tbuckley/cabot-search huggingface dataset:
Loss of the <i>hSNF5</i> Gene Concomitantly Inactivates p21CIP/WAF1 and p16INK4a Activity Associated with Replicative Senescence in A204 Rhabdoid Tumor Cells
Authors: Jingjing Chai, Aubri L. Charboneau, Bryan L. Betz, Bernard E. Weissman
Journal: Cancer Research (2005)

Abstract hSNF5, the smallest member of the SWI/SNF chromatin remodeling complex, is lost in most malignant rhabdoid tumors (MRT). In MRT cell lines, reexpression of hSNF5 induces G1 cell cycle arrest, elevated p16INK4a, and activated replicative senescence markers, such as β-galactosidase (β-Gal) and plasminogen activator inhibitor-1. To compare the replicative senescence caused by hSNF5 in A204 cells to normal cellular senescence, we examined the activation of both p16INK4a and p21CIP/WAF1. Analogous to normal cellular senescence, both p16INK4a and p21CIP/WAF1 were up-regulated following hSNF5 restoration. Furthermore, we found that hSNF5 bound the p16INK4a and p21CIP/WAF1 promoters, suggesting that it directly regulates transcription of these genes. Using p16INK4a RNA interference, we showed its requirement for the replicative senescence caused by hSNF5 but not the growth arrest. Instead, p21CIP/WAF1 remained activated by hSNF5 in the absence of high p16INK4a expression, apparently causing the growth arrest in A204. Interestingly, we also found that, in the absence of p16INK4a, reexpression of hSNF5 also increased protein levels of a second cyclin-dependent kinase (CDK) inhibitor, p18INK4c. However, our data show that lack of hSNF5 does not abrogate cellular responsiveness to DNA damage or growth-inhibitory factors. In summary, our studies suggest that hSNF5 loss may influence the regulation of multiple CDK inhibitors involved in replicative senescence.
<i>In vitro</i> and <i>In vivo</i> Effects and Mechanisms of Celecoxib-Induced Growth Inhibition of Human Hepatocellular Carcinoma Cells
Authors: Wei Cui, Chang-Hong Yu, Ke-Qin Hu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Cyclooxygenase-2 (COX-2) inhibitors cause growth inhibition of human hepatocellular carcinoma cells but it remains unclear whether this is both COX-2 dependent and independent. The related mechanisms remain to be determined. The present study was aimed to determine the effect of celecoxib on growth of hepatocellular carcinoma cells and xenografts and the related mechanisms. Experimental Design: Both low COX-2 expressing PLC/PRF/5 and high COX-2 expressing HuH7 cells, and nude mice bearing hepatocellular carcinoma xenografts were used to study the effect and mechanisms of celecoxib on hepatocellular carcinoma cell growth. Results: Celecoxib resulted in a comparable growth inhibition of both hepatocellular carcinoma cells that was associated with decreased production of prostaglandin E2 and increased peroxisome proliferator-activated receptor γ in both cells. Addition of prostaglandin E2 only partially counteracted the effect of celecoxib on both cells. Celecoxib resulted in a significant reduction of retinoblastoma phosphorylation and DP1/E2F1 complex in both cells. Celecoxib caused a significant increase of apoptosis and activation of caspase-3 and caspase-9 in both cells. In nude mice inoculated with HuH7 cells, celecoxib resulted in decreased frequency and mean weight of hepatocellular carcinoma xenografts. Conclusion: The present study showed that celecoxib causes COX-2-dependent and COX-2-independent growth inhibition of hepatocellular carcinoma cells and xenografts by (a) decreased retinoblastoma phosphorylation and DP1/E2F1 complex; (b) increased activation of caspase-3 and caspase-9; and (c) increased expression of proliferator-activated receptor γ. The present study significantly extended our knowledge on the effect and mechanisms of celecoxib-induced inhibition of hepatocellular carcinoma cell growth.
Pravastatin attenuates allergic airway inflammation by suppressing antigen sensitisation, interleukin 17 production and antigen presentation in the lung
Authors: M Imamura, K Okunishi, H Ohtsu, K Nakagome, H Harada, R Tanaka, K Yamamoto, M Dohi
Journal: Thorax (2008)

