tbuckley/cabot-search huggingface dataset:
Advanced Poorly Differentiated Carcinoma of Unknown Primary Site: Recognition of a Treatable Syndrome
Authors: F. ANTHONY GRECO
Journal: Annals of Internal Medicine (1986)

We describe the clinical characteristics and prognostic features of 71 patients with advanced poorly differentiated carcinoma of unknown primary site. These patients had at least one component of the extragonadal germ cell cancer syndrome that we have previously described. Of 68 patients who received therapy, 62 were given intensive cisplatin-based combination chemotherapy that is used for treatment of germinal neoplasms. Fifteen patients (22%) had complete responses, and 9 patients (13%) have remained free of tumor after a minimum follow-up of 36 months (range, 36 to 67 months). Tumor in the mediastinum, retroperitoneum, and lymph nodes was associated with a favorable outcome of treatment when compared with tumor in other locations (p = 0.0016, Cox regression analysis). Although the histogenesis of tumors in many of these patients remains unclear, we believe the tumors most likely originate from germ cells. Patients with advanced poorly differentiated carcinoma should be considered for treatment with cisplatin-based combination chemotherapy, particularly if tumors occur predominantly in the mediastinum, retroperitoneum, or lymph nodes.
Nebivolol Reduces Nitroxidative Stress and Restores Nitric Oxide Bioavailability in Endothelium of Black Americans
Authors: R. Preston Mason, Leszek Kalinowski, Robert F. Jacob, Adam M. Jacoby, Tadeusz Malinski
Journal: Circulation (2005)

Background— Alterations in endothelial function may contribute to increased susceptibility of black Americans to cardiovascular disease. The ability to pharmacologically reverse endothelial dysfunction in blacks was tested with nebivolol, a β 1 -selective agent with vasodilating and antioxidant properties. Methods and Results— The effects of nebivolol on endothelial nitric oxide (NO), superoxide (O 2 − ), and peroxynitrite concentration (ONOO − ) release were studied in human umbilical vein endothelial cells and iliac artery endothelial cells isolated from age-matched black and white donors. Kinetics and concentrations of NO/O 2 − /ONOO − were measured simultaneously with nanosensors from single cells and shown to have significant interracial differences. The rate of NO release was &amp;5 times slower in blacks than in whites (94 versus 505 nmol · L −1 · s −1 ), whereas the rates of release were faster by &amp;2 times for O 2 − and &amp;4 times for ONOO − (22.1 versus 9.4 nmol · L −1 · s −1 for O 2 − and 810 versus 209 nmol · L −1 · s −1 for ONOO − ). Pretreatment with 1.0 to 5.0 μmol/L nebivolol restored NO bioavailability in endothelial cells from black donors with concurrent reductions in O 2 − and ONOO − release, similar to levels in the endothelium of whites. The effects of nebivolol were dose-dependent and not observed with atenolol; similar effects were observed with apocynin, an NAD(P)H oxidase inhibitor. Conclusions— Reduced endothelial NO bioavailability in American blacks is mainly due to excessive O 2 − and ONOO − generation by NAD(P)H and uncoupled endothelial NO synthase. Nebivolol decreased O 2 − and ONOO − concentrations and restored NO bioavailability in blacks to the level recorded in cells from whites, independently of β 1 -selective blockade.
Arrhythmias and Mortality After Myocardial Infarction in Diabetic Patients: Relationship to diabetes treatment
Authors: Timothy M E Davis, Richard W Parsons, Robin J Broadhurst, Michael S T Hobbs, Konrad Jamrozik
Journal: Diabetes Care (1998)

