tbuckley/cabot-search huggingface dataset:
Brain-Derived Neurotrophic Factor Promotes Tumorigenesis via Induction of Neovascularization: Implication in Hepatocellular Carcinoma
Authors: Chi-Tat Lam, Zhen-Fan Yang, Chi-Keung Lau, Ka-Ho Tam, Sheung-Tat Fan, Ronnie T.P. Poon
Journal: Clinical Cancer Research (2011)

Brain-derived neurotrophic factor (BDNF) has emerged as a novel angiogenic factor, and yet its impact on tumorigenesis is unclear. This study aimed at investigating the roles of BDNF in angiogenesis and tumor development.BDNF was overexpressed in a mouse endothelial cell (EC) line by stable transfection, and angiogenic properties of the transfectants were assessed. Microarray analysis was employed to explore the molecular pathways. The impact of modulating BDNF levels in two mouse EC lines on tumorigenic potential of a transformed mouse liver cell line was evaluated by an in vivo cotransplantation model. BDNF and tropomyosin receptor kinase B (TrkB) protein levels were determined in 50 pairs of human hepatocellular carcinoma (HCC) tissues by Western blotting and immunohistochemistry. Survival analysis was carried out to determine their clinical significance.Overexpression of BDNF could promote EC proliferation, migration, invasion, and survival. Microarray and molecular studies showed that RhoA, caspase-9, caspase-3, growth arrest specific 6, and VEGF could mediate BDNF/TrkB-induced angiogenesis. The cotransplantation experiment showed that high BDNF-expressing ECs could facilitate tumor angiogenesis and growth, whereas knockdown of BDNF by short hairpin RNAs impaired such effects. Furthermore, examination on human HCC tissues revealed upregulation of BDNF and TrkB protein levels in 46.0% and 33.3% of the cases studied, respectively. Immunohistochemistry disclosed strong BDNF reactivity in both tumor and endothelial cells. High TrkB expression was associated with shorter overall survival.BDNF/TrkB system was crucial for tumor angiogenesis and growth, which may represent a potential target for antiangiogenic therapy in HCC.
The Natural Course of Healthy Obesity Over 20 Years
Authors: Joshua A. Bell, Mark Hamer, Séverine Sabia, Archana Singh-Manoux, G. David Batty, Mika Kivimaki
Journal: Journal of the American College of Cardiology (2015)

Intense interest surrounds the “healthy” obese phenotype, which is defined as obesity in the absence of metabolic risk factor clustering [(1)][1]. Efforts to understand the cardiovascular consequences of healthy obesity are ongoing [(2)][2]; however, its conceptual validity and clinical value
Massive Weight Loss Decreases Corticosteroid-Binding Globulin Levels and Increases Free Cortisol in Healthy Obese Patients
Authors: Melania Manco, José M. Fernández-Real, Maria E. Valera-Mora, Henri Déchaud, Giuseppe Nanni, Vincenzo Tondolo, Menotti Calvani, Marco Castagneto, Michel Pugeat, Geltrude Mingrone
Journal: Diabetes Care (2007)