Statins are widely used to treat hyperlipidaemia. Their immunosuppressive effect has recently been confirmed in various immune mediated disease models. However, relatively few studies have been conducted on allergic inflammation, so the precise mechanisms of their actions against allergies have not been fully clarified. On the other hand, the role of interleukin (IL)17 in immune responses has been recently highlighted, but whether statins affect IL17 production has not been well studied. The effect of pravastatin on allergic airway inflammation in a mouse model was examined to elucidate the mechanism of action, focusing on its effect on IL17 production.BALB/c mice were immunised with ovalbumin (OVA) and then challenged with OVA aerosol. Pravastatin was delivered by intraperitoneal injection during either sensitisation or the challenge.When delivered during systemic sensitisation, pravastatin suppressed OVA induced proliferation and production of Th2 type cytokines such as IL5 in spleen cells ex vivo and in vitro. IL17 production was also suppressed. Furthermore, pavastatin delivered during the inhalation of OVA attenuated eosinophilic airway inflammation, OVA specific IgE production in serum and OVA induced IL17 production in the thoracic lymph node. We also found that pravastatin attenuated the antigen presenting capacity of CD11c(+) cells obtained from the OVA challenged lung.Pravastatin suppresses the systemic sensitisation to allergen with downregulation of IL17 production. It also suppresses an ongoing immune response in the airway partly by suppressing antigen presentation in the lung. Therefore, statins could be a novel therapeutic option for treatment of asthma.
Prospective evaluation of protein bound vitamin B<sub>12</sub>(cobalamin) malabsorption in the elderly using trout flesh labelled in vivo with <sup>57</sup>Co-cobalamin
Authors: I Aimone-Gastin, H Pierson, C Jeandel, J P Bronowicki, F Plénat, D Lambert, F Nabet-Belleville, J L Guéant
Journal: Gut (1997)

Background —The frequency of dietary protein bound vitamin B 12 malabsorption in elderly patients remains controversial. Aims —To evaluate this malabsorption in elderly hospitalised patients using a modified Schilling test. Patients —Fourteen elderly patients with low B 12 blood levels were prospectively selected from 394 hospitalised patients. Methods —The modified Schilling test was performed with trout labelled in vivo. Results —The test was normal in five healthy elderly subjects, in 7/8 patients with pancreatic insufficiency, and in nine non-elderly patients with antral gastritis. The low decision limit was established at 3.3% (median 4.8%). From the 14 elderly patients with low B 12 prospectively selected from 394 hospitalised patients, seven had a real deficiency with anaemia and an increased homocysteine and/or methylmalonate serum level. The modified Schilling test showed malabsorption in five of these patients, including two in which the standard Schilling test was normal, and three in which the standard Schilling test was partially corrected by an intrinsic factor. Conclusions —Protein bound vitamin B 12 malabsorption was detected in at least 0.5% of elderly hospitalised patients, using the labelled trout flesh absorption test.
Integrating the Universal Metabolism into a Phylogenetic Analysis
Authors: C. Cunchillos
Journal: Molecular Biology and Evolution (2004)

The darwinian concept of “descent with modification” applies to metabolic pathways: pathways sharing similarities must have inherited them from an exclusive, hypothetical ancestral pathway. Comparative anatomy of biochemical pathways is performed using five criteria of homology. Primary homologies of “type I” were defined as several pathways sharing the same enzyme with high specificity for its substrate. Primary homologies of “type II” were defined as the sharing of similar enzymatic functions, cofactors, functional family, or recurrence of a set of reactions. Standard cladistic analysis is used to infer the evolutionary history of metabolic development and the relative ordering of biochemical reactions through time, from a single matrix integrating the whole basic universal metabolism. The cladogram shows that the earliest pathways to emerge are metabolism of amino acids of groups I and II (Asp, Asn, Glu, and Gln). The earliest enzymatic functions are mostly linked to amino acid catabolism: deamination, transamination, and decarboxylation. For some amino acids, catabolism and biosynthesis occur at the same time (Asp, Glu, Lys, and Met). Catabolism precedes anabolism for Asn, Gln, Arg, Trp, His, Tyr, and Phe, and anabolism precedes catabolism for Pro, Ala, Leu, Val, Ile, Cys, Gly, Ser, and Thr. The urea cycle evolves from arginine synthesis. Metabolism of fatty acids and sugars develops after the full development of metabolism of amino acids of groups I and II, and they are associated with the anabolism of amino acids of groups III and IV. Syntheses of aromatic amino acids are branched within sugar metabolism. The Krebs cycle occurs relatively late after the setting of metabolism of amino acids of groups I and II. One portion of the Krebs cycle has a catabolic origin, whereas the other portion has an anabolic origin in pathways of amino acids of groups III and IV. It is not possible to order glycolysis and gluconeogenesis with regard to the Krebs cycle, as they all belong to “period 6.” Pentose-phosphate and Calvin cycles are later (periods 7 and 8, respectively). Cladistic analysis of the structure of biochemical pathways makes hypotheses in biochemical evolution explicit and parsimonious.
Na+/K+-ATPase 2-subunit (AMOG) expression abrogates invasion of glioblastoma-derived brain tumor-initiating cells
Authors: M. Z. Sun, J. M. Kim, M. C. Oh, M. Safaee, G. Kaur, A. J. Clark, O. Bloch, M. E. Ivan, R. Kaur, T. Oh, S. D. Fouse, J. J. Phillips, M. S. Berger, A. T. Parsa
Journal: Neuro-Oncology (2013)

