tbuckley/cabot-search huggingface dataset:
Multiplex Analysis of Serum Cytokines in Melanoma Patients Treated with Interferon-α2b
Authors: Zoya R. Yurkovetsky, John M. Kirkwood, Howard D. Edington, Adele M. Marrangoni, Lyudmila Velikokhatnaya, Matthew T. Winans, Elieser Gorelik, Anna E. Lokshin
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Interferon (IFN)-α2b is the only Food and Drug Administration–approved treatment for operable high-risk melanoma that has been shown to significantly and durably prolong relapse-free survival (RFS) of patients with stage IIB-III melanoma. Development of reliable serum assays may contribute to the development of methods for earlier detection of melanoma and the selection of patients who may be most susceptible to current available interventions with IFNα. Experimental Design: A powerful high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) was used to simultaneously test 29 cytokines, chemokines, angiogenic as well as growth factors, and soluble receptors in the sera of 179 patients with high-risk melanoma and 378 healthy individuals. Results: Serum concentrations of interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-12p40, IL-13, granulocyte colony-stimulating factor, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1β, IFNα, tumor necrosis factor (TNF)-α, epidermal growth factor, vascular endothelial growth factor (VEGF), and TNF receptor II were found to be significantly higher in patients with resected high-risk melanoma compared with healthy controls. Bayesian Network algorithm classification of the data offered 90% sensitivity at 98% specificity with 96.5% of melanoma patients distinguished from healthy individuals. IFN-α2b therapy resulted in a significant decrease of serum levels of immunosuppressive and tumor angiogenic/growth stimulatory factors (VEGF, epidermal growth factor, and hepatocyte growth factor) and increased levels of antiangiogenic IFN-γ inducible protein 10 (IP-10) and IFN-α. Pretreatment levels of proinflammatory cytokines IL-1β, IL-1α, IL-6, TNF-α, and chemokines MIP-1α and MIP-1β were found to be significantly higher in the serum of patients with longer RFS values of 1 to 5 and &amp;gt;5 years when compared with patients with shorter RFS of &amp;lt;1 year. Conclusion: These data show that multiplexed analysis of serum biomarkers is useful for the evaluation of prognostic markers of clinical outcome and potential predictive markers of response to IFN-α2b in patients with high-risk operable melanoma.
Clinical management of tuberculosis and HIV-1 co-infection
Authors: C. Schutz, G. Meintjes, F. Almajid, R.J. Wilkinson, A. Pozniak
Journal: European Respiratory Journal (2010)

In many parts of the world the commonest serious opportunistic infection that occurs in HIV-1 infected persons is tuberculosis (TB). HIV-1 co-infection modifies the natural history and clinical presentation, and adversely affects the outcome of TB. Severe disseminated disease is well-recognised but it is increasingly appreciated that early disease characterised by very few or no symptoms is also common. Immunodiagnostic methods to ascertain latent TB in HIV-1 infected persons are compromised in sensitivity. Chemoprevention of HIV-1-associated TB is effective, its benefits are restricted to those which have evidence of immune sensitisation and appear short-lived in areas of high TB burden. Although promising advances in the microbiological diagnosis of TB have recently occurred, the diagnosis of HIV-1-associated TB remains difficult because of more frequent presentation as sputum negative or extrapulmonary disease. Management of co-infected patients can be complex because of overlapping drug toxicities and interactions. Nevertheless consensus is developing that antiretroviral therapy should be provided as soon as practicable after starting TB treatment in HIV-1 co-infected persons. This has the consequence of increasing the frequency of immune reconstitution inflammatory syndrome, the pathogenesis and management of which is poorly defined.
Glucose phosphorylation is required for insulin-dependent mTOR signalling in the heart
Authors: S SHARMA, P GUTHRIE, S CHAN, S HAQ, H TAEGTMEYER
Journal: Cardiovascular Research (2007)