Obesity, insulin resistance, and weight loss have been associated with changes in hypothalamic-pituitary-adrenal (HPA) axis. So far, no conclusive data relating to this association are available. In this study, we aim to investigate the effects of massive weight loss on cortisol suppressibility, cortisol-binding globulin (CBG), and free cortisol index (FCI) in formerly obese women.Ten glucose-normotolerant, fertile, obese women (BMI >40 kg/m2, aged 38.66 +/- 13.35 years) were studied before and 2 years after biliopancreatic diversion (BPD) when stable weight was achieved and were compared with age-matched healthy volunteers. Cortisol suppression was evaluated by a 4-mg intravenous dexamethasone suppression test (DEX-ST). FCI was calculated as the cortisol-to-CBG ratio. Insulin sensitivity was measured by an euglycemic-hyperinsulinemic clamp, and insulin secretion was measured by a C-peptide deconvolution method.No difference was found in cortisol suppression after DEX-ST before or after weight loss. A decrease in ACTH was significantly greater in control subjects than in obese (P = 0.05) and postobese women (P < or = 0.01) as was the decrease in dehydroepiandrosterone (P < or = 0.05 and P < or = 0.01, respectively). CBG decreased from 51.50 +/- 12.76 to 34.33 +/- 7.24 mg/l (P < or = 0.01) following BPD. FCI increased from 11.15 +/- 2.85 to 18.16 +/- 6.82 (P < or = 0.05). Insulin secretion decreased (52.04 +/- 16.71 vs. 30.62 +/- 16.32 nmol/m(-2); P < or = 0.05), and insulin sensitivity increased by 163% (P < or = 0.0001). Serum CBG was related to BMI (r(0) = 0.708; P = 0.0001), body weight (r(0) = 0.643; P = 0.0001), body fat percent (r(0) = 0.462; P = 0.001), C-reactive protein (r(0) = 0.619; P = 0.004), and leptin (r(0) = 0.579; P = 0.007) and negatively to M value (r(0) = -0.603; P = 0.005).After massive weight loss in morbidly obese subjects, an increase of free cortisol was associated with a simultaneous decrease in CBG levels, which might be an adaptive phenomenon relating to environmental changes. This topic, not addressed before, adds new insight into the complex mechanisms linking HPA activity to obesity.
Improvements in the NHS are patchy, report says
Authors: R. Coombes
Journal: BMJ (2003)

The NHS is improving, but progress is still too patchy, a report from the Commission for Health Improvement (CHI) said last week. It identified as problems poor infection control, too great a concentration on waiting lists, and a lack of doctors in management positions.

The commission's first annual report on the state of the care of patients draws on over 170 reviews of NHS organisations carried out by the independent watchdog since its establishment three years ago.

The “bottom line” was that the NHS was “on the whole getting better,” said the report. But it warned that the rigid focus on waiting list targets and service redesigns was putting improvements at risk.

Dame Deirdre Hine, CHI's chairwoman, said that national standards, based on NICE guidance or national service frame-works, had …
Effect of a specific iron chelating agent on animal models of inflammation.
Authors: D R Blake, N D Hall, P A Bacon, P A Dieppe, B Halliwell, J M Gutteridge
Journal: Annals of the Rheumatic Diseases (1983)

Iron is an important catalyst of oxidative radical reactions and promotes the formation of the hydroxyl radical from the superoxide anion radical and hydrogen peroxide. The stimulatory effect of the hydroxyl radical on lipid peroxidation prompted the speculation that free iron may directly promote inflammation and that iron chelating agents may have useful anti-inflammatory properties. This hypothesis is tested in animal models of inflammation with a specific iron chelating agent, desferrioxamine. At low doses (6 . 6 mg/kg) intraperitoneal desferrioxamine stimulated the induction of acute foot pad swelling in rats by monosodium urate but at higher doses (above 200 mg/kg) it suppressed this inflammatory reaction. A similar anti-inflammatory effect was observed in carrageenan-induced foot pad swelling. In guinea-pigs in which a Glynn-Dumonde synovitis was induced with bovine gammaglobulin, desferrioxamine (100 mg/kg) stimulated the acute inflammatory induction phase of this chronic allergic monoarthritis model. Repeated administration of desferrioxamine (100 mg/kg) from the seventh to the twelfth day after intra-articular challenge with bovine gammaglobulin markedly depressed the chronic inflammatory phase. In-vitro experiments suggest that desferrioxamine inhibits iron-catalysed lipid peroxidation when it is poorly saturated with iron, but loses this effect when it is iron saturated. Such an effect may explain our results with desferrioxamine in the animal studies and suggests that effective iron chelation and its removal may modify the inflammatory process in man.
Protective role of intracoronary fatty acid binding protein in ischemic and reperfused myocardium.
Authors: B N Srimani, R M Engelman, R Jones, D K Das
Journal: Circulation Research (1990)

