tbuckley/cabot-search huggingface dataset:
BIOMARKERS IN PSYCHOTROPIC DRUG DEVELOPMENT: Integration of Data across Multiple Domains
Authors: Peter R. Bieck, William Z. Potter
Journal: The Annual Review of Pharmacology and Toxicology (2004)

This review focuses on the current status of biomarkers and/or approaches critical to assessing novel neuroscience targets with an emphasis on new paradigms and challenges in this field of research. The importance of biomarker data integration for psychotropic drug development is illustrated with examples for clinically used medications and investigational drugs. The question remains how to verify access to the brain. Early imaging studies including micro-PET can help to overcome this. However, in case of delayed tracer development or because of no feasible application of brain imaging effects of the molecule, using CSF as a matrix could fill this gap. Proteomic research using CSF will hopefully have a major impact on the development of treatments for psychiatric disorders.
The Indian Ocean Dipole and Cholera Incidence in Bangladesh: A Time-Series Analysis
Authors: Masahiro Hashizume, A.S.G. Faruque, Toru Terao, Md Yunus, Kim Streatfield, Taro Yamamoto, Kazuhiko Moji
Journal: Environmental Health Perspectives (2010)

BackgroundIt has been reported that the El Niño–Southern Oscillation (ENSO) influences the interannual variation of endemic cholera in Bangladesh. There is increased interest in the influence of the Indian Ocean dipole (IOD), a climate mode of coupled ocean–atmosphere variability, on regional ocean climate in the Bay of Bengal and on Indian monsoon rainfall.ObjectivesWe explored the relationship between the IOD and the number of cholera patients in Bangladesh, controlling for the effects of ENSO.MethodsTime-series regression was performed. Negative binomial models were used to estimate associations between the monthly number of hospital visits for cholera in Dhaka and Matlab (1993–2007) and the dipole mode index (DMI) controlling for ENSO index [NINO3, a measure of the average sea surface temperature (SST) in the Niño 3 region], seasonal, and interannual variations. Associations between cholera cases and SST and sea surface height (SSH) of the northern Bay of Bengal were also examined.ResultsA 0.1-unit increase in average DMI during the current month through 3 months before was associated with an increase in cholera incidence of 2.6% [(95% confidence interval (CI), 0.0–5.2; p = 0.05] in Dhaka and 6.9% (95% CI, 3.2–10.8; p < 0.01) in Matlab. Cholera incidence in Dhaka increased by 2.4% (95% CI, 0.0–5.0; p = 0.06) after a 0.1-unit decrease in DMI 4–7 months before. Hospital visits for cholera in both areas were positively associated with SST 0–3 months before, after adjusting for SSH (p < 0.01).ConclusionsThese findings suggest that both negative and positive dipole events are associated with an increased incidence of cholera in Bangladesh with varying time lags.
Telomeres and Cardiovascular Disease
Authors: Antonio L. Serrano, Vicente Andrés
Journal: Circulation Research (2004)

Telomeres-the specialized DNA-protein structures at the ends of eukaryotic chromosomes-are essential for maintaining genome stability and integrity and for extended proliferative life span in both cultured cells and in the whole organism. Telomerase and additional telomere-associated proteins are necessary for preserving telomeric DNA length. Age-dependent telomere shortening in most somatic cells, including vascular endothelial cells, smooth muscle cells, and cardiomyocytes, is thought to impair cellular function and viability of the aged organism. Telomere dysfunction is emerging as an important factor in the pathogenesis of hypertension, atherosclerosis, and heart failure. In this Review, we discuss present studies on telomeres and telomere-associated proteins in cardiovascular pathobiology and their implications for therapeutics.
Role of NADPH oxidase 4 in lipopolysaccharide-induced proinflammatory responses by human aortic endothelial cells
Authors: H PARK, J CHUN, H JUNG, C CHOI, Y BAE
Journal: Cardiovascular Research (2006)

Objective: We investigated the role of NADPH oxidase 4 (Nox4) on lipopolysaccharide (LPS)-induced proinflammatory responses by human aortic endothelial cells (HAECs).
A Prospective Patient-centred Evaluation of Urethroplasty for Anterior Urethral Stricture Using a Validated Patient-reported Outcome Measure
Authors: Matthew J. Jackson, Ishaan Chaudhury, Altaf Mangera, Andrew Brett, Nick Watkin, Christopher R. Chapple, Daniela E. Andrich, Robert S. Pickard, Anthony R. Mundy
Journal: European Urology (2013)
Chronic lymphocytic leukemia and other chronic lymphoid proliferations: surface marker phenotypes and clinical correlations.
Authors: R O Dillman, J C Beauregard, J W Lea, M R Green, R E Sobol, I Royston
Journal: Journal of Clinical Oncology (1983)