Insulin regulates both glucose uptake and postnatal cardiac growth. The anabolic effects of insulin are mediated by the mammalian target of rapamycin (mTOR), an evolutionarily conserved kinase which is also a convergence point between nutrient sensing and cell growth. We postulated that mTOR signalling in the heart requires the metabolism of glucose.We interrogated the insulin-mediated mTOR signalling pathway in response to different metabolic interventions regulating substrate metabolism in the isolated working rat heart and in isolated cardiomyocytes.Although insulin enhanced Akt activity, phosphorylation of mTOR and its downstream targets (p70S6K and 4EBP1) required the addition of glucose. Glucose-dependent p70S6K phosphorylation was independent of the hexosamine biosynthetic pathway, the AMP kinase pathway, and the pentose phosphate pathway. However, inhibition of glycolysis downstream of hexokinase markedly enhanced p70S6K phosphorylation. Furthermore, 2-deoxyglucose activated p70S6K suggesting that phosphorylation of glucose is required for carbohydrate-mediated mTOR signalling in the heart. Lastly, we also found enhanced p70S6K phosphorylation in the hearts of diabetic rats.Phosphorylation of glucose is necessary for insulin-dependent mTOR activity in the heart, suggesting a link between intermediary metabolism and cardiac growth.
Dietary Fat and Incidence of Type 2 Diabetes in Older Iowa Women
Authors: Katie A. Meyer, Lawrence H. Kushi, David R. Jacobs, Aaron R. Folsom
Journal: Diabetes Care (2001)

OBJECTIVE—To examine the associations between reported intakes of dietary fat and incident type 2 diabetes. RESEARCH DESIGN AND METHODS—We studied the relation between dietary fatty acids and diabetes in a prospective cohort study of 35,988 older women who initially did not have diabetes. Diet was assessed with a food frequency questionnaire at baseline, and 1,890 incident cases of diabetes occurred during 11 years of follow-up. RESULTS—After adjusting for age, smoking, alcohol consumption, BMI, waist-to-hip ratio, physical activity, demographic factors, and dietary magnesium and cereal fiber, diabetes incidence was negatively associated with dietary polyunsaturated fatty acids, vegetable fat, and trans fatty acids and positively associated with ω-3 fatty acids, cholesterol, and the Keys score. After simultaneous adjustment for other dietary fat, only vegetable fat remained clearly related to diabetes risk. Relative risks across quintiles of vegetable fat intake were 1.00, 0.90, 0.87, 0.84, and 0.82 (P = 0.02). Diabetes risk was also inversely related to substituting polyunsaturated fatty acids for saturated fatty acids and positively correlated to the Keys dietary score. CONCLUSIONS—These data support an inverse relation between incident type 2 diabetes and vegetable fat and substituting polyunsaturated fatty acids for saturated fatty acids and cholesterol.
Decline in rehabilitation services
Authors: A. Savage
Journal: Journal of the Royal Society of Medicine (2002)

Professor Grahame (March 2002 JRSM1) suggests that an escalation in the cost of disability benefits may be due to the decline in rehabilitation services. I was fortunate to gain experience in medical rehabilitation in the 1960s, while registrar in Dr Frank Cooksey's department at King's College Hospital. There, short but intensive courses of rehabilitation were offered with the purpose of a return to employment in suitable work or, in the case of housewives, independence in the home and kitchen. It became clear to me, at that time, that without motivation this exercise was not as fruitful as one would wish. This impression is supported by the extremely good outcome from rehabilitation reported in airmen in the Second World War, a highly motivated group of people.

The sharp rise in non-means-tested benefits in the past ten years could in part be due to lack of rehabilitation shortly after the incident causing the disability. However, my experience as a medical member on benefit appeals tribunals suggests that the main problem is often a lack of motivation for improvement. This is at times due to cultural differences in coping with disability. It is also due to the intervention of certain welfare rights organizations that urge clients to claim greater disability than can be objectively demonstrated, with a hope of obtaining the highest benefits.

It therefore appears to me that the present system and criteria for obtaining financial benefits does not encourage or motivate claimants to improve, and expensive rehabilitation, unfortunately, would yield only a marginal improvement.
The acute inflammatory response to photodynamic therapy
Authors: S.H. Ibbotson
Journal: British Journal of Dermatology (2013)

Journal Article The acute inflammatory response to photodynamic therapy Get access S.H. Ibbotson S.H. Ibbotson Photobiology Unit University Department of Dermatology Ninewells Hospital and Medical School Dundee DD1 9SY U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 169, Issue 3, 1 September 2013, Pages 491–492, https://doi.org/10.1111/bjd.12495 Published: 01 September 2013
Benefits of bariatric surgery: an issue of microbial-host metabolism interactions?
Authors: P. D. Cani, N. M. Delzenne
Journal: Gut (2011)