In this study, fatty acid binding protein was used to protect an ischemic heart from reperfusion injury. Isolated rat heart was preperfused in the presence of 1.4 microM liposome-bound fatty acid binding protein for 15 minutes, followed by 30 minutes of ischemia and 30 minutes of reperfusion. Our results indicated better preservation of myocardial high-energy phosphate compounds (including ATP and creatine phosphate), reduced creatine kinase and lactate dehydrogenase release from the heart, and improved coronary flow in hearts treated with fatty acid binding protein compared with untreated controls. Fatty acid binding protein enhanced reacylation of arachidonic acid into phospholipids, thereby preserving membrane phospholipids and reducing free fatty acid contents during ischemia and reperfusion. In addition, fatty acid binding protein-bound long-chain free fatty acids and their thioesters as well as carnitine esters were increased in the cytosolic compartment of the heart. These results suggest that fatty acid binding protein may be used as a possible therapeutic agent to improve myocardial function during reperfusion of ischemic heart.
Global Financing and Long-Term Technical Assistance for Multidrug-Resistant Tuberculosis: Scaling Up Access to Treatment
Authors: Thomas J. Hwang, Salmaan Keshavjee
Journal: PLoS Medicine (2014)

Multidrug-resistant tuberculosis (MDR-TB), strains of Mycobacterium tuberculosis resistant to the first-line antituberculosis drugs rifampicin and isoniazid, is a global public health concern and remains a leading cause of mortality and morbidity in low-and middle-income countries [1].In response, World Health Organization (WHO) member states have called for action to ''achieve universal access to diagnosis and treatment of multidrugresistant and extensively drug-resistant tuberculosis'' [2].However, the drive to eradicate MDR-TB using current strategies remains an uphill battle [3,4].Extensively drug-resistant tuberculosis (XDR-TB), a form of MDR-TB with additional resistance to the backbone of the secondline antituberculosis regimen-fluoroquinolones and injectable agents-has been officially reported in 92 countries [5].Making MDR-TB treatment more affordable would be an important step towards improving patient access to care and reducing the significant public health burdens arising from the spread of this highly contagious airborne disease [6,7].Here, we assess changes in MDR-TB drug prices since 2001 and identify limitations in the current system, focusing on the barriers to care delivery posed by high costs of treatment and weak health systems.Using pneumococcal vaccine as a case study to inform the fight against the global tuberculosis (TB) pandemic, we argue that a market-based strategy coupled with long-term in-country technical assistance should be utilised to scale up access to MDR-TB treatment.Policy Forum articles provide a platform for health policy makers from around the world to discuss the challenges and opportunities in improving health care to their constituencies.
Gene Therapy with Galectin-3 Inhibits Bronchial Obstruction and Inflammation in Antigen-challenged Rats through Interleukin-5 Gene Downregulation
Authors: Victoria del Pozo, Marta Rojo, Maria L. Rubio, Isabel Cortegano, Blanca Cárdaba, Soledad Gallardo, Mercedes Ortega, Esther Civantos, Esther López, Carmen Martín-Mosquero, Germán Peces-Barba, Pilar Palomino, Nicolas González-Mangado, Carlos Lahoz
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

The pathophysiology of asthma involves an intricate network of molecular and cellular interactions. Elevated Th2 cytokines (interleukin [IL]-5 and IL-4) associated with eosinophilic inflammation characterize allergic diseases and provide potential targets for immunomodulation. Recent evidence has demonstrated that galectin-3 induces selective downregulation of IL-5 gene expression in several cell types (eosinophils, T cell lines, and antigen specific T cells). Accordingly, we sought to elucidate whether in vivo intratracheal instillation of plasmid DNA encoding galectin-3 would inhibit an experimental asthmatic reaction in a rat model with increased eosinophils and T cells in bronchoalveolar fluid and impaired pulmonary function. We found that instillation of galectin-3 gene in these rats led to normalization of the eosinophil and T cell count in bronchoalveolar lavage fluid and that there was a strong concomitant inhibition of IL-5 mRNA in the lungs. As a consequence, galectin-3-treated rats showed recovery of pulmonary functional parameters, such as pulmonary pressure and expiratory flows. These data emphasize the potential utility of galectin-3 as a novel therapeutic approach for treatment of allergic asthma.
Systematic review of supportive care needs in patients with primary malignant brain tumors
Authors: E. Ford, S. Catt, A. Chalmers, L. Fallowfield
Journal: Neuro-Oncology (2012)