OBJECTIVE To assess the relationship between clinical course after acute myocardial infarction (AMI) and diabetes treatment. RESEARCH DESIGN AND METHODS Retrospective analysis of data from all patients aged 25–64 years admitted to hospitals in Perth, Australia, between 1985 and 1993 with AMI diagnosed according to the International Classification of Diseases (9th revision) criteria was conducted. Short- (28-day) and long-term survival and complications in diabetic and nondiabetic patients were compared. For diabetic patients, 28-day survival, dysrhythmias, heart block, and pulmonary edema were treated as outcomes, and factors related to each were assessed using multiple logistic regression. Diabetes treatment was added to the model to assess its significance. Long-term survival was compared by means of a Cox proportional hazards model. RESULTS Of 5,715 patients, 745 (12.9%) were diabetic. Mortality at 28 days was 12.0 and 28.1% for nondiabetic and diabetic patients, respectively (P &amp;lt; 0.001); there were no significant drug effects in the diabetic group. Ventricular fibrillation in diabetic patients taking glibenclamide (11.8%) was similar to that of nondiabetic patients (11.0%) but was lower than that for those patients taking either gliclazide (18.0%; 0.1 &amp;gt; P &amp;gt; 0.05) or insulin (22.8%; P &amp;lt; 0.05). There were no other treatment-related differences in acute complications. Long-term survival in diabetic patients was reduced in those taking digitalis and/or diuretics but type of diabetes treatment at discharge had no significant association with outcome. CONCLUSIONS These results do not suggest that ischemic heart disease should influence the choice of diabetes treatment regimen in general or of sulfonylurea drug in particular.
Transferability of tag SNPs in genetic association studies in multiple populations
Authors: Paul I W de Bakker, Noël P Burtt, Robert R Graham, Candace Guiducci, Roman Yelensky, Jared A Drake, Todd Bersaglieri, Kathryn L Penney, Johannah Butler, Stanton Young, Robert C Onofrio, Helen N Lyon, Daniel O Stram, Christopher A Haiman, Matthew L Freedman, Xiaofeng Zhu, Richard Cooper, Leif Groop, Laurence N Kolonel, Brian E Henderson, Mark J Daly, Joel N Hirschhorn, David Altshuler
Journal: Nature Genetics (2006)
Allorecognition and Effector Pathways of Islet Allograft Rejection in Normal versus Nonobese Diabetic Mice
Authors: Leila Makhlouf, Akira Yamada, Toshiro Ito, Reza Abdi, Mohammed Javeed I. Ansari, Chau Q. Khuong, Henry J. Winn, Hugh Auchincloss, Mohamed H. Sayegh
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Islet transplantation is becoming an accepted therapy to cure type I diabetes mellitus. The exact mechanisms of islet allograft rejection remain unclear, however. In vivo CD4+ and CD8+ T cell-depleting strategies and genetically altered mice that did not express MHC class I or class II antigens were used to study the allorecognition and effector pathways of islet allograft rejection in different strains of mice, including autoimmunity-prone nonobese diabetic (NOD) mice. In BALB/c mice, islet rejection depended on both CD4+ and CD8+ T cells. In C57BL/6 mice, CD8+ T cells could eventually mediate islet rejection by themselves, but they produced rejection more efficiently with help from CD4+ T cells stimulated through either the direct or indirect pathway. In C57BL/6 mice, CD4+ T cells alone caused islet rejection when only the direct pathway was available but not when only the indirect pathway was available. In contrast, in NOD mice, CD4+ T cells alone, with only the indirect pathway, could mediate islet and cardiac allograft rejection. These findings indicate that different mouse strains can make use of different pathways for T cell-mediated rejection of islet allografts. In addition, they demonstrate that NOD mice, which develop autoimmunity and are known to be resistant to tolerance induction, have an unusually powerful CD4+ cell indirect mechanism that can cause rejection of both islet and cardiac allografts. These data shed light on the mechanisms of islet allograft rejection in different responder strains, including those with autoimmunity. E-mail: [email protected]
Impact of HMG CoA reductase inhibition on small GTPases in the heart
Authors: Ulrich Laufs, Heiko Kilter, Christian Konkol, Sven Wassmann, Michael Böhm, Georg Nickenig
Journal: Cardiovascular Research (2002)

