tbuckley/cabot-search huggingface dataset:
Hypoxia-Inducible Factor 1α Mediates Anoikis Resistance via Suppression of α5 Integrin
Authors: Nadine Rohwer, Martina Welzel, Katjana Daskalow, David Pfander, Bertram Wiedenmann, Katharina Detjen, Thorsten Cramer
Journal: Cancer Research (2008)

Abstract The transcription factor hypoxia-inducible factor 1 (HIF-1) α is abundantly expressed in the majority of human carcinomas and their metastases. HIF-1α controls central metastasis-associated pathways such as glycolysis, angiogenesis, and invasion. Functional inhibition of HIF-1α leads to impaired metastasis formation in murine tumor models. However, the precise molecular mechanisms underlying the metastasis-promoting role of HIF-1α have not been fully characterized. The ability of transformed epithelial cells to initiate the metastatic cascade relies on their ability to escape anoikis, a default program of apoptosis induction following loss of integrin anchoring to the extracellular matrix. Therefore, we addressed the function of HIF-1α in anoikis resistance and anchorage-independent growth. Inhibition of HIF-1α via RNA interference resulted in up-regulation of α5 integrin on the cell surface of human gastric cancer cells, whereas other integrins remained unaffected. Integrin α5 induction occurred at the level of transcription and was dependent on elevated intracellular superoxide in HIF-1α-knockdown cells. HIF-1α–deficient cells displayed significantly increased anoikis susceptibility due to up-regulated α5 integrin. Finally, colony formation in soft agar was shown to be dependent on HIF-1α as HIF-1α–deficient cells displayed a 70% reduction in anchorage-independent proliferation. Results obtained by RNA interference could be entirely confirmed by application of the pharmacologic HIF-1α-inhibitor 2-methoxyestradiol. Hence, our data argue for a pivotal role for HIF-1α in anoikis control via suppression of α5 integrin. HIF-1α–inhibiting drugs might therefore offer an innovative strategy for antimetastatic cancer therapy. [Cancer Res 2008;68(24):10113–20]
Dual Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Inhibition with NVP-AEE788 for the Treatment of Aggressive Follicular Thyroid Cancer
Authors: Maher N. Younes, Yasemin D. Yazici, Seungwon Kim, Samar A. Jasser, Adel K. El-Naggar, Jeffrey N. Myers
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Patients with radioiodine-resistant follicular thyroid cancer (FTC) have a poor prognosis, if metastasized, with currently available treatment modalities. Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) and their receptors (EGFR and VEGFR) have been reported to be overexpressed in FTC and have been implicated in FTC development. We hypothesized that inhibiting the phosphorylation of EGFR and VEGFR by treatment with NVP-AEE788 (AEE788), a novel dual specific EGFR and VEGFR inhibitor, either alone or in combination with paclitaxel, would inhibit the growth of FTC xenografts in an orthotopic nude mouse model. Experimental Design: To confirm previous reports, EGF and EGFR expression and vascularity were analyzed in human samples of FTC, Hürthle cell carcinoma, and normal thyroid tissues. EGFR expression in four FTC cell lines was measured using Western blotting. The antitumor effect of AEE788 on FTC cells in vitro was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and Western blotting. The effect of AEE788, alone and in combination with paclitaxel, on FTC tumor growth in an orthotopic nude mouse model was also investigated. Immunohistochemical analysis of EGFR and VEGFR signaling status, cell proliferation, apoptosis, and microvessel density was done. Results: EGF, EGFR, and vascularity were increased in human thyroid tumor samples and EGFR was increased in FTC cells. AEE788 inhibited FTC cell growth in vitro and reduced the phosphorylation status of EGFR, VEGFR, and two downstream targets, AKT and mitogen-activated protein kinase, in FTC cells. AEE788 alone and, to a greater extent, AEE788 plus paclitaxel suppressed FTC tumor growth in the thyroids of nude mice. Conclusion: Dual inhibition of EGFR and VEGFR by AEE788 could represent a novel approach to the treatment of radioiodine-resistant FTC.
United Health Group settles with US securities watchdog
Authors: J. Hopkins Tanne
Journal: BMJ (2009)

The US stock market watchdog, the Securities and Exchange Commission (SEC), filed a settlement agreement with United Health Group in December over charges that the company violated security laws.

