tbuckley/cabot-search huggingface dataset:
Survival in patients with different groups of pulmonary hypertension
Authors: Henning Tiede, Janine Felix, Ewout Steyerberg, Martin Wilkins, Oscar Franco, Jacqueline Witteman, Werner Seeger, Friedrich Grimminger, Ardeschir Ghofrani
Journal: European Respiratory Journal (2012)

Background - Several markers have been suggested to be associated with severity and/or prognosis of disease in patients with pulmonary hypertension (PH). Reports on survival and its determinants in patients with pulmonary hypertension mostly focus on the subgroup of pulmonary arterial hypertension (PAH). Data on other subgroups is rare.  Methods and Results - Every consecutive patient undergoing right heart catheterization with proven PH was included in the Giessen registry from 1994 to 2011. Differences in survival between the etiological groups were highly significant (p  Conclusions - In this report we present data on long term survival and its determinants from patients with all subtypes of pulmonary hypertension. We aim to assess the utility and validity of a new prognostic score for different forms of PH based on comprehensive databases from the PH centers Giessen and Imperial College in London.
Preclinical and Clinical Studies of Gamma Secretase Inhibitors with Docetaxel on Human Breast Tumors
Authors: Anne F. Schott, Melissa D. Landis, Gabriela Dontu, Kent A. Griffith, Rachel M. Layman, Ian Krop, Lacey A. Paskett, Helen Wong, Lacey E. Dobrolecki, Michael T. Lewis, Amber M. Froehlich, Jaya Paranilam, Daniel F. Hayes, Max S. Wicha, Jenny C. Chang
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy. Experimental Design: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. Results: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44+/CD24−, ALDH+, and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies. Conclusions: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer. Clin Cancer Res; 19(6); 1512–24. ©2012 AACR.
Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed.
Authors: D Lamontagne, U Pohl, R Busse
Journal: Circulation Research (1992)

We investigated the mechanisms that are responsible for the basal release of endothelium-derived relaxing factor (EDRF), which is likely to be identical with nitric oxide, in the intact coronary circulation. The increase in cGMP content of platelets passing through the coronary bed of the isolated rabbit heart was used as an index of EDRF release. Platelet cGMP content after passage through the heart under control conditions (flow rate of 20 ml/min) amounted to 0.50 +/- 0.10 pmol/mg protein. Inhibition of endothelial nitric oxide synthesis by 30 microM NG-nitro-L-arginine (L-NNA) reduced this amount by more than 60%. Increasing flow rate from 20 ml/min to 40 and 60 ml/min led to flow-dependent dilation as reflected by the subsequent drop in perfusion pressure after an initial rise. The flow-dependent dilation was associated with a significant increase in the normalized platelet cGMP content. L-NNA abolished completely both the flow-dependent dilation and the increase in platelet cGMP content. Increasing shear stress by a strong vasoconstriction (1 nM endothelin-1) at constant flow was also accompanied by a 2.5-fold increase in platelet cGMP content. To investigate whether mechanical forces applied to the vascular wall by the myocardial contraction cycle were also a stimulus for EDRF release, cardiac arrest was induced by a continuous infusion of mepivacaine (final concentration, 0.02%). Under these conditions, a decrease in platelet cGMP content comparable to that after nitric oxide synthesis inhibition was observed in the arrested heart.(ABSTRACT TRUNCATED AT 250 WORDS)
Virus-Associated RNA I–Deleted Adenovirus, a Potential Oncolytic Agent Targeting EBV-Associated Tumors
Authors: Yaohe Wang, Shao-An Xue, Gunnel Hallden, Jennelle Francis, Ming Yuan, Beverly E. Griffin, Nick R. Lemoine
Journal: Cancer Research (2005)