Objective: Members of the Rho GTPase family, Rac1 and RhoA have been suggested to be mediators of cardiac hypertrophy in mice. Rho proteins are posttranslationally isoprenylated. In addition to cholesterol-lowering, statins inhibit the isoprenylation of small G proteins. Therefore, it was tested if these drugs inhibit Rac1 and RhoA activity in cardiomyocytes and, thereby, prevent angiotensin II-mediated expression of atrial natriuretic factor (ANF) and myosin light chain (MLC)-2 in the heart. Methods and results: Western and Northern analysis of rat neonatal cardiomyocytes and H9C2 cells showed inhibition of basal and angiotensin-stimulated Rac1 expression, membrane-translocation and activity after statin treatment. Similarly, basal and stimulated RhoA membrane expression was inhibited. Statins concentration- and time-dependently downregulated basal as well as angiotensin-induced expression of ANF by 86±2.3% and 89±1.7%, as well as MLC-2 by 75±4.1% and 84±6%, respectively. Direct inhibition of Rac GTPase by overexpression of the dominant negative mutant RacN17 or by Clostridium sordellii lethal toxin in rat H9C2 cells inhibited ANF expression by 70±4.9% and 78±10%, respectively. Inhibition of RhoA by Clostridium botulinum C3 transferase or the dominant negative mutant RhoN19 reduced ANF mRNA by 19±11% and 23±8%, respectively. To test these findings in vivo, spontaneously hypertensive rats were treated with atorvastatin, leading to a decrease in cardiac Rac1 and RhoA activity as determined by [35S]-GTPγS-binding assays by 61±16% and 72±24%, and downregulation of MLC-2 as well as ANF mRNA expression by 31±16% and 80±24%, respectively. Conclusions: (1) Statins downregulate the activity of small G proteins in cardiomyocytes in culture as well as in vivo. (2) Inhibition of Rac1 and RhoA by statins reduces myocardial expression of ANF and MLC-2. (3) Targeting myocardial Rho GTPases by statins may be a novel treatment strategy to prevent cardiac hypertrophy.
Phase II study of neo-adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus
Authors: M.B. Polee, H.W. Tilanus, F.A.L.M. Eskens, R. Hoekstra, M.E.L. Van der Burg, P.D. Siersema, G. Stoter, A. Van der Gaast
Journal: Annals of Oncology (2003)
Electromagnetic Versus Fluoroscopic Mapping of the Inferior Isthmus for Ablation of Typical Atrial Flutter
Authors: Hans Kottkamp, Burkhardt Hügl, Beate Krauss, Ulrike Wetzel, Anne Fleck, Gerhard Schuler, Gerhard Hindricks
Journal: Circulation (2000)

Radiofrequency catheter ablation within the tricuspid annulus-inferior caval vein isthmus can cure typical atrial flutter. The target for ablation, nonetheless, is relatively wide, and standard ablation procedures may require significant exposure to radiation.A total of 50 patients (mean age, 58+/-11 years) with typical atrial flutter were prospectively randomized to receive isthmus ablation using conventional fluoroscopy for catheter navigation (group I, n=24) or electromagnetic mapping (group II, n=26). Complete bidirectional isthmus block was verified with double potential mapping. If complete isthmus block could not be achieved after 20 radiofrequency pulses or 25 minutes of fluoroscopy, the patients were switched to the other group. Eight patients from group I (33%) but only 1 patient from group II (4%) were switched. Overall, complete isthmus block was achieved in 47 of 50 patients (94%). The overall fluoroscopy time, including the placement of the diagnostic catheters, was 22.0+/-6.3 minutes in group I and 3.9+/-1.5 minutes in group II (P:<0.0001). The fluoroscopy time needed for isthmus mapping was 17.7+/-6.5 minutes in group I and 0.2+/-0.3 minutes in group II (P:<0.0001).Electromagnetic mapping during the induction of linear lesions for the ablation of atrial flutter permitted a highly significant reduction in exposure to fluoroscopy while maintaining high efficacy, and it allowed the time required for fluoroscopy to be reduced to levels anticipated for diagnostic electrophysiological studies.
Blocking Tumor Necrosis Factor α Enhances CD8 T-cell–Dependent Immunity in Experimental Melanoma
Authors: Florie Bertrand, Julia Rochotte, Céline Colacios, Anne Montfort, Anne-Françoise Tilkin-Mariamé, Christian Touriol, Philippe Rochaix, Isabelle Lajoie-Mazenc, Nathalie Andrieu-Abadie, Thierry Levade, Hervé Benoist, Bruno Ségui
Journal: Cancer Research (2015)

