). Structural analysis was carried out by x ray powder diffraction (XRD) and the proportions of monoclinic to triclinic CPPD were estimated from densitometric measurements of selected key reflections. RESULTS--The mean crystal size, by HRTEM, indicated that the crystals in the acute sample were larger than those in the interval sample. The ratio of monoclinic to triclinic CPPD, whether estimated from their morphological appearance by HRTEM, or from XRD, was greater in the acute than in the interval sample in all nine patients. The total amount of extracted mineral varied, but in every patient the concentration of CPPD per ml of fluid, and the total mineral per joint, were greater in the acute sample than in the interval sample. CONCLUSION--In this highly selected group of patients, the large numbers of CPPD crystals associated with attacks of pseudogout included a greater proportion of monoclinic crystals, and larger crystals, than those present when inflammation had subsided. A special, phlogistic population of crystals may exist, originating in different joint tissues, or cleared in a different manner, than the more common populations of smaller crystals with a greater proportion of triclinic CPPD, seen in chronic disease.
Imaging of integrin αvβ3 expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography
Authors: Oliver Schnell, Bjarne Krebs, Janette Carlsen, Isabelle Miederer, Claudia Goetz, Roland H. Goldbrunner, Hans-Jürgen Wester, Roland Haubner, Gabriele Pöpperl, Markus Holtmannspötter, Hans A. Kretzschmar, Horst Kessler, Jörg-Christian Tonn, Markus Schwaiger, Ambros J. Beer
Journal: Neuro-Oncology (2009)

Inhibitors targeting the integrin alpha(v)beta(3) are promising new agents currently tested in clinical trials for supplemental therapy of glioblastoma multiforme (GBM). The aim of our study was to evaluate (18)F-labeled glycosylated Arg-Gly-Asp peptide ([(18)F]Galacto-RGD) PET for noninvasive imaging of alpha(v)beta(3) expression in patients with GBM, suggesting eligibility for this kind of additional treatment. Patients with suspected or recurrent GBM were examined with [(18)F]Galacto-RGD PET. Standardized uptake values (SUVs) of tumor hotspots, galea, and blood pool were derived by region-of-interest analysis. [(18)F]Galacto-RGD PET images were fused with cranial MR images for image-guided surgery. Tumor samples taken from areas with intense tracer accumulation in the [(18)F]Galacto-RGD PET images and were analyzed histologically and immunohistochemically for alpha(v)beta(3) integrin expression. While normal brain tissue did not show significant tracer accumulation (mean SUV, 0.09 +/- 0.04), GBMs demonstrated significant but heterogeneous tracer uptake, with a maximum in the highly proliferating and infiltrating areas of tumors (mean SUV, 1.6 +/- 0.5). Immunohistochemical staining was prominent in tumor microvessels as well as glial tumor cells. In areas of highly proliferating glial tumor cells, tracer uptake (SUVs) in the [(18)F]Galacto-RGD PET images correlated with immunohistochemical alpha(v)beta(3) integrin expression of corresponding tumor samples. These data suggest that [(18)F] Galacto-RGD PET successfully identifies alpha(v)beta(3) expression in patients with GBM and might be a promising tool for planning and monitoring individualized cancer therapies targeting this integrin.
HIGHER SEMI-AUTOMATED GRAY-SCALE THRESHOLDS YIELD THE CLOSEST APPROXIMATION OF THE EXTENT OF LATE GADOLINIUM ENHANCEMENT IDENTIFIED WITH HISTOLOGICAL SCAR BURDEN IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
Authors: Patrick Collier, Xiaopeng Zhou, Zoran Popovic, Milind Desai, Harry Lever, Brian Griffin, Carmela Tan, E. Rodriguez, Scott Flamm, Deborah Kwon
Journal: Journal of the American College of Cardiology (2013)
Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task Force
Authors: Mei Chung, Jounghee Lee, Teruhiko Terasawa, Joseph Lau, Thomas A. Trikalinos
Journal: Annals of Internal Medicine (2011)

Background: Studies suggest that vitamin D supplementation may reduce cancer and fracture risks. Purpose: To examine the benefits and harms of vitamin D with or without calcium supplementation on clinical outcomes of cancer and fractures in adults. Data Sources: English-language studies identified from MEDLINE and the Cochrane Central Register of Controlled Trials through July 2011. Study Selection: Randomized, controlled trials (RCTs), prospective cohort studies, and nested case–control studies reporting incidence of or death from cancer and fracture outcomes. Data Extraction: Multiple reviewers extracted details about participant characteristics, including baseline vitamin D status and use of supplements; details of statistical analyses, including adjustments for confounding; and methodological quality. Differences were resolved by consensus. Data Synthesis: 19 RCTs (3 for cancer and 16 for fracture outcomes) and 28 observational studies (for cancer outcomes) were analyzed. Limited data from RCTs suggested that high-dose (1000 IU/d) vitamin D supplementation can reduce the risk for total cancer, and data from observational studies suggested that higher blood 25-hydroxyvitamin D (25-[OH]D) concentrations might be associated with increased risk for cancer. Mixed-effects dose–response meta-analyses showed that each 10-nmol/L increase in blood 25-(OH)D concentration was associated with a 6% (95% CI, 3% to 9%) reduced risk for colorectal cancer but no statistically significant dose–response relationships for prostate and breast cancer. Random-effects model meta-analysis showed that combined vitamin D and calcium supplementation reduced fracture risk (pooled relative risk, 0.88 [CI, 0.78 to 0.99]) in older adults, but the effects differed according to study setting: institution (relative risk, 0.71 [CI, 0.57 to 0.89]) versus community-dwelling (relative risk, 0.89 [CI, 0.76 to 1.04]). One RCT showed adverse outcomes associated with supplementation, including increased risk for renal and urinary tract stones. Limitations: Most trial participants were older (aged ≥65 years) postmenopausal women. Observational studies were heterogeneous and were limited by potential confounders. Conclusion: Combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller among community-dwelling older adults than among institutionalized elderly persons. Appropriate dose and dosing regimens, however, require further study. Evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer. Primary Funding Source: Agency for Healthcare Research and Quality.