In a separate settlement, this month the company signed an agreement with the New York state attorney general, Andrew Cuomo, to replace its Ingenix reimbursement system for patients who use “out of network” doctors—doctors who are not part of an insurance company’s network. Ingenix, a wholly owned subsidiary of United Health, is the nation’s largest provider of healthcare billing information. Its information is used by United Health and many other health insurance companies.

United Health Group, the second largest US health insurance company, is the parent of several health insurance and related companies. It insures more than 70 million US residents.

The Securities and Exchange Commission announced last month that it had settled enforcement actions against United Health and its former general counsel, David Lubben. The commission had alleged that the company “engaged in a scheme to backdate stock options.” It said, “Without admitting or denying the allegations, United Health agreed to settle charges that it violated the reporting, books and records, and internal controls provisions of the federal securities laws.”

The commission said that it “declined to charge the company with fraud or seek a monetary penalty, based on the company’s extraordinary cooperation in the Commission’s investigation, as well as its extensive remedial measures.”

In a statement the company said, “United Health Group is pleased to have resolved this matter with the SEC and will continue to focus on serving its customers, growing its businesses, reinforcing its community and customer relationships, and helping people live healthier lives. Over the past two years, the company has substantially improved its governance, administrative processes, and internal controls, helping it become one of the …
Failure of epinephrine to improve the balance between myocardial oxygen supply and demand during closed-chest resuscitation in dogs.
Authors: R V Ditchey, J Lindenfeld
Journal: Circulation (1988)

Although large doses of epinephrine increase coronary perfusion pressure and flow during cardiopulmonary resuscitation, epinephrine also increases myocardial oxygen consumption during ventricular fibrillation. To test the hypothesis that epinephrine improves the balance between myocardial oxygen supply and demand during cardiopulmonary resuscitation, myocardial adenosine 5'-triphosphate (ATP) and lactate concentrations were measured before and immediately after 10 minutes of cardiopulmonary resuscitation in 10 control dogs and 10 dogs given intravenous epinephrine (1-mg bolus followed by 0.2 mg/min). Left ventricular myocardial blood flow during cardiopulmonary resuscitation was measured with radioactive microspheres and was significantly higher in the epinephrine group (48 +/- 11 vs. 21 +/- 4 ml/min/100 g, p less than 0.05). However, myocardial lactate concentration increased significantly (p less than 0.01) after cardiopulmonary resuscitation in both groups and tended to increase more in epinephrine-treated animals. Myocardial ATP concentration decreased significantly (p less than 0.05) and by comparable amounts in the two groups. These findings suggest that large doses of epinephrine may fail to improve the balance between myocardial oxygen supply and demand during cardiopulmonary resuscitation, even when they result in a substantial increase in coronary blood flow.
ACAT2 Is Localized to Hepatocytes and Is the Major Cholesterol-Esterifying Enzyme in Human Liver
Authors: Paolo Parini, Matthew Davis, Aaron T. Lada, Sandra K. Erickson, Teresa L. Wright, Ulf Gustafsson, Staffan Sahlin, Curt Einarsson, Mats Eriksson, Bo Angelin, Hiroshi Tomoda, Satoshi Ōmura, Mark C. Willingham, Lawrence L. Rudel
Journal: Circulation (2004)