In adults, primary malignant brain tumors (PMBT) are rare, but they have a devastating impact and the chances for survival are limited. UK clinical guidance on supportive care for patients with brain and central nervous system tumors was published in 2006 and relied on very limited evidence. The current article reviews literature from 2005 through 2011 on the psychosocial and supportive needs of patients with PMBT and their families or caregivers. Searches were conducted in PubMed, Web of Science, Psychinfo, Cochrane, Scopus, ASSIA, and Sciencedirect. The search initially yielded 6220 articles, of which 60 were found to be eligible (1%). Eleven qualitative and 49 quantitative studies are reviewed here and mapped onto the structure of the existing UK clinical guidance. Studies suggest rates of depression and anxiety up to 48% in patients and up to 40% in caregivers, with many unmet needs and dissatisfaction with health care provider communication and information. Cognitive deficits increase as the disease progresses, hampering communication and decision-making. A range of neurological and physical symptoms at the end of life need recognition. Some successful supportive and neuropsychological interventions are reported. Although the volume of available studies has increased since UK guidance, many remain observational in nature, with few trials of interventions. However, this review provides an up to date resource for clinicians involved with patients with PMBT, describing current knowledge on patients' psychosocial needs, the type of care which has been found to be beneficial, and highlighting areas where more research needs to be done.
Right ventricular dysfunction in patients with obstructive sleep apnoea syndrome
Authors: BM Sanner, M Konermann, A Sturm, HJ Muller, W Zidek
Journal: European Respiratory Journal (1997)

There is conclusive evidence that obstructive sleep apnoea syndrome (OSAS) influences right heart haemodynamics and can also induce pulmonary hypertension. It is not known, however, whether right ventricular dysfunction can occur in patients with OSAS in the absence of lung disease. We studied 107 patients (94 males, 13 females, mean age 55 +/- 11 yrs) with polysomnographically verified OSAS in whom clinically significant lung disease was excluded. Right ventricular ejection fraction (RVEF) was determined by radionuclide ventriculography. In addition, pulmonary function tests, arterial blood gas analysis and right heart catheterization were performed. RVEF was impaired in 19 patients (18%). Eighteen (95%) had signs or symptoms consistent with mild right ventricular failure. Patients with or without impaired RVEF did not differ with respect to body mass index, age or lung function. Stepwise multiple logistic regression analysis revealed that RVEF was significantly associated with the apnoea/hypopnoea index (r = -0.68; p = 0.0009) and the extent of nocturnal oxyhaemoglobin saturation (r = 0.42; p = 0.035), but not with age, body mass index, blood gas analysis, gender, lung function, pulmonary artery pressure and left ventricular ejection fraction. We conclude that in patients with otherwise unexplained right ventricular failure, obstructive sleep apnoea syndrome may underlie the right ventricular dysfunction.
Induced pluripotent stem cell–derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice
Authors: Silvia Espejel, Garrett R. Roll, K. John McLaughlin, Andrew Y. Lee, Jenny Y. Zhang, Diana J. Laird, Keisuke Okita, Shinya Yamanaka, Holger Willenbring
Journal: Journal of Clinical Investigation (2010)

