tbuckley/cabot-search huggingface dataset:
Evidence for Efficacy of New Hsp90 Inhibitors Revealed by <i>Ex Vivo</i> Culture of Human Prostate Tumors
Authors: Margaret M. Centenera, Joanna L. Gillis, Adrienne R. Hanson, Shalini Jindal, Renea A. Taylor, Gail P. Risbridger, Peter D. Sutherland, Howard I. Scher, Ganesh V. Raj, Karen E. Knudsen, Trina Yeadon, Wayne D. Tilley, Lisa M. Butler
Journal: Clinical Cancer Research (2012)

Targeting Hsp90 has significant potential as a treatment for prostate cancer, but prototypical agents such as 17-allylamino-17 demethoxygeldanamycin (17-AAG) have been ineffective in clinical trials. Recently, a phase I study aimed at defining a biologically active dose reported the first response to an Hsp90 inhibitor in a patient with prostate cancer, which supports the development of new generation compounds for this disease.The biological actions of two new synthetic Hsp90 inhibitors, NVP-AUY922 and NVP-HSP990, were evaluated in the prostate cancer cell lines PC-3, LNCaP, and VCaP and in an ex vivo culture model of human prostate cancer.In cell lines, both NVP-AUY922 and NVP-HSP990 showed greater potency than 17-AAG with regard to modulation of Hsp90 client proteins, inhibition of proliferation, and induction of apoptotic cell death. In prostate tumors obtained from radical prostatectomy that were cultured ex vivo, treatment with 500 nmol/L of NVP-AUY922, NVP-HSP990, or 17-AAG caused equivalent target modulation, determined by the pharmacodynamic marker Hsp70, but only NVP-AUY922 and NVP-HSP990 showed antiproliferative and proapoptotic activity.This study provides some of the first evidence that new generation Hsp90 inhibitors are capable of achieving biologic responses in human prostate tumors, with both NVP-AUY922 and NVP-HSP990 showing potent on-target efficacy. Importantly, the ex vivo culture technique has provided information on Hsp90 inhibitor action not previously observed in cell lines or animal models. This approach, therefore, has the potential to enable more rational selection of therapeutic agents and biomarkers of response for clinical trials.
The link between fungi and severe asthma: a summary of the evidence
Authors: D. W. Denning, B. R. O'Driscoll, C. M. Hogaboam, P. Bowyer, R. M. Niven
Journal: European Respiratory Journal (2006)

There is current evidence to demonstrate a close association between fungal sensitisation and asthma severity. Whether such an association is causal remains to be confirmed, but this is explored by means of a detailed literature review. There is evidence from two randomised controlled trials that, in the example of allergic bronchopulmonary aspergillosis (ABPA), treatment with systemic antifungal therapy can offer a therapeutic benefit to approximately 60% of patients. ABPA is only diagnosed if a combination of clinical and immunological criteria is achieved. It is not known whether such cases are a discrete clinical entity or part of a spectrum of the pulmonary allergic response to fungi or fungal products. This paper describes the epidemiological evidence that associates severity of asthma with fungi and discusses possible pathogenetic mechanisms. Many airborne fungi are involved, including species of Alternaria, Aspergillus, Cladosporium and Penicillium, and exposure may be indoors, outdoors or both. The potential for a therapeutic role of antifungal agents for patients with severe asthma and fungal sensitisation is also explored. Not only are many patients with severe asthma desperately disabled by their disease, but, in the UK alone, asthma accounts for 1,500 deaths per yr. The healthcare costs of these patients are enormous and any treatment option merits close scrutiny. Within this report, the case for the consideration of a new term related to this association is put forward. The current authors propose the term "severe asthma with fungal sensitisation". However, it is recognised that enhanced and precise definition of fungal sensitisation will require improvements in diagnostic testing.
The influence of pre-existing diabetes mellitus on the host immune response and outcome of pneumonia: analysis of two multicentre cohort studies
Authors: S. Yende, T. van der Poll, M. Lee, D. T. Huang, A. B. Newman, L. Kong, J. A. Kellum, T. B. Harris, D. Bauer, S. Satterfield, D. C. Angus
Journal: Thorax (2010)