TNF plays a dual, still enigmatic role in melanoma, either acting as a cytotoxic cytokine or favoring a tumorigenic inflammatory microenvironment. Herein, the tumor growth of melanoma cell lines expressing major histocompatibility complex class I molecules at high levels (MHC-I(high)) was dramatically impaired in TNF-deficient mice, and this was associated with enhanced tumor-infiltrating CD8(+) T lymphocytes. Immunodepletion of CD8 T cells fully restored melanoma growth in TNF(-/-) mice. Systemic administration of Etanercept inhibited MHC-I(high) melanoma growth in immunocompetent but not in immunodeficient (IFNγ(-/-), nude, or CD8(-/-)) mice. MHC-I(high) melanoma growth was also reduced in mice lacking TNF-R1, but not TNF-R2. TNF(-/-) and TNF-R1(-/-) mice as well as Etanercept-treated WT mice displayed enhanced intratumor content of high endothelial venules surrounded by high CD8(+) T-cell density. Adoptive transfer of activated TNF-R1-deficient or -proficient CD8(+) T cells in CD8-deficient mice bearing B16K1 tumors demonstrated that TNF-R1 deficiency facilitates the accumulation of live CD8(+) T cells into the tumors. Moreover, in vitro experiments indicated that TNF triggered activated CD8(+) T cell death in a TNF-R1-dependent manner, likely limiting the accumulation of tumor-infiltrating CD8(+) T cells in TNF/TNF-R1-proficient animals. Collectively, our observations indicate that TNF-R1-dependent TNF signaling impairs tumor-infiltrating CD8(+) T-cell accumulation and may serve as a putative target to favor CD8(+) T-cell-dependent immune response in melanoma.
C-C Chemokine Receptor 2 and Sarcoidosis
Authors: Paolo Spagnolo, Elisabetta A. Renzoni, Athol U. Wells, Hiroe Sato, Jan C. Grutters, Piersante Sestini, Atiyeh Abdallah, Enzo Gramiccioni, Henk J. T. Ruven, Roland M. du Bois, Kenneth I. Welsh
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Sarcoidosis is thought to result from the interaction between an unknown environmental antigenic trigger and the host's genetic susceptibility. We hypothesized that sarcoidosis, or one of the disease subsets, could be associated with single nucleotide polymorphisms of C-C chemokine receptor 2 (CCR2) gene. Eight single-nucleotide polymorphisms in CCR2 were studied in a total of 304 Dutch individuals (90 non-Löfgren sarcoidosis, 47 Löfgren's syndrome, 167 control subjects). From the investigated CCR2 polymorphisms, nine haplotypes were deduced (haplotypes 1-9). In patients with Löfgren's syndrome, a strongly significant increase in the frequency of CCR2-haplotype 2, which includes four unique alleles (A at nucleotide position -6752, A at 3,000, T at 3,547, and T at 4,385), was observed compared with control subjects (74% vs. 38% respectively, p < 0.0001), whereas no difference was found between non-Löfgren sarcoidosis and control subjects (both 38%). The association between CCR2-haplotype 2 carriage frequency and Löfgren's syndrome (odds ratio, 4.4; p < 0.0001) remained significant after adjustment for human leukocyte antigen haplotype DRB1*0301-DQB1*0201 (odds ratio, 11.5; p < 0.0001) and female sex (odds ratio, 3.2; p = 0.003), two known risk factors for Löfgren's syndrome. In conclusion, this report describes a strong association between CCR2-haplotype 2 and Löfgren's syndrome. Further studies are needed to understand the molecular mechanisms underlying this association.
Variations in mortality in acute COPD may reflect nihilism as well as resources.
Authors: M J Wildman
Journal: Thorax (2004)