Abstract Given the growing number of tumor types recognizably associated with EBV infection, it is critically important that therapeutic strategies are developed to treat such tumors. Replication-selective oncolytic adenoviruses represent a promising new platform for anticancer therapy. Virus-associated I (VAI) RNAs of adenoviruses are required for efficient translation of viral mRNAs. When the VAI gene is deleted, adenovirus replication is impeded in most cells (including HEK 293 cells). EBV-encoded small RNA1 is uniformly expressed in most EBV-associated human tumors and can functionally substitute for the VAI RNAs of adenovirus. It enables replication to proceed through complementation of VAI-deletion mutants. We hypothesized that VAI-deleted adenovirus would selectively replicate in EBV-positive tumor cells due to the presence of EBV-encoded small RNA1 with no (or poor) replication in normal or EBV-negative tumor cells. In this report, we show that high levels of replication occurred in the VAI-deleted mutant in the EBV-positive tumor cells compared with low (or negligible) levels in EBV-negative and normal human primary cells. Correspondingly, high toxicity levels were observed in EBV-positive tumor cells but not in EBV-negative tumor or normal human primary cells. In vivo, VAI-deleted adenovirus showed superior antitumoral efficacy to wild-type adenovirus in EBV-positive tumor xenografts, with lower hepatotoxicity than wild-type adenovirus. Our data suggest that VAI-deleted adenovirus is a promising replication-selective oncolytic virus with targeting specificity for EBV-associated tumors.
A U.S. Population-Based Survey of <i>Staphylococcus aureus</i> Colonization
Authors: Philip L. Graham, Susan X. Lin, Elaine L. Larson
Journal: Annals of Internal Medicine (2006)

Background: The epidemiology of staphylococcal colonization and community-associated methicillin-resistant Staphylococcus aureus (MRSA) is changing, and little is known from the national perspective. Objective: To describe the U.S. epidemiology of S. aureus nasal colonization, compare risk factors for colonization with methicillin-sensitive S. aureus (MSSA) versus MRSA, and compare antibiotic resistance patterns and genetic factors of colonizing strains of S. aureus. Design: Secondary analysis of data from the National Health and Nutrition Examination Survey (NHANES), a stratified, multistage probability sample. Setting: United States. Participants: 2001–2002 NHANES participants older than 1 year of age. Measurements: Colonization of MSSA and MRSA, risk factors for colonization, antimicrobial resistance, and percentage of isolates with selected genetic factors. Results: The prevalence of colonization with S. aureus and with MRSA was 31.6% and 0.84%, respectively, in the noninstitutionalized U.S. population. People younger than 65 years of age, men, persons with less education, and persons with asthma were more likely to acquire S. aureus. Persons of black race and those of Mexican birth had lower risk for S. aureus colonization. Persons 65 years of age or older, women, persons with diabetes, and those who were in long-term care in the past year were more likely to have MRSA colonization. Hispanic persons had statistically significantly less risk than white persons. Isolates of MRSA with staphylococcal chromosomal cassette mec type IV (which is often associated with community-associated MRSA) were statistically significantly more likely to be sensitive to erythromycin, clindamycin, and ciprofloxacin. Limitations: Colonizing isolates may be different from isolates associated with infection. Risk factors identified may differ from those associated with invasive disease. The 2001–2002 NHANES data are several years old and may not reflect the most recent changes in epidemiology, but they are the only national data available. Conclusions: Characteristics of persons with MSSA and MRSA seem to differ. These findings may be useful for differentiating those who may be at risk for MRSA.
N<scp>UTRITIONAL</scp>M<scp>ANAGEMENT OF</scp>M<scp>AINTENANCE</scp>D<scp>IALYSIS</scp>P<scp>ATIENTS</scp>: Why Aren't We Doing Better?
Authors: Rajnish Mehrotra, Joel D Kopple
Journal: Annual Review of Nutrition (2001)