Mechanisms of glioma invasion remain to be fully elucidated. Glioma cells within glioblastoma multiforme (GBM) range from well-differentiated tumor cells to less-differentiated brain tumor-initiating cells (BTICs). The β2-subunit of Na+/K+-ATPase, called the adhesion molecule on glia (AMOG), is highly expressed in normal glia but is thought to be universally downregulated in GBM. To test our hypothesis that expression of AMOG is heterogeneous in GBM and confers a less invasive phenotype, we compared it between BTICs and differentiated cells from patient-matched GBM and then tested GBM invasion in vitro after AMOG overexpression. Immunohistochemistry, immunoblotting, and real-time PCR were used to characterize AMOG protein and mRNA expression in tumor samples, BTICs, and differentiated cells. Matrigel invasion assay, scratch assay, and direct cell counting were used for testing in vitro invasion, migration, and proliferation, respectively. While AMOG expression is heterogeneous in astrocytomas of grades II–IV, it is lost in most GBM. BTICs express higher levels of AMOG mRNA and protein compared with patient-matched differentiated tumor cells. Overexpression of AMOG decreased GBM cell and BTIC invasion without affecting migration or proliferation. Knockdown of AMOG expression in normal human astrocytes increased invasion. AMOG expression inhibits GBM invasion. Its downregulation increases invasion in glial cells and may also represent an important step in BTIC differentiation. These data provide compelling evidence implicating the role of AMOG in glioma invasion and provide impetus for further investigation.
EULAR recommendations for calcium pyrophosphate deposition. Part II: Management
Authors: W Zhang, M Doherty, E Pascual, V Barskova, P-A Guerne, T L Jansen, B F Leeb, F Perez-Ruiz, J Pimentao, L Punzi, P Richette, F Sivera, T Uhlig, I Watt, T Bardin
Journal: Annals of the Rheumatic Diseases (2011)

Objectives To develop evidence-based recommendations for management of calcium pyrophosphate deposition (CPPD). Methods A multidisciplinary guideline development group of 15 experts, representing 10 European countries, generated key propositions for management of CPPD using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the effect size and number needed to treat for efficacy and RR or OR for side effects were calculated for individual treatment modalities. Strength of recommendation was assessed by the European League Against Rheumatism visual analogue scale. Results Nine key recommendations were generated, including topics for general management, treatment of acute attacks, prophylaxis against recurrent acute attacks and management of chronic symptoms. It was recommended that optimal treatment requires both non-pharmacological and pharmacological treatments. For acute CPP crystal arthritis, cool packs, temporary rest and joint aspiration combined with steroid injection are often sufficient. For prophylaxis or chronic inflammatory arthritis with CPPD, oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5–1.0 mg daily may be used. Other recommendations included parenteral or oral corticosteroid for acute CPP arthritis in those unresponsive or unsuited to other measures, and low-dose corticosteroid, methotrexate or hydroxychloroquine for chronic inflammatory arthritis with CPPD. Asymptomatic CPPD requires no treatment. Strength of recommendations varies from 79% to 95%. Conclusion Nine key recommendations for management of CPP crystal associated arthritis were developed using both research evidence and expert consensus. Strength of recommendations was provided to assist the application of these recommendations.
The Ethics and Economics of Pharmaceutical Pricing
Authors: Sara Parker-Lue, Michael Santoro, Greg Koski
Journal: The Annual Review of Pharmacology and Toxicology (2014)