I read with great interest the paper by Roberts et al 1 and the accompanying editorial by Rudolf2. The study highlights important variations in the outcomes of patients with a common chronic disease, and once more illustrates that doctor:patient ratios may be an important contributor to this. It is also likely that some of the observed variation may arise as a result of variations in decision making by individual clinicians.

A recent study carried out in the eight hospitals in the Heart of England Critical Care network interviewed 98 clinicians who made end of life decisions for patients with chronic obstructive pulmonary disease (COPD).3 Each had made a median of 10 end of life decisions for COPD patients in the previous 12 months. There was considerable variability in the decision whether or not to admit identical patients to the critical care unit, with those choosing not to admit patients forming very pessimistic predictions of outcome compared with clinicians who would admit. It seems possible that poor outcomes for patients with COPD may not simply reflect a …
Inhibition of Angiogenesis: Thalidomide or Low-Molecular-Weight Heparin?
Authors: Metin Ozkan, Bulent Eser, Ozlem Er, Gamze Gokoz Dogu, Mustafa Altinbas
Journal: Journal of Clinical Oncology (2005)

TO THE EDITOR: In the July 15, 2004, issue of the Journal of Clinical Oncology, Dahut et al showed that the addition of thalidomide to docetaxel resulted in an encouraging prostatespecific antigen decline and overall median survival rate in patients with metastatic androgen-independent prostate cancer. In this study, low-molecular-weight heparin (LMWH) was offered to patients in the combination arm for median 6 months, but not offered to patients in the control arm. Preclinical evidence suggests that angiogenesis is important for tumor progression in prostate cancer. LMWH inhibits angiogenesis, and this effect seems to be independent of the anticoagulant actions. In a recent randomized study, we tested the effect on patient mortality of a prophylactic dose of LMWH (dalteparin; 5,000 U/d subcutaneously) given in combination with chemotherapy versus chemotherapy alone in patients with small-cell lung cancer (42 patients per group). This trial demonstrated an improvement in overall survival for those patients randomly assigned to receive LMWH. In another recent randomized study, the FAMOUS (Fragmin Advanced Malignancy Outcome Study) Trial, 385 patients with advanced solid cancers were randomly assigned to receive a prophylactic dose of the dalteparin or placebo for up to 1 year. There was suggestion of a marked survival advantage for patients with a better prognosis receiving LMWH therapy. We think that LMWH could provide a therapeutic and survival advantage for patients in the thalidomide arm in the Dahut et al study. To understand whether this survival advantage is depending on thalidomide, the authors should have used LMWH on the control arm as well.
A novel Aβ-fibrinogen interaction inhibitor rescues altered thrombosis and cognitive decline in Alzheimer’s disease mice
Authors: Hyung Jin Ahn, J. Fraser Glickman, Ka Lai Poon, Daria Zamolodchikov, Odella C. Jno-Charles, Erin H. Norris, Sidney Strickland
Journal: The Journal of Experimental Medicine (2014)