A diagnosis of chronic lymphocytic leukemia (CLL) was made in 81 patients referred for peripheral blood lymphocyte typing (PBL). A retrospective review was undertaken to see if correlations existed between surface marker phenotype-determined subclasses and clinical features. Surface markers utilized were surface immunoglobulin (sIg), sheep erythrocyte receptor (E), 65,000-dalton human T lymphocyte antigen (T65), Ia antigen, and for sIg+ cells, heavy and light chains. All patients were Ia+. Cells of 70% of patients were sIg+ E- T65+ Ia+, and the clinical heterogeneity was that of classical CLL. Eight of the nine patients with sIg+ E- T65- Ia+ cells had a paraprotein. The sIg- E+ T65+ Ia+ phenotype represented classical T cell CLL. Three of the five patients in the sEg- E- T65+ Ia+ group had significant albuminuria, and two had nephrotic-range proteinuria. Use of additional monoclonal antibodies to B cell surface antigens should further subclassify CLL and other lymphoproliferative disorders. Interesting clinical correlations with certain phenotypic subclasses do exist, and further subclassification and long-term follow-up may yield correlations between phenotypes and prognosis.
Pressor responses to norepinephrine in rabbits with 3-day and 30-day renal artery stenosis. The role of angiotensin II.
Authors: S Ichikawa, J A Johnson, W L Fowler, C G Payne, K Kurz, W F Keitzer
Journal: Circulation Research (1978)

Pressor responses to norepinephrine (NE) infusions were examined in normal rabbits, in rabbits with renal artery stenosis of over 30 days' duration (chronic renal hypertensive rabbits), and in rabbits with renal artery stenosis of 3 days' duration (3-day clipped rabbits). The 3-day clipped rabbits did not have hypertension, but they showed the same increased pressor responses to NE as did the chronic renal hypertensive rabbits, which was about 2.5 times that of the normal rabbits. Plasma renin activity (PRA) was the same in the 3-day clipped rabbits as in the normal group, but in the chronic renal hypertensive rabbits the PRA was significantly below normal. Infusions of angiotensin II (A II) in either subpressor or pressor amounts potentiated the pressor responses to NE in normal rabbits, whereas, in 3-day clipped rabbits and chronic renal hypertensive rabbits, A II in subpressor or pressor doses did not alter the pressor responses to NE. Infusion of the A II antagonist, [1-sarcosine, 8-isoleucine]angiotensin II, did not alter the pressor responses of normal rabbits to NE, but this A II analogue completely abolished the pressor hyperresponsiveness to NE in the 3-day clipped rabbits and greatly reduced the NE hyperresponsiveness in the chronic renal hypertensive rabbits; this A II antagonist did not alter the control arterial pressure in any of the three groups of rabbits. These studies show that the increased pressor response to NE in rabbits with renal artery stenosis occurs before the onset of hypertension and thus is not merely a result of the hypertension. Also, these results provide evidence that A II plays an important role in the increased pressor responses to NE in hypertensive and prehypertensive rabbits.
193-nm Excimer Photorefractive Keratectomy in High Myopia
Authors: Neal A. Sher, David R. Hardten, Brad Fundingsland, Janet DeMarchi, Emmet Carpel, Donald J. Doughman, Stephen S. Lane, Charles Ostrov, Richard Eiferman, Jonathan M. Frantz, Jeffery Robin, William Telfair, Richard L. Lindstrom
Journal: Ophthalmology (1994)
Long-lived and transferable tumor immunity in mice after targeted interleukin-2 therapy.
Authors: J C Becker, N Varki, S D Gillies, K Furukawa, R A Reisfeld
Journal: Journal of Clinical Investigation (1996)