<h3>Objective</h3> To investigate whether cholinesterase inhibitors (ChEIs) are associated with slower cognitive decline in Alzheimer dementia and decreased risk of severe dementia or death. <h3>Methods</h3> Patients with Alzheimer dementia from the Swedish Dementia Registry starting on ChEIs within 3 months of the dementia diagnosis were included and compared to nontreated patients with Alzheimer dementia. In a propensity score–matched cohort, the association between ChEI use and cognitive trajectories assessed by Mini-Mental State Examination (MMSE) scores was examined with a mixed model, and severe dementia (MMSE score &lt;10) or death as an outcome was assessed with Cox proportional hazards models. <h3>Results</h3> The matched cohort included 11,652 ChEI users and 5,826 nonusers. During an average of 5 years of follow-up, 255 cases developed severe dementia, and 6,055 (35%) died. ChEI use was associated with higher MMSE score at each visit (0.13 MMSE points per year; 95% confidence interval [CI] 0.06–0.20). ChEI users had a 27% lower risk of death (0.73, 95% CI 0.69–0.77) compared with nonusers. Galantamine was associated with lower risk of death (0.71, 95% CI 0.65–0.76) and lower risk of severe dementia (0.69, 95% CI 0.47–1.00) and had the strongest effect on cognitive decline of all the ChEIs (0.18 MMSE points per year, 95% CI 0.07–0.28). <h3>Conclusions</h3> ChEIs are associated with cognitive benefits that are modest but persist over time and with reduced mortality risk, which could be explained partly by their cognitive effects. Galantamine was the only ChEI demonstrating a significant reduction in the risk of developing severe dementia. <h3>Classification of Evidence</h3> This study provides Class III evidence that for patients with Alzheimer dementia ChEIs decrease long-term cognitive decline and risk of death and that galantamine decreases the risk of severe dementia.
Increased Circulating Levels of Betatrophin in Newly Diagnosed Type 2 Diabetic Patients
Authors: Hao Hu, Wenjun Sun, Shuqin Yu, Xiafei Hong, Weiyun Qian, Bingqian Tang, Dong Wang, Ling Yang, Jifang Wang, Caoming Mao, Libin Zhou, Guoyue Yuan
Journal: Diabetes Care (2014)

Betatrophin, a newly identified hormone, has been recently characterized as a potent stimulator that increases the production and expansion of insulin-secreting β-cells in mice, but the physiological role of betatrophin remains poorly understood. This study measured for the first time serum betatrophin levels in newly diagnosed patients with type 2 diabetes (T2DM) and explored the correlations between its serum levels and various metabolic parameters in T2DM.We analyzed the concentrations of betatrophin by ELISA in blood samples of 166 well-characterized individuals in whom anthropometric parameters, oral glucose tolerance test (OGTT), glycosylated hemoglobin, blood lipids, insulin sensitivity (1/homeostasis model assesment of insulin resistance [1/HOMA-IR] and Matsuda index [ISIM]), and insulin secretion were measured. The participants were divided into newly diagnosed T2DM patients (n = 83) and age-, sex- and BMI-matched healthy control subjects (n = 83).Serum betatrophin levels were significantly higher in T2DM patients than in healthy control subjects (613.08 [422.19-813.08] vs. 296.57 [196.53-509.46] pg/mL; P < 0.01). Serum betatrophin positively correlated with age, 2-h post-OGTT glucose (2hPG), and postprandial serum insulin (PSI), but negatively with 1/HOMA-IR and ISIM in T2DM patients. In the control group, betatrophin was only positively associated with age. In T2DM subjects, multivariate regression analyses showed that age, 2hPG, and PSI were independent factors influencing serum betatrophin levels.Circulating concentrations of betatrophin are significantly increased in T2DM patients. Our results suggest that betatrophin may play a role in the pathogenesis of T2DM.
Bronchiolitis obliterans in systemic lupus erythematosus: beneficial effect of intravenous cyclophosphamide.
Authors: B Godeau, C Cormier, C J Menkes
Journal: Annals of the Rheumatic Diseases (1991)