Two acyl-coenzyme A:cholesterol acyltransferase (ACAT) genes, ACAT1 and ACAT2, have been identified that encode 2 proteins responsible for intracellular cholesterol esterification.In this study, immunohistology was used to establish their cellular localization in human liver biopsies. ACAT2 protein expression was confined to hepatocytes, whereas ACAT1 protein was found in Kupffer cells only. Studies with a highly specific ACAT2 inhibitor, pyripyropene A, in microsomal activity assays demonstrated that ACAT2 activity was highly variable among individual human liver samples, whereas ACAT1 activity was more similar in all specimens. ACAT2 provided the major cholesterol-esterifying activity in 3 of 4 human liver samples examined.The data suggest that in diseases in which dysregulation of cholesterol metabolism occurs, such as hypercholesterolemia and atherosclerosis, ACAT2 should be considered a target for prevention and treatment.
A Randomized Phase II Trial of Granulocyte-Macrophage Colony-Stimulating Factor Therapy in Severe Sepsis with Respiratory Dysfunction
Authors: Jeffrey J. Presneill, Trudi Harris, Alastair G. Stewart, John F. Cade, John W. Wilson
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates hemopoiesis and effector functions of granulocytes and macrophages and is involved in pulmonary surfactant homeostasis. We investigated whether GM-CSF therapy improved clinically diagnosed severe sepsis and respiratory dysfunction in critically ill patients. This randomized, double-blind, placebo-controlled phase II study added low-dose (3 mcg/kg) intravenous recombinant human GM-CSF daily for 5 days to conventional therapy in 10 patients, with a further eight patients receiving placebo. GM-CSF–treated patients showed improvement in PaO2/FiO2 over 5 days (p = 0.02) and increased peripheral blood neutrophils (p = 0.08), whereas alveolar neutrophils decreased (p = 0.02). GM-CSF therapy was not associated with decreased 30-day survival or with increased acute respiratory distress syndrome or extrapulmonary organ dysfunction. GM-CSF therapy was associated with increased blood granulocyte superoxide production and restoration or preservation of blood and alveolar leukocyte phagocytic function. We conclude that low-dose GM-CSF was associated with improved gas exchange without pulmonary neutrophil infiltration, despite functional activation of both circulating neutrophils and pulmonary phagocytes. In addition, GM-CSF therapy was not associated with worsened acute respiratory distress syndrome or the multiple organ dysfunction syndrome, suggesting a homeostatic role for GM-CSF in sepsis-related pulmonary dysfunction.
Limitation of the Coronary Vascular Response to Ischemia in the Awake Dog
Authors: ROBERT J. BACHE, FREDERICK R. COBB, JOSEPH C. GREENFIELD
Journal: Circulation Research (1974)

During reactive hyperemia following a brief coronary artery occlusion, excess arterial inflow exceeds the blood flow debt incurred during occlusion by 300-600%. The present study was performed to determine whether this marked reactive hyperemia is essential for restoration of coronary vascular tone. Coronary blood flow was measured in unanesthetized dogs with electromagnetic flowmeters and hydraulic occluders chronically implanted on their left circumflex coronary arteries. When 10-second coronary artery occlusions were performed in pairs separated by a brief interval during which excess arterial inflow equaled the blood flow debt incurred during the first occlusion, reactive hyperemia following the second occlusion was no greater than that following an isolated control occlusion. Thus, approximately 100% repayment of the blood flow debt resulted in restoration of normal reactivity to a second occlusion. To further ascertain whether coronary vascular tone could be regained without the usual excess inflow, the reactive hyperemia following a 10-second occlusion was mechanically limited by partial inflation of the occluder. When reactive hyperemia equal to 115 ± 10% repayment of the blood flow debt was allowed, final complete release of the occluder was followed by no additional hyperemia. These studies demonstrated that the markedly excess arterial inflow which occurs during coronary reactive hyperemia is not essential for restoration of coronary vascular tone.
Cancer survival in UK is improving but could be better
Authors: Adrian O'Dowd
Journal: BMJ (2007)

Survival of UK patients after cancer is improving but still lags behind the European average, despite the United Kingdom spending more than other countries on cancer, different sources of data published this week show.Figures from the Office for National Statistics (ONS) show that between 1999 and 2004 survival rates for most cancers in England improved.However, two studies published in Lancet Oncology (
The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91phox mediate hepatic fibrosis in mice
Authors: Yong-Han Paik, Keiko Iwaisako, Ekihiro Seki, Sayaka Inokuchi, Bernd Schnabl, Christoph H. Österreicher, Tatiana Kisseleva, David A. Brenner
Journal: Hepatology (2011)