The cost of drugs is a major and rapidly rising component of health-care expenditures. We survey recent literature on the ethics and economics of skyrocketing pharmaceutical prices and find that advances in economic research have increased the sharpness and focus of the ethically based calls to increase access by modifying patent protection and reducing prices. In some cases, research supports ethical arguments for broader access. Other research suggests that efforts to broaden access result in unintended consequences for innovation and the medical needs of patients. Both ethicists and economists need to be more cognizant of the real clinical settings in which physicians practice medicine with real patients. Greater cross-disciplinary interaction among economists, ethicists, and physicians can help reduce the disjunction between innovation and access and improve access and patient care. This dialogue will impact private industry and may spur new multistakeholder paradigms for drug discovery, development, and pricing.
Patterns of Heterotypic Continuity Associated With the Cross-Sectional Correlational Structure of Prevalent Mental Disorders in Adults
Authors: Benjamin B. Lahey, David H. Zald, Jahn K. Hakes, Robert F. Krueger, Paul J. Rathouz
Journal: JAMA Psychiatry (2014)

Mental disorders predict future occurrences of both the same disorder (homotypic continuity) and other disorders (heterotypic continuity). Heterotypic continuity is inconsistent with a view of mental disorders as fixed entities. In contrast, hierarchical-dimensional conceptualizations of psychopathology, in which each form of psychopathology is hypothesized to have both unique and broadly shared etiologies and mechanisms, predict both homotypic and heterotypic continuity.
Surgical Mortality in Patients With Esophageal Cancer: Development and Validation of a Simple Risk Score
Authors: Ewout W. Steyerberg, Bridget A. Neville, Linetta B. Koppert, Valery E.P.P. Lemmens, Hugo W. Tilanus, Jan-Willem W. Coebergh, Jane C. Weeks, Craig C. Earle
Journal: Journal of Clinical Oncology (2006)

Purpose Surgery has curative potential in a proportion of patients with esophageal cancer, but is associated with considerable perioperative risks. We aimed to develop and validate a simple risk score for surgical mortality that could be applied to administrative data. Patients and Methods We analyzed 3,592 esophagectomy patients from four cohorts. We applied logistic regression analysis to predict mortality occurring within 30 days after esophagectomy for 1,327 esophageal cancer patients older than 65 years of age, diagnosed between 1991 and 1996 in the linked Surveillance, Epidemiology and End Results (SEER) - Medicare database. A simple score chart for preoperative risk assessment of surgical mortality was developed and validated on three other cohorts, including 714 SEER-Medicare patients diagnosed between 1997 and 1999, 349 patients from a population-based registry in the Netherlands diagnosed between 1993 and 2001, and 1,202 patients from a referral hospital in the Netherlands diagnosed between 1980 and 2002. Results Surgical mortality in the four cohorts was 11% (147 of 1,327), 10% (74 of 714), 7% (25 of 349), and 4% (45 of 1,202), respectively. Predictive patient characteristics included age, comorbidity (cardiac, pulmonary, renal, hepatic, and diabetes), preoperative radiotherapy or combined chemoradiotherapy, and a relatively low hospital volume. At validation, the simple score showed good agreement of predicted risks with observed mortality rates (calibration), but low discrimination (area under the receiver operating characteristic curve 0.58 to 0.66). Conclusion A simple risk score combining clinical characteristics along with hospital volume to predict surgical mortality after esophagectomy from administrative data may form a basis for risk adjustment in quality of care assessment.
Thrombosis Modulates Arterial Drug Distribution for Drug-Eluting Stents
Authors: Chao-Wei Hwang, Andrew D. Levin, Michael Jonas, Pamela H. Li, Elazer R. Edelman
Journal: Circulation (2005)