A major goal of tumor immunotherapy is the induction of tumor-specific T cell responses that are effective in eradicating disseminated tumor, as well as mounting a persistent tumor-protective immunity. We demonstrate here that a genetically engineered fusion protein consisting of human/mouse chimeric anti-ganglioside GD2 antibody and human interleukin-2 is able to induce eradication of established B78-D14 melanoma metastases in immunocompetent syngeneic C57BL/6J mice. This therapeutic effect is mediated by host immune cells, particularly CD8+ T cells and is associated with the induction of a long-lived immunity preventing tumor growth in the majority of animals when challenged up to four months later with B78-D14 cells. This effect was tumor-specific, since no cross-protection against syngeneic, ganglioside GD2+ EL-4 thymoma cells was observed. Furthermore, this tumor-specific protection can be transmitted horizontally to naive, syngeneic SCID mice by passive transfer of CD8+ T lymphocytes derived from immune animals. These results suggest that antibody-targeted delivery of cytokines provides a means to elicit effective immune responses against established tumors in the immunotherapy of neoplastic disease.
Antigen capture and major histocompatibility class II compartments of freshly isolated and cultured human blood dendritic cells.
Authors: H W Nijman, M J Kleijmeer, M A Ossevoort, V M Oorschot, M P Vierboom, M van de Keur, P Kenemans, W M Kast, H J Geuze, C J Melief
Journal: The Journal of Experimental Medicine (1995)

Dendritic cells (DC) represent potent antigen-presenting cells for the induction of T cell-dependent immune responses. Previous work on antigen uptake and presentation by human DC is based largely on studies of blood DC that have been cultured for various periods of time before analysis. These cultured cells may therefore have undergone a maturation process from precursors that have different capacities for antigen capture and presentation. We have now used immunoelectron microscopy and antigen presentation assays to compare freshly isolated DC (f-DC) and cultured DC (c-DC). f-DC display a round appearance, whereas c-DC display characteristic long processes. c-DC express much more cell surface major histocompatibility complex (MHC) class II than f-DC. The uptake of colloidal gold-labeled bovine serum albumin (BSA), however, is greater in f-DC, as is the presentation of 65-kD heat shock protein to T cell clones. The most striking discovery is that the majority of MHC class II molecules in both f-DC and c-DC occur in intracellular vacuoles with a complex shape (multivesicular and multilaminar). These MHC class II enriched compartments (MIIC) represent the site to which BSA is transported within 30 min. Although MIIC appear as more dense structures with less MHC class II molecules in f-DC than c-DC, the marker characteristics are very similar. The MIIC in both types of DC are acidic, contain invariant chain, and express the recently described HLA-DM molecule that can contribute to antigen presentation. CD19+ peripheral blood B cells have fewer MIIC and surface MHC class II expression than DCs, while monocytes had low levels of MIIC and surface MHC class II. These results demonstrate in dendritic cells the elaborate development of MIIC expressing several of the components that are required for efficient antigen presentation.
Occupational asthma caused by stainless steel welding fumes: a clinical study
Authors: T. Hannu, R. Piipari, M. Tuppurainen, H. Nordman, T. Tuomi
Journal: European Respiratory Journal (2006)

The aim of the present study was to describe the cases of occupational asthma (OA) due to stainless steel welding fumes diagnosed at the Finnish Institute of Occupational Health during the period 1994-2003. OA was diagnosed according to patient history, lung function examinations and welding challenge tests with measurements of the forced expiratory volume in one second (FEV(1)) and peak expiratory flow (PEF) values. The present series comprised 34 patients, all male, with a mean age of 44.7 yrs (range 22-57), mainly working as welders. The mean duration of exposure was 22.4 yrs, and the mean duration of exposure before the onset of respiratory symptoms was 18 yrs. Dyspnoea was the most frequently reported work-related respiratory symptom. During the inhalation challenge tests, the mode of the asthmatic FEV(1)/PEF reaction was delayed in 16 (47%) patients, immediate in nine (26%) patients and dual (both immediate and delayed) in nine (26%) patients. In the follow-up assessment 6 months later, only six patients were considered able to continue performing welding tasks, whereas occupational injury pension was recommended for seven, and measures of vocational rehabilitation for 14 patients. In most cases, after the diagnosis of occupational asthma, the continuation of welding work was not possible.
Microbial protection and virulence in periodontal tissue as a function of polymicrobial communities: symbiosis and dysbiosis
Authors: Frank A. Roberts, Richard P. Darveau
Journal: Periodontology 2000 (2015)