Although diabetes mellitus is implicated in susceptibility to infection, the association of diabetes with the subsequent course and outcome is unclear.A retrospective analysis of two multicentre cohorts was carried out. The effect of pre-existing diabetes on the host immune response, acute organ function and mortality in patients hospitalised with community-acquired pneumonia (CAP) in the GenIMS study (n=1895) and on mortality following either CAP or non-infectious hospitalisations in the population-based cohort study, Health ABC (n=1639) was determined. Measurements included the mortality rate within the first year, risk of organ dysfunction, and immune responses, including circulating inflammatory (tumour necrosis factor, interleukin 6, interleukin 10), coagulation (Factor IX, thrombin-antithrombin complexes, antithrombin), fibrinolysis (plasminogen-activator inhibitor-1 and D-dimer) and cell surface markers (CD120a, CD120b, human leucocyte antigen (HLA)-DR, Toll-like receptor-2 and Toll-like receptor-4).In GenIMS, diabetes increased the mortality rate within the first year after CAP (unadjusted HR 1.41, 95% CI 1.12 to 1.76, p=0.002), even after adjusting for pre-existing cardiovascular and renal disease (adjusted HR 1.3, 95% CI 1.03 to 1.65, p=0.02). In Health ABC, diabetes increased the mortality rate within the first year following CAP hospitalisation, but not after hospitalisation for non-infectious illnesses (significant interaction for diabetes and reason for hospitalisation (p=0.04); HR for diabetes on mortality over the first year after CAP 1.87, 95% CI 0.76 to 4.6, p=0.16, and after non-infectious hospitalisation 1.16, 95% CI 0.8 to 1.6, p=0.37). In GenIMS, immediate immune response was similar, as evidenced by similar circulating immune marker levels, in the emergency department and during the first week. Those with diabetes had a higher risk of acute kidney injury during hospitalisation (39.3% vs 31.7%, p=0.005) and they were more likely to die due to cardiovascular and kidney disease (34.4% vs 26.8% and 10.4% vs 4.5%, p=0.03).Pre-existing diabetes was associated with a higher risk of death following CAP. The mechanism is not due to an altered immune response, at least as measured by a broad panel of circulating and cell surface markers, but may be due to worsening of pre-existing cardiovascular and kidney disease.
Community-acquired pneumonia: the annual cost to the National Health Service in the UK
Authors: JF Guest, A Morris
Journal: European Respiratory Journal (1997)

The aim of this study was to estimate the direct annual healthcare costs to the UK National Health Service (NHS) of managing community-acquired pneumonia. Using a prevalence-based burden of illness approach, health service resource use and corresponding costs attributable to the management of community-acquired pneumonia during 1992/1993 in the UK were obtained from published sources and commercial databases, and supplemented by a telephone survey of general practitioners, finance directors, community nurses, receptionists and nurses in out-patient respiratory clinics, ambulance services, and consultant respiratory physicians. The study was appraised by a Peer Review Panel, representing a cross-section of experts from different locations. This study was a predefined subgroup analysis of a previous, larger study that estimated the annual cost to the NHS of treating all community-acquired lower respiratory tract infections. The analysis shows that there are 261,000 episodes of community-acquired pneumonia annually in the UK, costing 440.7 million pounds at 1992/1993 prices (32% of the annual cost for all community-acquired lower respiratory tract infections). Approximately 83,153 annual cases of community-acquired pneumonia are treated in hospital (32% of all episodes) and account for 96% of the annual cost. The average cost for managing pneumonia in the community is 100 pounds per episode, compared to 1,700-5,100 pounds when the patient is hospitalized, depending on the length of hospitalization. Hospitalization accounts for 87% of the total annual cost. In conclusion, community-acquired pneumonia in the UK incurs a direct healthcare cost of 440.7 million pounds annually at 1992/1993 prices. Developing and implementing strategies to prevent and minimize hospitalization will significantly reduce this annual cost and should be assessed in future studies.
In Vivo Analysis of an Essential Myosin Light Chain Mutation Linked to Familial Hypertrophic Cardiomyopathy
Authors: Atsushi Sanbe, David Nelson, James Gulick, Elizabeth Setser, Hanna Osinska, Xuejun Wang, Timothy E. Hewett, Raisa Klevitsky, Eric Hayes, David M. Warshaw, Jeffrey Robbins
Journal: Circulation Research (2000)