Drug-eluting stents deliver potent compounds directly to arterial segments but can become clot laden when deployed. The question arises as to whether thrombi affect drug elution and arterial uptake.Paclitaxel transport and retention were assessed in clots of different blood components. Diffusivity, affected by clot organization, is fastest in fibrin (approximately 347 microm2/s), slower in fibrin-red blood cell clots (34.98 microm2/s), and slowest in whole-blood clots (3.55 microm2/s). Blood cells bind and retain paclitaxel such that levels in clot increase linearly with red cell fraction. At physiological hematocrit, clot retains 3 times the amount of paclitaxel in surrounding solutions. Computational models predict that the potential of thrombus to absorb, retain, and release drug or to act as a barrier to drug delivery depends on clot geometry and strut position in clot relative to the vessel wall. Clot between artery and stent can reduce uptake 10-fold, whereas clot overlying the stent can shield drug from washout, increasing uptake. Model assumptions were confirmed and predictions were validated in a novel rat model that introduces thrombosis within stented aortas where nonocclusive thrombus acts as capacitive space for drug and shifts drug levels to decrease tissue uptake 2-fold.Thrombus apposed on stents creates large variations in drug uptake and can act to either increase or decrease wall deposition according to the clot and stent geometry. Arterial deposition of drug from stents deployed in clots will be highly variable and unpredictable unless the clot can be adequately controlled or removed.
Energy metabolism and T-cell-mediated cytolysis. II. Selective inhibition of cytolysis by 2-deoxy-D-glucose.
Authors: H R MacDonald
Journal: The Journal of Experimental Medicine (1977)

The effect of the hexose analogue 2-deoxy-D-glucose (2-DG) on T-cell-mediated cytolysis has been investigated. 2-DG inhibited cytolysis in glucose-free medium but not in medium containing equimolar concentrations of glucose. This inhibition was reversible and quantitatively competitive with glucose. Among other natural sugars examined, only mannose competed effectively with 2-DG and reversed the inhibition of cytolysis, whereas sodium pyruvate, fructose, galactose, fucose, and glucosamine were without effect. Mannose and glucose were equally effective in competing with 2-DG on a molar basis. When other glucose analogues such as 5-thio-D-glucose (5-SH-G) and 3-O-methylglucose were investigated under the same conditions, no inhibition of cytolysis was observed however, 5-SH-G (but not 3-O-methylglucose) was able to reverse the inhibitory effect of 2-DG in a competitive fashion. Taken together with the data presented in the accompanying paper, these findings provide strong evidence that 2-DG inhibits T-cell-mediated cytolysis by a mechanism that is unrelated to energy production. The possibility that inhibition is related to interference with membrane glycoprotein synthesis is discussed.
Pulmonary Haemosiderosis (apparently Idiopathic) associated with Myocarditis, with Bilateral Penetrating Corneal Ulceration, and with Diabetes Mellitus
Authors: K. J. Murphy
Journal: Thorax (1965)

The literature of pulmonary haemosiderosis includes an account by Campbell and Macafee (1959) of idiopathic pulmonary haemosiderosis associated with myocarditis. Their patient first had symptoms of shortness of breath at the age of 7; he was found to have the radiological changes of pulmonary haemosiderosis at the age of 12, and he died when 14 years old. Death was due to cardiac failure, and at necropsy the heart showed a marked degree of fibrosis and there was infiltration by polymorphs, mononuclears, and lymphocytes. The following case is reported because of the appearance of pulmonary haemosiderosis and the subsequent development of cardiac manifestations plus a number of other features.
Changes in rib cage geometry during childhood.
Authors: P Openshaw, S Edwards, P Helms
Journal: Thorax (1984)

Age related changes in rib cage geometry were found from measurements made on chest radiographs from 38 individuals aged from 1 month to 31 years and on computed tomography (CT) scans in another 28 individuals, aged from 3 months to 18 years. Chest radiographs were taken for minor respiratory symptoms or fever and only films showing no abnormality were used. CT scans were obtained in children undergoing staging for solid tumours in whom no intrathoracic deposits were found. In infants and very young children the ribs were found to be more horizontal and the sternal clavicular heads and diaphragmatic domes higher than in older children and young adults. Most of these changes were observed in the first two years of life, with something close to the adult pattern by the age of 2 years. Similarly cross sectional chest shape changed from the rounded infantile form to the more ovoid adult form by the same age. The configuration of the ribs observed in infancy and early childhood reduces the potential for thoracic expansion and may contribute to the frequency of respiratory problems found in the very young.
Fostering the Ethics of Ethics Consultants in Health Care: An Ongoing Participatory Approach
Authors: Bert Molewijk, Laura Hartman, Froukje Weidema, Yolande Voskes, Guy Widdershoven
Journal: The American Journal of Bioethics (2015)

We appreciate the process and content of the code of ethics for ethics consultants described by Tarzian and colleagues (Tarzian et al. 2015). Both method and results are in line with our view that ...