Abstract This review discusses polymicrobial interactions with the host in both health and disease. As our ability to identify specific bacterial clonal types, with respect to their abundance and location in the oral biofilm, improves, we will learn more concerning their contribution to both oral health and disease. Recent studies examining host– bacteria interactions have revealed that commensal bacteria not only protect the host simply by niche occupation, but that bacterial interactions with host tissue can promote the development of proper tissue structure and function. These data indicate that our host‐associated polymicrobial communities, such as those found in the oral cavity, co‐evolved with us and have become an integral part of who we are. Understanding the microbial community factors that underpin the associations with host tissue that contribute to periodontal health may also reveal how dysbiotic periodontopathic oral communities disrupt normal periodontal tissue functions in disease. A disruption of the oral microbial community creates dysbiosis, either by overgrowth of specific or nonspecific microorganisms or by changes in the local host response where the community can now support a disease state. Dysbiosis provides the link between systemic changes (e.g. diabetes) and exogenous risk factors (e.g. smoking), and the dysbiotic community, and can drive the destruction of periodontal tissue. Many other risk factors associated with periodontal disease, such as stress, aging and genetics, are also likely to affect the microbial community, and more research is needed, utilizing sophisticated bacterial taxonomic techniques, to elucidate these effects on the microbiome and to develop strategies to target the dysbiotic mechanisms and improve periodontal health.
Correlations between immune response and vascularization qRT-PCR gene expression clusters in squamous cervical cancer
Authors: Simone Punt, Jeanine J Houwing-Duistermaat, Iris A Schulkens, Victor L Thijssen, Elisabeth M Osse, Cornelis D de Kroon, Arjan W Griffioen, Gert Jan Fleuren, Arko Gorter, Ekaterina S Jordanova
Journal: Molecular Cancer (2015)

The tumour microenvironment comprises a network of immune response and vascularization factors. From this network, we identified immunological and vascularization gene expression clusters and the correlations between the clusters. We subsequently determined which factors were correlated with patient survival in cervical carcinoma.The expression of 42 genes was investigated in 52 fresh frozen squamous cervical cancer samples by qRT-PCR. Weighted gene co-expression network analysis and mixed-model analyses were performed to identify gene expression clusters. Correlations and survival analyses were further studied at expression cluster and single gene level.We identified four immune response clusters: 'T cells' (CD3E/CD8A/TBX21/IFNG/FOXP3/IDO1), 'Macrophages' (CD4/CD14/CD163), 'Th2' (IL4/IL5/IL13/IL12) and 'Inflammation' (IL6/IL1B/IL8/IL23/IL10/ARG1) and two vascularization clusters: 'Angiogenesis' (VEGFA/FLT1/ANGPT2/ PGF/ICAM1) and 'Vessel maturation' (PECAM1/VCAM1/ANGPT1/SELE/KDR/LGALS9). The 'T cells' module was correlated with all modules except for 'Inflammation', while 'Inflammation' was most significantly correlated with 'Angiogenesis' (p < 0.001). High expression of the 'T cells' cluster was correlated with earlier TNM stage (p = 0.007). High CD3E expression was correlated with improved disease-specific survival (p = 0.022), while high VEGFA expression was correlated with poor disease-specific survival (p = 0.032). Independent predictors of poor disease-specific survival were IL6 (hazard ratio = 2.3, p = 0.011) and a high IL6/IL17 ratio combined with low IL5 expression (hazard ratio = 4.2, p = 0.010).'Inflammation' marker IL6, especially in combination with low levels of IL5 and IL17, was correlated with poor survival. This suggests that IL6 promotes tumour growth, which may be suppressed by a Th17 and Th2 response. Measuring IL6, IL5 and IL17 expression may improve the accuracy of predicting prognosis in cervical cancer.
Hormonal regulation of expression of the angiotensinogen gene in cultured opossum kidney proximal tubular cells.
Authors: J S Chan, M Ming, Z R Nie, R Sikstrom, S Lachance, S Carrière
Journal: Journal of the American Society of Nephrology (1992)

Angiotensinogen (ANG) messenger RNA is expressed in cultured opossum kidney (OK) proximal tubular cells. The aim of these studies was to investigate whether steroid hormones (dexamethasone, estradiol, testosterone, and progesterone) could stimulate the expression of renal ANG gene in vitro. Fusion genes consisting of various lengths of the 5'-flanking region of the rat ANG gene linked to a chloramphenicol acetyl transferase (CAT) reporter gene were constructed and introduced into cultured OK cells. The level of expression of fusion genes was determined by the level of cellular CAT enzymatic activity. The addition of dexamethasone (10(-12) to 10(-6) M) stimulates the expression of the pOCAT (ANG N-1498/+18) fusion gene in OK cells in a dose-dependent manner with a maximum stimulation at 10(-6) M and a half-maximal stimulation at 10(-9) M. Combination of dexamethasone (10(-6) M) and thyroid hormone, L-T3 (10(-6) M), further enhanced the effect of the dexamethasone alone. Testosterone (10(-6) M), estradiol (10(-6) M), and progesterone (10(-6) M) did not have this effect. Moreover, dexamethasone also stimulates the expression of the pOCAT (ANG N-688/+18) but not pOCAT (ANG N-110/+18), pOCAT (ANG N-53/+18) and pOCAT (ANG N-35/+18). These studies demonstrate that the glucocorticoid hormone is effective at stimulating the transcription of the ANG gene in OK cells, but stimulation is not observed from testosterone, estradiol, or progesterone. Moreover, glucocorticoid and L-T3 act synergistically to stimulate the transcription of the ANG gene.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood flow in microvascular networks. Experiments and simulation.
Authors: A R Pries, T W Secomb, P Gaehtgens, J F Gross
Journal: Circulation Research (1990)