▪ Abstract About 40% of patients undergoing maintenance dialysis suffer from varying degrees of protein-energy malnutrition. This is a problem of substantial importance because many measures of nutritional status correlate with the risk of morbidity and mortality. There are many causes of protein-energy malnutrition in maintenance dialysis patients. Evidence indicates that nutritional decline begins even when the reduction in glomerular filtration rate is modest, and it is likely that the observed decrease in dietary protein and energy intake plays an important role. The nutrient intake of patients receiving maintenance dialysis also is often inadequate, and several lines of evidence suggest that toxins that accumulate with renal failure suppress appetite and contribute to nutritional decline once patients are on maintenance dialysis. Recent epidemiologic studies have suggested that both increased serum levels of leptin and inflammation may reduce nutrient intake and contribute to the development of protein-energy malnutrition. It is likely that associated illnesses, which are highly prevalent, contribute to malnutrition in maintenance dialysis patients. Recent data from the United States Renal Data System registry suggest that in the United States, the mortality rate of dialysis patients is improving. However, it remains high. We offer suggestions for predialysis and dialysis care of these patients that can result in improvement in their nutritional status. Whether this improvement will result in a decrease in patient morbidity and mortality is unknown.
Pharmacological induction of interferon type I activity following treatment with rituximab determines clinical response in rheumatoid arthritis
Authors: Saskia Vosslamber, Hennie G Raterman, Tineke C T M van der Pouw Kraan, Marco W J Schreurs, B Mary E von Blomberg, Michael T Nurmohamed, Willem F Lems, Ben A C Dijkmans, Alexandre E Voskuyl, Cornelis L Verweij
Journal: Annals of the Rheumatic Diseases (2011)

Objective Despite the fact that rituximab depletes B cells in all treated patients with RA, not all patients show a favourable clinical response. The goal of this study was to provide insight into pharmacological changes in peripheral blood that are associated with clinical response to rituximab. Methods Gene expression profiling was performed on peripheral blood RNA of 13 patients with RA (test group) using Illumina HumanHT beadchip microarrays. An independent group of nine patients was used for validation using TaqMan quantitative PCR. Clinical responder status was determined after 6 months using change in 28-joint Disease Activity Score (ΔDAS28) and European League Against Rheumatism (EULAR) response criteria. Significance analysis of microarrays and ontology analysis were used for data analysis and interpretation. Results Pharmacogenomic analyses demonstrated marked interindividual differences in the pharmacological responses at 3 and 6 months after start of treatment with rituximab. Interestingly, only differences in the regulation of type I interferon (IFN)-response genes after 3 months correlated with the ΔDAS28 response. Good responders (∆DAS&gt;1.2; n=7) exhibited a selective increase in the expression of type I IFN-response genes, whereas this activity was unchanged or hardly changed in non-responders (∆DAS&lt;1.2; n=6) (p=0.0040 at a cut-off of 1.1-fold induction). Similar results were obtained using EULAR response criteria. These results were validated in an independent cohort of nine patients (five non-responders and four responders, p=0.0317). Conclusions A good clinical response to rituximab in RA is associated with a selective drug-induced increase in type I IFN-response activity in patients with RA. This finding may provide insight in the biological mechanism underlying the therapeutic response to rituximab.
IN VITRO INTERACTION OF MOUSE HEPATITIS VIRUS AND MACROPHAGES FROM GENETICALLY RESISTANT MICE
Authors: Ilan Shif, Frederik B. Bang
Journal: The Journal of Experimental Medicine (1970)

A variant mouse hepatitis virus MHV(C(3)H) to which cultured peritoneal macrophages from both PRI and C(3)H mice were susceptible was isolated from stocks of the MHV(PRI) strain of mouse hepatitis virus. It was cloned on C(3)H macrophage monolayers and killed both adult PRI and C(3)H mice when injected intraperitoneally. This new variant was antigenically indistinguishable from the wild type virus. While the emergence of the variant virus was delayed in the course of infecting C(3)H macrophages with large inocula of MHV(PRI), the second passage grew to a high titer in both cell types without delay. Thus, adaptation to the new host was immediate. Interference, apparently not interferon-mediated, between the two variant viruses may have been the cause for the delay in the emergence of the variant virus. The delayed destruction of C(3)H-cultured macrophages by large inocula of MHV(PRI) uniformly resulted in the emergence of MHV(C(3)H). Whether the new variant emerged as a result of a selection of a pre-existing stable mutant or was conditioned by "growth" in the resistant host was not determined.
Comparison of human B cell antigen receptor complexes: membrane-expressed forms of immunoglobulin (Ig)M, IgD, and IgG are associated with structurally related heterodimers.
Authors: C J Van Noesel, G S Brouns, G M van Schijndel, R J Bende, D Y Mason, J Borst, R A van Lier
Journal: The Journal of Experimental Medicine (1992)