A 49 year old white woman with systemic lupus erythematosus and bronchiolitis obliterans was treated with prednisone (1 mg/kg daily), which led to a transitory improvement in pulmonary status. Cyclophosphamide was then added--4 mg/kg daily intravenously for five days, then 2 mg/kg daily orally--and this was followed by a dramatic and prolonged improvement.
Update in Cystic Fibrosis 2005
Authors: Frank J. Accurso
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Cystic fibrosis (CF) is a complex, hereditary disease involving several organ systems (1).CF is caused by mutations in the gene that codes for the CF transmembrane conductance regulator (CFTR), a membrane glycoprotein that contributes to regulation of ion flux at certain epithelial surfaces.Lung disease results in most of the morbidity and mortality in CF.Advances in CF over the past several decades have recently been reviewed with an emphasis on the development and importance of CF care centers and on opportunities for new treatments (2).The many threads of CF research in 2005 can be appreciated in Figure 1, showing the general headings (1 ) Molecular and Cellular Biology and Genetics, (2 ) Pathophysiology, and (3 ) Clinical Care and Treatment, along with several subheadings.This brief update reviews representative, significant articles in 2005.
Antiangiogenic Tetrathiomolybdate Protects against Her2/neu-Induced Breast Carcinoma by Hypoplastic Remodeling of the Mammary Gland
Authors: Quintin Pan, Devin T. Rosenthal, Liwei Bao, Celina G. Kleer, Sofia D. Merajver
Journal: Clinical Cancer Research (2009)

The objective of the present study was to delineate the efficacy of tetrathiomolybdate (TM), a novel antiangiogenic anticancer agent, as a chemopreventative agent.Nulliparous Her2/neu transgenic mice were treated with water or TM for 180 days and observed for tumor development during treatment and for 180 days after treatment. Mammary gland composition and architecture were also observed following TM treatment of Her2/neu transgenic and normal FVB mice.At the 1-year follow-up, 86.7% of control and 40% of TM-treated Her2/neu mice had palpable mammary tumors with a median time to tumor development of 234 days (95% confidence interval, 202-279 days) for control and >460 days for TM-treated mice (P < 0.0005, n = 15). The mammary glands from TM-treated Her2/neu and FVB mice showed a blunted epithelial ductal branching system due to a significant decrease in the number of secondary branches and total number of differentiated mammary epithelial cells. Microvessel density in Her2/neu and FVB mammary glands was lowered by 65.6 +/- 6.2% and 50.9 +/- 4.5% (P < 0.005), respectively, following TM therapy, consistent with the antiangiogenic effect of TM. Lastly, TM treatment resulted in a 2-fold increase in the absolute number of aldehyde dehydrogenase-positive mammary stem cells in Her2/neu and FVB mammary glands.Taken together, these results strongly support that TM is a potent chemopreventative agent as a consequence of hypoplastic remodeling of the mammary gland through modulation of the mammary stem cell compartment.
Molecular analysis of aldolase B genes in hereditary fructose intolerance
Authors: N.C.P. Cross, T.M. Cox, R. de Franchis, G. Sebastio, C. Dazzo, D.R. Tolan, C. Grégori, M. Odievre, M. Vidailhet, V. Romano, G. Mascali, C. Romano, S. Musumeci, B. Steinmann, R. Gitzelmann
Journal: The Lancet (1990)
P17.08 * RENAL THROMBOTIC MICROANGIOPATHY INDUCED BY BEVACIZUMAB IN HIGH GRADE GLIOMA PATIENTS - ABOUT SIX CASES
Authors: M. Blonski, L. Simon, C. Houillier, A. Idbaih, B. Wittwer, P. Beauchesne, K. Hoang-Xuan, L. Taillandier
Journal: Neuro-Oncology (2014)