Many Alzheimer’s disease (AD) patients suffer from cerebrovascular abnormalities such as altered cerebral blood flow and cerebral microinfarcts. Recently, fibrinogen has been identified as a strong cerebrovascular risk factor in AD, as it specifically binds to β-amyloid (Aβ), thereby altering fibrin clot structure and delaying clot degradation. To determine if the Aβ–fibrinogen interaction could be targeted as a potential new treatment for AD, we designed a high-throughput screen and identified RU-505 as an effective inhibitor of the Aβ–fibrinogen interaction. RU-505 restored Aβ-induced altered fibrin clot formation and degradation in vitro and inhibited vessel occlusion in AD transgenic mice. Furthermore, long-term treatment of RU-505 significantly reduced vascular amyloid deposition and microgliosis in the cortex and improved cognitive impairment in mouse models of AD. Our studies suggest that inhibitors targeting the Aβ–fibrinogen interaction show promise as therapy for treating AD.
Associations between Fine and Coarse Particles and Mortality in Mediterranean Cities: Results from the MED-PARTICLES Project
Authors: Evangelia Samoli, Massimo Stafoggia, Sophia Rodopoulou, Bart Ostro, Christophe Declercq, Ester Alessandrini, Julio Díaz, Angeliki Karanasiou, Apostolos G. Kelessis, Alain Le Tertre, Paolo Pandolfi, Giorgia Randi, Cecilia Scarinzi, Stefano Zauli-Sajani, Klea Katsouyanni, Francesco Forastiere
Journal: Environmental Health Perspectives (2013)

Few studies have investigated the independent health effects of different size fractions of particulate matter (PM) in multiple locations, especially in Europe.We estimated the short-term effects of PM with aerodynamic diameter ≤ 10 μm (PM10), ≤ 2.5 μm (PM2.5), and between 2.5 and 10 μm (PM2.5-10) on all-cause, cardiovascular, and respiratory mortality in 10 European Mediterranean metropolitan areas within the MED-PARTICLES project.We analyzed data from each city using Poisson regression models, and combined city-specific estimates to derive overall effect estimates. We evaluated the sensitivity of our estimates to co-pollutant exposures and city-specific model choice, and investigated effect modification by age, sex, and season. We applied distributed lag and threshold models to investigate temporal patterns of associations.A 10-μg/m3 increase in PM2.5 was associated with a 0.55% (95% CI: 0.27, 0.84%) increase in all-cause mortality (0-1 day cumulative lag), and a 1.91% increase (95% CI: 0.71, 3.12%) in respiratory mortality (0-5 day lag). In general, associations were stronger for cardiovascular and respiratory mortality than all-cause mortality, during warm versus cold months, and among those ≥ 75 versus < 75 years of age. Associations with PM2.5-10 were positive but not statistically significant in most analyses, whereas associations with PM10 seemed to be driven by PM2.5.We found evidence of adverse effects of PM2.5 on mortality outcomes in the European Mediterranean region. Associations with PM2.5-10 were positive but smaller in magnitude. Associations were stronger for respiratory mortality when cumulative exposures were lagged over 0-5 days, and were modified by season and age.
Contaminant-related suppression of delayed-type hypersensitivity and antibody responses in harbor seals fed herring from the Baltic Sea.
Authors: P S Ross, R L De Swart, P J Reijnders, H Van Loveren, J G Vos, A D Osterhaus
Journal: Environmental Health Perspectives (1995)

Recent mass mortalities among several marine mammal populations have led to speculation about increased susceptibility to viral infections as a result of contaminant-induced immunosuppression. In a 2.5-year study, we fed herring from either the relatively uncontaminated Atlantic Ocean or the contaminated Baltic Sea to two groups of captive harbor seals and monitored immune function in the seals. Seals fed the contaminated fish were less able to mount a specific immunological response to ovalbumin, as measured by in vivo delayed-type hypersensitivity (DTH) reactions and antibody responses. The skin reaction to this protein antigen was characterized by the appearance of mononuclear cells which peaked at 24 hr after intradermal administration, characteristic of DTH reactions in other animals studied. These DTH responses correlated well with in vitro tests of T-lymphocyte function, implicating this cell type in the reaction. Aryl-hydrocarbon (Ah) receptor-dependent toxic equivalent (TEQ) profiles in blubber biopsies taken from the seals implicated polychlorinated biphenyls rather than dioxins or furans in the observed immunosuppression. Marine mammal populations currently inhabiting polluted coastal environments in Europe and North America may therefore have an increased susceptibility to infections, and pollution may have played a role in recent virus-induced mass mortalities.