We have recently reported that on human B lymphocytes, membrane IgM (mIgM) associates with a heterodimer of 47- and 37-kD polypeptides, the 47-kD subunit being encoded by the mb-1 gene. We show here that expression of mb-1, both at the mRNA and the protein level, is not restricted to IgM+ B cells but can also be found in IgM- pre-B cells and mIgM-IgG+ B cells. Membrane forms of IgD and IgG, isolated from freshly isolated human B cells and B cell lines, are expressed together with heterodimeric protein structures biochemically similar to the mIgM-associated polypeptides, and these were shown to comprise the products of the mb-1 and B29 genes, or homologous genes. Finally, all three classes of antigen receptors are linked to protein kinases, capable of phosphorylating the Ig-associated heterodimers. Our findings provide insight in the structural organization of the different antigen receptors on human B cells and have implications for their function.
Fenofibrate and losartan
Authors: T Bardin
Journal: Annals of the Rheumatic Diseases (2003)

Should we take advantage of their uricosuric properties in clinical practice?

The interesting study published in this issue of the journal by Takahashi et al sheds light on two drugs, losartan and fenofibrate, which have hypouricaemic properties, in addition to their main therapeutic effects.1

Losartan potassium is an orally active angiotensin II receptor antagonist used for the treatment of hypertension. This product and its long life metabolite E-3174 are potent antagonists at the AT1 receptor. The observation that losartan increases urinary uric acid excretion and reduces serum uric acid level was first made in a pilot study conducted in healthy subjects and published in 1992. Uric acid fractional clearance was mainly increased during the first four hours after drug intake in a time course consistent with a direct effect of the drug. The increase was found to be dose dependent and to persist after seven days of administration.2 Angiotensin is known to lower uric acid renal clearance,3 but the uricosuric effect of losartan did not appear to be mediated by angiotensin inhibition: in one study, infusion of E-3174, the active metabolite of losartan, did not modify uric acid excretion, although it efficiently decreased blood pressure.4 The early and transient uricosuric action of losartan was therefore attributed mainly to the mother compound. Further suggestions of an effect independent of angiotensin II receptor blockade came from the observation that the uricosuric effect did not vary with a sodium diet5 and was not seen with other angiotensin II receptor antagonists.6–8

“Losartan and E-3174 target the urate anion exchanger URAT1” 

Losartan and its metabolite E-3174 …
Autologous Melanoma Vaccine Induces Antitumor and Self-Reactive Immune Responses That Affect Patient Survival and Depend on MHC Class II Expression on Vaccine Cells
Authors: Michal Lotem, Arthur Machlenkin, Tamar Hamburger, Aviram Nissan, Luna Kadouri, Shoshana Frankenburg, Zvi Gimmon, Orit Elias, Inna Ben David, Anna Kuznetz, Eitan Shiloni, Tamar Peretz
Journal: Clinical Cancer Research (2009)