Abstract Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a multicomponent enzyme that mediates electron transfer from nicotinamide adenine dinucleotide phosphate to molecular oxygen, which leads to the production of superoxide. NOX2/gp91phox is a catalytic subunit of NOX expressed in phagocytic cells. Several homologues of NOX2, including NOX1, have been identified in nonphagocytic cells. We investigated the contributory role of NOX1 and NOX2 in hepatic fibrosis. Hepatic fibrosis was induced in wild-type (WT) mice, NOX1 knockout (NOX1KO) mice, and NOX2 knockout (NOX2KO) mice by way of either carbon tetrachloride (CCl4) injection or bile duct ligation (BDL). The functional contribution of NOX1 and NOX2 in endogenous liver cells, including hepatic stellate cells (HSCs), and bone marrow (BM)-derived cells, including Kupffer cells (KCs), to hepatic reactive oxygen species (ROS) generation and hepatic fibrosis was assessed in vitro and in vivo using NOX1 or NOX2 BM chimeric mice. Hepatic NOX1 and NOX2 messenger RNA expression was increased in the two experimental mouse models of hepatic fibrosis. Whereas NOX1 was expressed in HSCs but not in KCs, NOX2 was expressed in both HSCs and KCs. Hepatic fibrosis and ROS generation were attenuated in both NOX1KO and NOX2KO mice after CCl4 or BDL. Liver fibrosis in chimeric mice indicated that NOX1 mediates the profibrogenic effects in endogenous liver cells, whereas NOX2 mediates the profibrogenic effects in both endogenous liver cells and BM-derived cells. Multiple NOX1 and NOX2 components were up-regulated in activated HSCs. Both NOX1- and NOX2-deficient HSCs had decreased ROS generation and failed to up-regulate collagen α1(I) and transforming growth factor β in response to angiotensin II. Conclusion: Both NOX1 and NOX2 have an important role in hepatic fibrosis in endogenous liver cells, including HSCs, whereas NOX2 has a lesser role in BM-derived cells. (Hepatology 2011;)
Service targeting hard to reach tuberculosis patients in London is cost effective
Authors: Sinan R Eccles
Journal: Thorax (2011)

The incidence of tuberculosis in the UK is increasing, particularly in hard-to-reach groups such as problematic drug users and homeless individuals. A ‘Find and Treat’ service, which provides mobile radiography and case management support, has been operating in London since 2007. This study assessed the cost effectiveness of the Find and Treat service …
P-glycoprotein Expression: Critical Determinant in the Response to Osteosarcoma Chemotherapy
Authors: H. S. L. Chan, G. Haddad, G. DeBoer, V. Ling, T. M. Grogan
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Fewer than 20% of patients with bone cancer who are treated with surgery alone are cured. Even with the best current treatment, surgery combined with chemotherapy, only 60%–80% of patients with nonmetastatic bone cancer and 10% of patients with metastatic bone cancer are cured. Thus far, the reason for treatment failure in the nonresponding subset has not been identified. It has been hypothesized that P-glycoprotein, which confers multidrug resistance, might be the cause. We sought to determine whether the expression of P-glycoprotein is associated with poor treatment outcome in osteosarcoma. Methods: In a retrospective study, we correlated P-glycoprotein expression with the outcome of conventional chemotherapy in 62 consecutive, clinically staged patients diagnosed as having osteosarcoma between 1980 and 1989. Results: P-glycoprotein was overexpressed in 27 patients but not in another 34 patients, and expression was ambiguous in the sample from one patient. At a median follow-up of 8.9 years, the 34 patients whose tumors did not express P-glycoprotein had significantly better relapse-free rates than the 27 subjects whose tumors expressed the protein (87% versus 0%; P <.00001) and had improved survival rates (94% versus 35%; P <.00001). Among the 46 patients who received chemotherapy before surgery, the 23 whose tumors were negative for P-glycoprotein showed significantly better long-term outcomes ( P <.00002), although differences in tumor necrosis in response to therapy were only of borderline significance (P = .057). Conclusions: P-glycoprotein expression does correlate with treatment failure in patients with osteosarcoma. This correlation raises the possibility that inhibiting the action of P-glycoprotein as part of therapy for this disease would improve outcome.
Diagnosis of nosocomial pneumonia in medical ward: repeatability of the protected specimen brush
Authors: B. Herer, C. Fuhrman, D. Demontrond, Z. Gazevic, B. Housset, C. Chouaïd
Journal: European Respiratory Journal (2001)