Mutations in cardiac motor protein genes are associated with familial hypertrophic cardiomyopathy. Mutations in both the regulatory (Glu22Lys) and essential light chains (Met149Val) result in an unusual pattern of hypertrophy, leading to obstruction of the midventricular cavity. When a human genomic fragment containing the Met149Val essential myosin light chain was used to generate transgenic mice, the phenotype was recapitulated. To unambiguously establish a causal relationship for the regulatory and essential light chain mutations in hypertrophic cardiomyopathy, we generated mice that expressed either the wild-type or mutated forms, using cDNA clones encompassing only the coding regions of the gene loci. Expression of the proteins did not lead to a hypertrophic response, even in senescent animals. Changes did occur at the myofilament and cellular levels, with the myofibrils showing increased Ca(2+) sensitivity and significant deficits in relaxation in a transgene dose-dependent manner. Clearly, mice do not always recapitulate important aspects of human hypertrophy. However, because of the discordance of these data with data obtained in transgenic mice containing the human genomic fragment, we believe that the concept that these point mutations by themselves can cause hypertrophic cardiomyopathy should be revisited.
Recognizing the forest for the trees: testing temporal patterns of cladogenesis using a null model of stochastic diversification
Authors: K Wollenberg, J Arnold, J C Avise
Journal: Molecular Biology and Evolution (1996)

Computer simulations are developed and employed to examine the expected temporal distributions of nodes under a null model of stochastic lineage bifurcation and extinction. These Markovian models of phylogenetic process were constructed so as to permit direct comparisons against empirical phylogenetic trees generated from molecular or other information available solely from extant species. For replicate simulated phylads with n extant species, cumulative distribution functions (cdf's) of branching times were calculated, and compared (using the Kolmogorov-Smirnov test statistic D) to those from three published empirical trees. Molecular phylogenies for columbine plants and avian cranes showed statistically significant departures from the null expectations, in directions indicating recent and ancient species' radiations, respectively, whereas a molecular phylogeny for the Drosophila virilis species group showed no apparent historical clustering of branching events. Effects of outgroup choice and phylogenetic frame of reference were investigated for the columbines and found to have a predictable influence on the types of conclusions to be drawn from such analyses. To enable other investigators to statistically test for nonrandomness in temporal cladogenetic pattern in empirical trees generated from data on extant species, we present tables of mean cdf's and associated probabilities under the null model for expected branching times in phylads of varying size. The approaches developed in this report complement and extend those of other recent methods for employing null models to assess the statistical significance of pattern in evolutionary trees.
MLL-AF9-Induced Leukemogenesis Requires Coexpression of the Wild-Type Mll Allele
Authors: Austin T. Thiel, Peter Blessington, Tao Zou, Danielle Feather, Xinjiang Wu, Jizhou Yan, Hui Zhang, Zuguo Liu, Patricia Ernst, Gary A. Koretzky, Xianxin Hua
Journal: Cancer Cell (2010)
Metformin Improves Endothelial Vascular Reactivity in First-Degree Relatives of Type 2 Diabetic Patients With Metabolic Syndrome and Normal Glucose Tolerance
Authors: L. G. K. de Aguiar
Journal: Diabetes Care (2006)