Autologous melanoma cells display a broad variety of tumor antigens and were used for treatment of American Joint Committee on Cancer stages III and IV melanoma as an adjuvant or active therapy. Survival data and immune response were evaluated in vaccinated patients.Forty-seven patients received 2,4-dinitrophenyl-conjugated autologous melanoma vaccine as an adjuvant (23 patients) or therapy (24 patients). CD4 and CD8 T-cell response in blood sampled before vaccination and after five or eight vaccine doses was evaluated against melanoma cells and autologous peripheral blood mononuclear cells using IFNgamma enzyme-linked immunospot. Serum levels of antilivin, an inhibitor of apoptosis, and anti-gp100 IgG were determined.The immunologic effect of the vaccine differed between the two groups of patients. In the adjuvant group, there was a significant increase in CD8 melanoma-reactive T cells (P = 0.035) after vaccination and an increase in antimelanoma CD4 T cells correlating with improved overall survival (P = 0.04). In the therapeutic group, there was no objective tumor regression; antimelanoma T-cell reactivity increased by a small amount, stayed the same, or in some cases decreased. In all patients, a significant increase was noted in CD4 T-cell reactivity against autologous peripheral blood mononuclear cells (P = 0.02), which did not affect survival. Increased antilivin IgG was associated with improved survival. Expression of MHC class II on melanoma cells was vital for the immunogenicity of the vaccine.Autologous melanoma cell vaccine is capable of inducing effective antimelanoma CD4 T-cell activity associated with improved survival. Patients with active metastatic disease generally displayed reduced immune response and gained little from active immunization.
Responsibility of sport and exercise medicine in preventing and managing chronic disease: applying our knowledge and skill is overdue: Figure 1
Authors: Gordon O Matheson, Martin Klügl, Jiri Dvorak, Lars Engebretsen, Willem H Meeuwisse, Martin Schwellnus, Steven N Blair, Willem van Mechelen, Wayne Derman, Mats Börjesson, Fredrik Bendiksen, Richard Weiler
Journal: British Journal of Sports Medicine (2011)

The rapidly increasing burden of chronic disease is difficult to reconcile with the large, compelling body of literature that demonstrates the substantial preventive and therapeutic benefits of comprehensive lifestyle intervention, including physical activity, smoking cessation and healthy diet. Physical inactivity is now the fourth leading independent risk factor for death caused by non-communicable chronic disease. Although there have been efforts directed towards research, education and legislation, preventive efforts have been meager relative to the magnitude of the problem. The disparity between our scientific knowledge about chronic disease and practical implementation of preventive approaches now is one of the most urgent concerns in healthcare worldwide and threatens the collapse of our health systems unless extraordinary change takes place.The authors believe that there are several key factors contributing to the disparity. Reductionism has become the default approach for healthcare delivery, resulting in fragmentation rather than integration of services. This, in turn, has fostered a disease-based rather than a health-based model of care and has produced medical school curricula that no longer accurately reflect the actual burden of disease. Trying to 'fit' prevention into a disease-based approach has been largely unsuccessful because the fundamental tenets of preventive medicine are diametrically opposed to those of disease-based healthcare.A clinical discipline within medicine is needed to adopt disease prevention as its own reason for existence. Sport and exercise medicine is well positioned to champion the cause of prevention by promoting physical activity.This article puts forward a strong case for the immediate, increased involvement of clinical sport and exercise medicine in the prevention and treatment of chronic disease and offers specific recommendations for how this may begin.
Antigenic drift in influenza A viruses. I. Selection and characterization of antigenic variants of A/PR/8/34 [HON1] influenza virus with monoclonal antibodies
Authors: W Gerhard, RG Webster
Journal: The Journal of Experimental Medicine (1978)

Antigenic variants of A/PR/8/34 [HON1] influenza virus were selected after a single passage of the parent virus in embryonated chicken eggs in the presence of monoclonal antibodies to this virus. The monoclonal antibodies were produced by a hybridoma and were specific for an antigenic determinant on the HA molecule of the parent virus. Seven antigenic variants were analyzed with 95 monoclonal anti-HA antibodies prepared in vitro in the splenic fragment culture system. Three subgroups of antigenic variants were distinguished. The antigenic changes were primarily recognized by monoclonal antibodies to the strain- specific determinants of the parental hemagglutinin (HA) molecule. Monoclonal antibodies to HA determinants shared (in an identical or cross-reactive form) by parental virus and more than three heterologous viruses of the HON1 and H1N1 subtypes were unable to recognize the antigenic change on the variants. Similarly, heterogeneous antibody preparations could not differentiate between parental and variant viruses. The results are compatible with the idea that the HA of PR8 has available a large repertoire of antigenic modifications that may result from single amino acid substitutions, and that antigenic changes can occur in the strain- specific determinants on the HA molecule in the absence of concomitant changes in the cross-reactive HA determinants. The findings suggest that antigenic drift, in order to be epidemiologically significant, probably requires a series of amino acid substitutions in, or close to, the antigenic area on the HA molecule.