The aims of this study were to assess the repeatability of two pairs of protected specimen brushes (PSB) done successively in the same lung area and either processed at the bedside or in the laboratory, and to provide a description of the bacteriological findings in 39 cases of suspected nosocomial pneumonia occurring in nonventilated patients. Four PSB were divided into two pairs. One pair of brushes (Pb) was prepared at bedside and then sent to the laboratory; the other pair (Pl) was immediately sent to the laboratory for complete processing. According to a 10 3 colony forming units (cfu)·mL −1 threshold, 49% out of 156 PSB were positive. Using the 10 3 cfu·mL threshold, the Pl brushes were 89.7% concordant while the Pb brushes were 76.9% concordant. The repeatability as expressed by Κ-value of the cultures of PSB was higher for Pl brushes than for Pb brushes (Κ-values of 0.795 and 0.537 respectively, p=0.12). Bacterial species were isolated in 58.3% of 156 PSB (176 isolates). In 14 cases, cultures of PSB disclosed more than one micro-organism in a concentration &gt;10 3 cfu·mL −1 . The most frequently isolated organisms were Pseudomonas spp. (23.9%), Enterobacteriaceae (23.3%), Streptococcus spp. (21.6%) and Staphylococcus spp. (13.1%). Polymicrobial cultures were more frequent if the patient had a tracheostomy (seven out of the nine patients with a tracheostomy versus seven out of the 30 patients without a tracheostomy, p&lt;0.01). Bacteriological discrepancies leading to a potential troublesome choice in antibiotherapy were observed in 31.8% of the patients for Pl brushes and 56.5% of the patients for Pb brushes. There is a low degree of repeatability of protected specimen brushes outside intensive care units which seem dependent on sampling processing. The distribution of pathogens found in case of suspicion of nosocomial pneumonia in nonventilated patients appears to be similar to that obtained in ventilator-associated pneumonia.
Association Between Older Age and More Successful Aging: Critical Role of Resilience and Depression
Authors: Dilip V. Jeste, Gauri N. Savla, Wesley K. Thompson, Ipsit V. Vahia, Danielle K. Glorioso, A’verria Sirkin Martin, Barton W. Palmer, David Rock, Shahrokh Golshan, Helena C. Kraemer, Colin A. Depp
Journal: American Journal of Psychiatry (2012)

There is growing public health interest in understanding and promoting successful aging. While there has been some exciting empirical work on objective measures of physical health, relatively little published research combines physical, cognitive, and psychological assessments in large, randomly selected, community-based samples to assess self-rated successful aging.In the Successful AGing Evaluation (SAGE) study, the authors used a structured multicohort design to assess successful aging in 1,006 community-dwelling adults in San Diego County, ages 50-99 years, with oversampling of people over 80. A modified version of random-digit dialing was used to recruit subjects. Evaluations included a 25-minute telephone interview followed by a comprehensive mail-in survey of physical, cognitive, and psychological domains, including positive psychological traits and self-rated successful aging, scaled from 1 (lowest) to 10 (highest).The mean age of the respondents was 77.3 years. Their mean self-rating of successful aging was 8.2, and older age was associated with a higher rating, despite worsening physical and cognitive functioning. The best multiple regression model achieved, using all the potential correlates, accounted for 30% of the variance in the score for self-rated successful aging and included resilience, depression, physical functioning, and age (entering the regression model in that order).Resilience and depression had significant associations with self-rated successful aging, with effects comparable in size to that for physical health. While no causality can be inferred from cross-sectional data, increasing resilience and reducing depression might have effects on successful aging as strong as that of reducing physical disability, suggesting an important role for psychiatry in promoting successful aging.
Prevalence of allergy, patterns of allergic sensitization and allergy risk factors in rural and urban children
Authors: B. Majkowska–Wojciechowska, J. Pełka, L. Korzon, A. Kozłowska, M. Kaczała, M. Jarzębska, T. Gwardys, M. L. Kowalski
Journal: Allergy (2007)

We aimed to compare the prevalence of allergic diseases and sensitization in children living in urban and rural areas and to identify potential risk/protection factors associated with allergy.School children 12-16 years old, from urban community (n = 201) and rural area (n = 203) were recruited. The data obtained by questionnaire were referred to doctors' diagnosis, skin prick tests (SPTs), and serum specific and total IgE assessment.The prevalence of allergic diseases in urban children was significantly higher as compared with rural children [asthma 16.42%vs 1.97% (P < 0.001) allergic rhinitis 38.81%vs 10.84% (P < 0.001)]. Positive SPTs to at least one allergen was found in 63.7% of urban and 22.7% rural children (P < 0.001). Significantly higher percentage of allergic rural than urban children were monosensitized or sensitized to 2-4 allergens, but almost a fourfold higher percentage of allergic urban children was found to be sensitized to five or more allergens (P < 0.0001). The history of frequent upper respiratory factor (URT) infections, antibiotic therapy, tonsiltectomy/adenoidectomy were positively associated with development of atopy and sensitization.Our findings confirm that residence of rural area is associated with a significant lower prevalence of allergic sensitization and symptoms in school children. Several risk and protective factors related to environment and style of life could be identified in both environments.