Endothelial dysfunction is an early marker of atherosclerosis seen in type 2 diabetic subjects. Metformin is commonly used in the treatment of type 2 diabetes and has known vasculoprotective effects beyond its hypoglycemic ones. We aimed to investigate the vascular effects of metformin in first-degree relatives with metabolic syndrome of type 2 diabetic patients.The study included 31 subjects (age 38.3 +/- 7.6 years and BMI 36.3 +/- 5.2 kg/m2), who were first-degree relatives of type 2 diabetic patients and who had metabolic syndrome and normal glucose tolerance. The subjects were randomly assigned 1:1 in a double-blind fashion to receive placebo (n = 15) or metformin (n = 16). Endothelial function was assessed by venous occlusion plethysmography, measuring forearm blood flow (FBF) and vascular resistance responses to three intra-arterial infusions of endothelium-dependent (acetylcholine 7.5, 15, and 30 microg/min) and independent (sodium nitroprusside 2, 4, and 8 microg/min) vasodilators. Weight, BMI, systolic and diastolic blood pressure, waist, and laboratory parameters (lipid profile and fasting plasma glucose [FPG]) were assessed at baseline and after treatment.The metformin and placebo groups did not differ in anthropometric, clinical, laboratory, and vascular measurements at baseline. The metformin group had decreased weight, BMI, systolic blood pressure, and FPG and improved lipid profile. Endothelium-dependent FBF responses were also improved, without any effect on endothelium-independent responses. There was no correlation between the improvement on FBF responses and the observed changes on anthropometric, clinical, and laboratory parameters.We concluded that metformin improved vascular endothelial reactivity in first-degree relatives with metabolic syndrome of type 2 diabetic patients, independently of its known antihyperglycemic effects.
Administration of hydrogen-saturated saline decreases plasma low-density lipoprotein cholesterol levels and improves high-density lipoprotein function in high-fat diet–fed hamsters
Authors: Chuanlong Zong, Guohua Song, Shutong Yao, Luqin Li, Yang Yu, Lei Feng, Shoudong Guo, Tian Luo, Shucun Qin
Journal: Metabolism (2011)
Infliximab for Inflammatory Bowel Disease in Denmark 1999–2005: Clinical Outcome and Follow-Up Evaluation of Malignancy and Mortality
Authors: Sarah Caspersen, Margarita Elkjaer, Lene Riis, Natalia Pedersen, Christian Mortensen, Tine Jess, Pernille Sarto, Tanja S. Hansen, Vibeke Wewer, Flemming Bendtsen, Flemming Moesgaard, Pia Munkholm
Journal: Clinical Gastroenterology and Hepatology (2008)
Health-Related Social Disengagement in Elderly Diabetic Patients
Authors: Yong-Fang Kuo, Mukaila A. Raji, M. Kristen Peek, James S. Goodwin
Journal: Diabetes Care (2004)

OBJECTIVE—We examined the relationship between health-related social disengagements, as opposed to disengagements related to financial and other non–health-related factors, and subsequent risk of disability and death among initially nondisabled elderly diabetic patients enrolled in Medicare Managed Care plans. RESEARCH DESIGN AND METHODS—We used data from the Medicare Health Outcomes Survey (HOS) Cohort 1 Baseline (1998) and Cohort 1 Follow-Up (2000). Through mail and telephone surveys, trained interviewers collected information on sociodemographic variables, physical and mental health functioning (using Medical Outcomes Study Short Form-36 [SF-36]), activities of daily living (ADL), and medical conditions. This study reported on diabetic subjects aged ≥65 years with no ADL disability at baseline (n = 8,949). Health-related social disengagement (degree to which physical health or emotional problems interfere with social activities) was derived from the social functioning subscale of SF-36 (range 0–100; higher scores depicting better social functioning). RESULTS—For each 10-point increase in social functioning score at baseline, older diabetic subjects in our study experienced an 18% less chance of any ADL disability (odds ratio [OR] 0.82, 95% CI 0.75–0.89; P &amp;lt; 0.001) and a 12% less chance of death (0.88, 0.78–1.00; P = 0.043) over a 2-year period, adjusting for demographic factors, comorbidities, depression, and general health (assessed by the SF-36). CONCLUSIONS—Among initially nondisabled older diabetic subjects, health-related interferences with social activities at baseline may be early warning signs of subsequent ADL disability and premature death, independent of other measures of health status.
Response to: ‘Impact of gender on outcomes in ankylosing spondylitis’ by Feldtkeller<i>et al</i>
Authors: Irene van der Horst-Bruinsma, Debra Zack, Annette Szumski, Andrew S Koenig
Journal: Annals of the Rheumatic Diseases (2013)