A theoretical model has been developed to simulate blood flow through large microcirculatory networks. The model takes into account the dependence of apparent viscosity of blood on vessel diameter and hematocrit (the Fahraeus-Lindqvist effect), the reduction of intravascular hematocrit relative to the inflow hematocrit of a vessel (the Fahraeus effect), and the disproportionate distribution of red blood cells and plasma at arteriolar bifurcations (phase separation). The model was used to simulate flow in three microvascular networks in the rat mesentery with 436,583, and 913 vessel segments, respectively, using experimental data (length, diameter, and topological organization) obtained from the same networks. Measurements of hematocrit and flow direction in all vessel segments of these networks tested the validity of model results. These tests demonstrate that the prediction of parameters for individual vessel segments in large networks exhibits a high degree of uncertainty; for example, the squared coefficient of correlation between predicted and measured hematocrit of single vessel segments ranges only between 0.15 and 0.33. In contrast, the simulation of integrated characteristics of the network hemodynamics, such as the mean segment hematocrit or the distribution of blood flow velocities, is very precise. In addition, the following conclusions were derived from the comparison of predicted and measured values: 1) The low capillary hematocrits found in mesenteric microcirculatory networks as well as their heterogeneity can be explained on the basis of the Fahraeus effect and phase-separation phenomena. 2) The apparent viscosity of blood in vessels of the investigated tissue with diameters less than 15 microns is substantially higher than expected compared with measurements in glass tubes with the same diameter.
Molecular analysis of transplant rejection: marching onward
Authors: Fadi G. Lakkis, Timothy R. Billiar
Journal: The Journal of Experimental Medicine (2013)

Transcriptional profiling of organ transplants is increasingly defining the biological pathways responsible for graft rejection at the molecular level and identifying gene transcripts that diagnose or predict rejection. These advances hold significant promise for the treatment of organ rejection and for improving clinical outcomes after transplantation, but hurdles remain.
Spatial heterogeneity of myocardial perfusion predicts local potassium channel expression and action potential duration
Authors: M. Stoll, M. Quentin, A. Molojavyi, V. Thamer, U. K.M. Decking
Journal: Cardiovascular Research (2007)

In the heart, there is not only a transmural gradient of left ventricular perfusion and action potential duration (APD), but also spatial heterogeneity within each myocardial layer, where local blood flow and energy turnover vary more than three-fold between individual regions. We analysed at high spatial resolution whether a corresponding heterogeneity also extends to ion channel gene expression and APD.In the open-chest beagle dog, left ventricular 300 microL samples of very low or high flow were identified by radioactive microspheres and expression levels determined by quantitative PCR. The distribution of epicardial APD was assessed by mapping local activation repolarization intervals (ARIs) and QT interval (QT). ERG, the potassium channel mediating IKr, and KChIP2, the interacting protein modulating Ito, were increased in Low flow (3.3- and 2.5-fold, P < 0.001 and <0.05, respectively; n = 6 hearts, 30-31 samples each) as compared with High flow areas. This suggested enhanced repolarizing currents in Low flow areas, and in consequence, mathematical model analysis predicted a shorter local APD upon enhanced ERG and IKr. Epicardial mapping revealed a patchy, temporally stable APD pattern (n = 11), a small apico-basal gradient and an APD prolongation induced by the ERG blocker dofetilide predominantly in areas of short basal ARI or QT, respectively (n = 9). In addition, in Short QT areas, ERG expression was three-fold increased (P < 0.05, n = 4).The spatial pattern of perfusion is matched by the novel patterns of K+ channel expression and APD. Whenever this newly recognized intramural dispersion of APD increases, it may contribute to arrhythmogenesis.