INTRODUCTION: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) has demonstrated its potential efficacy in glioblastoma (GBM). Prospective trials have been performed to investigate its interest as first line treatment in GBM. With the expanding use of bevacizumab, specific adverse effects have been described. Renal complications are well known (hypertension, proteinuria). Nevertheless, thrombotic microangiopathy (TMA) is rare. No case of TMA induced by bevacizumab in glioma patients has been reported. METHODS: Glioma patients with TMA induced by bevacizumab were retrospectively selected from two french neurooncological centers (Pitié Salpêtrière, Nancy). Clinical, biological data and renal biopsy results were recorded. RESULTS: Six patients (median age of 58 years, range 32 to 72 years) with high grade gliomas presented a TMA induced by bevacizumab. TMA was diagnosed after a median of 17 doses of bevacizumab (range 13 to 20). Proteinuria was increased in the six patients (median of 1890 mg of protein per 24 hours, range 1290 to 8090). The platelet count and the haptoglobin were low in three patients. The lactic dehydrogenase was elevated in three patients. The blood pressure level was increased in six patients and required antihypertensive therapy with a median of two antihypertensive drugs (range one to five drugs). Bevacizumab discontinuation allowed decrease of blood pressure and proteinuria in four patients. Two patients developped haemolytic-uraemic syndrom with intravascular haemolysis that required plasmapheresis in one patient. This patient had a low level of ADAMTS 13 activity (50%). Renal biopsy was performed in three cases and confirmed TMA. CONCLUSIONS: No case of TMA associated to bevacizumab treatment has been described in glioma patients. This complication remains rare and the pathophysiology is not clearly understood. Considering the large use of bevacizumab in high grade gliomas, TMA would be more frequent. The strict monitoring of blood pressure and proteinuria is essential in patients with bevacizumab treatment.
Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease
Authors: Y.-H. Suh
Journal: Pharmacological Reviews (2002)

Alzheimer9s disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing β-amyloid (Aβ) derived from amyloid precursor protein (APP) and τ-rich neurofibrillary tangles. To date, the cause and progression of both familial and sporadic AD have not been fully elucidated. The autosomal-dominant inherited forms of early-onset Alzheimer9s disease are caused by mutations in the genes encoding APP, presenilin-1 (chromosome 14), and presenilin-2 (chromosome 1). APP is processed by several different proteases such as secretases and/or caspases to yield Aβ and carboxyl-terminal fragments, which have been implicated in the pathogenesis of Alzheimer9s disease. Alzheimer9s disease and Parkinson9s disease are associated with the cerebral accumulation of Aβ and α-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways. Recent studies have strongly suggested the possible pathogenic interactions between Aβ, presenilins, and/or α-synuclein. Therefore, treatments that block the accumulation of Aβ and α-synuclein might benefit a broad spectrum of neurodegenerative disorders. This review covers the trafficking and processing of APP, amyloid cascade hypothesis in AD pathogenesis, physiological and pathological roles of presenilins, molecular characteristics of α-synuclein, their interactions, and therapeutic strategies for AD.
Cysteine Catabolism: A Novel Metabolic Pathway Contributing to Glioblastoma Growth
Authors: Antony Prabhu, Bhaswati Sarcar, Soumen Kahali, Zhigang Yuan, Joseph J. Johnson, Klaus-Peter Adam, Elizabeth Kensicki, Prakash Chinnaiyan
Journal: Cancer Research (2013)

The relevance of cysteine metabolism in cancer has gained considerable interest in recent years, largely focusing on its role in generating the antioxidant glutathione. Through metabolomic profiling using a combination of high-throughput liquid and gas chromatography-based mass spectrometry on a total of 69 patient-derived glioma specimens, this report documents the discovery of a parallel pathway involving cysteine catabolism that results in the accumulation of cysteine sulfinic acid (CSA) in glioblastoma. These studies identified CSA to rank as one of the top metabolites differentiating glioblastoma from low-grade glioma. There was strong intratumoral concordance of CSA levels with expression of its biosynthetic enzyme cysteine dioxygenase 1 (CDO1). Studies designed to determine the biologic consequence of this metabolic pathway identified its capacity to inhibit oxidative phosphorylation in glioblastoma cells, which was determined by decreased cellular respiration, decreased ATP production, and increased mitochondrial membrane potential following pathway activation. CSA-induced attenuation of oxidative phosphorylation was attributed to inhibition of the regulatory enzyme pyruvate dehydrogenase. Studies performed in vivo abrogating the CDO1/CSA axis using a lentiviral-mediated short hairpin RNA approach resulted in significant tumor growth inhibition in a glioblastoma mouse model, supporting the potential for this metabolic pathway to serve as a therapeutic target. Collectively, we identified a novel, targetable metabolic pathway involving cysteine catabolism contributing to the growth of aggressive high-grade gliomas. These findings serve as a framework for future investigations designed to more comprehensively determine the clinical application of this metabolic pathway and its contributory role in tumorigenesis.