The ability to generate induced pluripotent stem (iPS) cells from a patient's somatic cells has provided a foundation for organ regeneration without the need for immune suppression. However, it has not been established that the differentiated progeny of iPS cells can effectively reverse failure of a vital organ. Here, we examined whether iPS cell–derived hepatocytes have both the functional and proliferative capabilities needed for liver regeneration in mice with fumarylacetoacetate hydrolase deficiency. To avoid biases resulting from random genomic integration, we used iPS cells generated without viruses. To exclude compensation by hepatocytes not derived from iPS cells, we generated chimeric mice in which all hepatocytes were iPS cell derived. In vivo analyses showed that iPS cells were intrinsically able to differentiate into fully mature hepatocytes that provided full liver function. The iPS cell–derived hepatocytes also replicated the unique proliferative capabilities of normal hepatocytes and were able to regenerate the liver after transplantation and two-thirds partial hepatectomy. Thus, our results establish the feasibility of using iPS cells generated in a clinically acceptable fashion for rapid and stable liver regeneration.
Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors
Authors: Steven JM Jones, Janessa Laskin, Yvonne Y Li, Obi L Griffith, Jianghong An, Mikhail Bilenky, Yaron S Butterfield, Timothee Cezard, Eric Chuah, Richard Corbett, Anthony P Fejes, Malachi Griffith, John Yee, Montgomery Martin, Michael Mayo, Nataliya Melnyk, Ryan D Morin, Trevor J Pugh, Tesa Severson, Sohrab P Shah, Margaret Sutcliffe, Angela Tam, Jefferson Terry, Nina Thiessen, Thomas Thomson, Richard Varhol, Thomas Zeng, Yongjun Zhao, Richard A Moore, David G Huntsman, Inanc Birol, Martin Hirst, Robert A Holt, Marco A Marra
Journal: Genome biology (2010)

Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment. In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways. We conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual.
Mitochondrial respiratory chain defect: a new etiology for neonatalcholestasis and early liver insufficiency
Authors: Isabel Goncalves, Dominique Hermans, Dominique Chretien, Pierre Rustin, Arnold Munnich, Jean Marie Saudubray, François Van Hoof, Raymond Reding, Jean de Ville de Goyet, Jean Bernard Otte, Jean Paul Buts, Etienne M. Sokal
Journal: Journal of Hepatology (1995)
Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment.
Authors: C Niederau, J H Grendell
Journal: Journal of Clinical Investigation (1988)

The appearance of vacuoles inside acinar cells characterizes an early stage of development in different models of acute pancreatitis and, possibly, also in human disease. The vacuoles have been shown to contain both digestive and lysosomal enzymes. This abnormal admixture may have important implications for the pathogenesis of pancreatitis because the lysosomal enzyme cathepsin B can activate trypsinogen and may, by this way, trigger pancreatic autodigestion. For the activation process of trypsinogen by cathepsin B, however, an acidic pH is required. This study, therefore, looked for evidence of vacuole acidification in two different models of acute pancreatitis. Edematous pancreatitis was induced in rats by hyperstimulation with cerulein and hemorrhagic pancreatitis was induced in mice by feeding a choline-deficient, ethionine-supplemented diet. Pancreatic acinar cells were isolated at different times after induction of pancreatitis and incubated with 50 microM of acridine orange to identify acidic intracellular compartments. As shown in previous work, zymogen granules are the main acidic compartment of normal acinar cells; they remained acidic throughout the course of pancreatitis in both models. Vacuoles became increasingly more frequent in both models as pancreatitis progressed. Throughout development of pancreatitis, vacuoles accumulated acridine orange indicating an acidic interior. Addition of a protonophore (10 microM monensin or 5 microM carbonyl cyanide m-chlorophenylhydrazone [CCCP] or a weak base (5 mM NH4Cl) completely and rapidly abolished acridine orange fluorescence inside both zymogen granules and vacuoles providing further evidence for an acidic interior. The acidification of vacuoles seen in two different models of pancreatitis may be an important requirement for activation of trypsinogen by cathepsin B and thus for the development of acute pancreatitis.