We would like to thank Dr Feldtkeller1 for his remarks regarding our manuscript.1 We do agree that in ankylosing spondylitis onset is more accurately described by onset of symptoms as opposed to age at diagnosis. Unfortunately, we did not collect the time-of-symptom-onset data in three of the four studies in this analysis. Thus, we used the age at diagnosis as proxy for disease onset. In the ASCEND study (women n=147; men n=419) we reviewed the onset of symptom data that was similar between women (mean 13.0 years) and men (mean 13.4 years), which supports Dr Feldtkeller's statement, “the average age of disease onset (first symptoms of AS) does not differ significantly between male and female patients with AS”.2–4 In addition, the mean age of diagnosis in the …
In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions.
Authors: A J Van den Eertwegh, R J Noelle, M Roy, D M Shepherd, A Aruffo, J A Ledbetter, W J Boersma, E Claassen
Journal: The Journal of Experimental Medicine (1993)

T-B cell interactions have a central role in the development of antibody responses. Upon activation, T helper (Th) cells express the ligand for CD40, gp39, which is essential for Th cell-dependent B cell activation. The cytokines produced by activated Th cells have a regulatory role in B cell differentiation. In this study, we investigated, using immunohistochemical techniques, the in vivo time course and localization of gp39 expression and cytokine production in relation to the specific antibody production. Both the immunization with keyhole limpet hemocyanin (KLH), a thymus-dependent (TD) antigen, and trinitrophenyl (TNP)-Ficoll, a thymus-independent type 2 (TI-2) antigen, induced Th cells to express gp39. The expression of gp39 was restricted to Th cells in the outer periarteriolar lymphocyte sheaths (outer-PALS) and around the terminal arterioles (TA). Incidentally, gp39+ Th cells were found in the corona of follicles, whereas gp39+ cells were never found in the germinal centers or marginal zones of the spleen. Maximum frequencies of gp39+ cells were observed 3 and 4 d after primary and secondary immunization with KLH. After injection of TNP-Ficoll, a marked increase in gp39+ cells was observed, confirming previous observations that activated T cells are involved in TI-2 antibody responses. Analysis of the in vivo cytokine production revealed that interleukin 2 (IL-2)-, IL-4- and interferon gamma (IFN-gamma)-producing cells (IFN-gamma-PC) developed according to similar kinetics as observed for gp39+ cells. IL-2-PC and IL-4-PC were present in higher frequencies as were IFN-gamma-PC in the immune response against TNP-KLH. Double staining experiments revealed gp39+ Th cells producing IL-2, IL-4, or IFN-gamma, suggesting that these cells were involved in both the initial activation as well as the differentiation process of B cells into antibody-forming cells. Dual immunohistochemical analysis revealed gp39+ T cells and cytokine-PC in close proximity to antigen-specific, antibody-forming B cells. In conclusion, this study shows that in vivo gp39 is expressed on activated Th cells after immunization with TD and TI-2 antigens. Furthermore, the time course and compartmentalization of gp39+ expression, cytokine production and antibody formation after immunization suggest that cognate T-B cell interactions and T cell-regulated B cell differentiation occur in the outer-PALS and around the TA of the spleen.
Principal Factor Waveforms of the Thoracic QRS Complex
Authors: LEO G. HORAN, NANCY C. FLOWERS, DANIEL A. BRODY
Journal: Circulation Research (1964)

High-speed, high-fidelity recordings from 150 to 180 systematically spaced points over the thoracic surface of both a dog and a man have yielded detailed maps of QRS waveforms. With the aid of digital computer analysis, these waveforms have been resolved into the minimum number of mathematically uncorrelated waveforms necessary for adequate resynthesis of all the original QRS complexes. Under the conditions imposed by the experimental design, seven (in the dog) and eight (in the man) such waveforms, or principal factors, were found. Maps were constructed for both the contribution of each principal factor to the various regions of the chest and also for the degree of reproducibility of the original waveforms by successive addition of the principal factors. The first three factors accounted for an average of 92.8% of the available information on the chest in the dog and 85.4% in the man. A resynthesis of over 99% of the information was achieved for both subjects when all remaining principal factors were also employed. This necessity for more than three factors or generating functions for reproduction of all the known surface potentials was interpreted as strong support to the equivalent multipole concept of the electrocardiographic generator. In addition, the reduction of total surface information into a compact set of waveforms of specified distribution opens an experimental avenue to the examination of such concepts in living subjects.