tbuckley/cabot-search huggingface dataset:
Inhibition of Nitric Oxide Synthesis Causes Myocardial Ischemia in Endotoxemic Rats
Authors: J. A. M. Avontuur, H. A. Bruining, C. Ince
Journal: Circulation Research (1995)

Abstract Inhibitors of nitric oxide (NO) synthesis have been used in the treatment of septic and endotoxic shock. However, several studies question the beneficial effect of inhibiting NO production in sepsis and endotoxemia. We have investigated the effect of inhibition of NO synthesis after endotoxemia in the isolated perfused rat heart. In hearts from endotoxin-treated animals, coronary flow was elevated 64% and oxygen consumption was elevated 20% compared with control hearts. NADH fluorescence imaging was used as an indicator of regional hypoperfusion. A homogeneous low-surface NADH fluorescence, indicative of adequate tissue perfusion, was observed in both control and endotoxin-treated hearts. The increase in coronary flow and oxygen consumption could only partially be prevented by pretreatment of the animals with dexamethasone. Addition of N ω -nitro- l -arginine (NNLA), an inhibitor of NO synthesis, to the perfusion medium eliminated differences in coronary flow and oxygen consumption between normal and endotoxin-treated hearts. However, NADH surface fluorescence images of endotoxin-treated hearts after NNLA revealed areas of high fluorescence, indicating local ischemia, whereas the control hearts remained without signs of ischemia. The ischemic areas were present at various perfusion pressures and disappeared after the infusion of l -arginine, the natural precursor of NO, or the exogenous NO donor sodium nitroprusside. Methylene blue (MB), an inhibitor of soluble guanylate cyclase, the effector enzyme of NO, also eliminated differences in coronary flow and produced similar areas of local myocardial ischemia in endotoxin-treated hearts but not in control hearts. Reducing coronary flow by direct vasoconstriction with vasopressin resulted in similar patterns of myocardial ischemia as with NNLA and MB. Our results suggest that the coronary vasodilation in the isolated rat heart after endotoxemia is caused by an increased release of NO. Coronary flow reduction with NNLA, MB, or direct vasoconstriction with vasopressin causes local areas of myocardial ischemia in endotoxin-treated hearts but not in untreated hearts. These data suggest that endotoxemia promotes myocardial ischemia in vulnerable areas of the heart after inhibition of the NO pathway or direct vasoconstriction.
Endothelin induces a nonselective cation current in vascular smooth muscle cells.
Authors: C Chen, P K Wagoner
Journal: Circulation Research (1991)

The potent vasoconstrictor endothelin leads to smooth muscle cell depolarization and increases in intracellular Ca2+. Although effects of endothelin on calcium channels have been described, it also has been speculated that endothelim may activate additional ion channels. The purpose of the present study was to identify an alternative ion current that could play a role in depolarizing cells in response to vasoconstrictors like endothelin and vasopressin. The effects of endothelin, vasopressin, sarafotoxin S6b, and phenylephrine were assessed using whole-cell patch-clamp recordings from primary dissociated rat aortic or mesenteric arterial smooth muscle cells cultured for 24-72 hours. From the usual resting potentials of these cells of -50 to -60 mV, endothelin (1-100 nM) induced a depolarization via an increase in membrane conductance. This depolarization was phasic, oscillating repeatedly from the resting potential to a relatively depolarized level and back to the resting potential. From a holding potential of -60 mV, endothelin-1, endothelin-3, vasopressin, or sarafotoxin S6b (but not phenylephrine) induced transient inward currents that also could be phasic. In external sodium, lithium, or cesium (but not Tris) and in internal potassium or cesium, these currents reversed near 0 mV. Although nifedipine-insensitive, the inward currents were absent in zero calcium, barium, or strontium, or in the presence of cobalt or nickel. These results represent the first report of a nonselective cation current in primary vascular smooth muscle cells that is calcium dependent and that could be responsible for the depolarizations induced from the resting potential by vasoconstrictors such as endothelin.
Clinical and radiological picture of Jaccoud arthropathy in the context of systemic sclerosis
Authors: M-F Spina, L Beretta, M Masciocchi, R Scorza
Journal: Annals of the Rheumatic Diseases (2008)

Jaccoud arthropathy (JA) is a non-erosive, deforming arthropathy of the metacarpophalangeal (MCP) and proximal interphalangeal joints, wrists and knees, first described as a rare complication of recurrent rheumatic fever1 and then extensively observed in systemic lupus erythaematosus (SLE) patients.2 3 Hand deformities present a typical picture of ulnar deviation and subluxation of the MCP, as observed in rheumatoid arthritis (RA). However, in JA, ligament laxity and muscle imbalance rather than the loss of bone and joint instability secondary to synovitis, determine the clinical picture.3 4 This hypothesis has been confirmed in an MRI study, as no signs of synovial …
Tamoxifen Therapy for Breast Cancer and Endometrial Cancer Risk
Authors: L. Bernstein, D. Deapen, J. R. Cerhan, S. M. Schwartz, J. Liff, E. McGann-Maloney, J. A. Perlman, L. Ford
Journal: JNCI Journal of the National Cancer Institute (1999)

Tamoxifen is effective in treating breast cancer, reduces breast cancer incidence among high-risk women, and is associated with increased endometrial cancer risk. This study was designed to examine the possible modifying effects of endometrial cancer risk factors on the tamoxifen-endometrial cancer association.We conducted a case-control study of endometrial cancer (324 case patients and 671 individually matched control subjects) nested within a population-based cohort of patients with breast cancer diagnosed from 1978 through 1992 within four regions of the United States. We obtained information on breast cancer treatment and endometrial cancer risk factors through interviews and reviews of medical records. All P values reported are two-sided.Endometrial cancer risk was associated with tamoxifen therapy for breast cancer (odds ratio = 1.52; 95% confidence interval [CI] = 1. 07-2.17). Risk increased with duration of tamoxifen use (P for trend =.0002). Women with more than 5 years of exposure to tamoxifen had 4. 06-fold greater odds of developing endometrial cancer than nonusers (95% CI = 1.74-9.47). Prior use of estrogen replacement therapy (ERT) increased risk associated with tamoxifen use (P for homogeneity of trends <.0001). Risk associated with tamoxifen use was stronger among heavier women than among thinner women, although trends did not differ statistically (P =.10). Tamoxifen dose-response effects were more pronounced among women with both previous ERT exposure and higher body mass index than among women in other risk groups.ERT use and obesity, both established endometrial cancer risk factors and markers of estrogen exposure, substantially modify the association between tamoxifen use and endometrial cancer risk among patients with breast cancer. Women with positive ERT histories and those who are obese, when prescribed tamoxifen, may warrant closer surveillance for endometrial cancer than women without such histories.
Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioning
Authors: Edward Seung, John P. Mordes, Aldo A. Rossini, Dale L. Greiner
Journal: Journal of Clinical Investigation (2003)

Allogeneic hematopoietic chimerism leading to central tolerance has significant therapeutic potential. Realization of that potential has been impeded by the need for myeloablative conditioning of the host and development of graft-versus-host disease (GVHD). To surmount these impediments, we have adapted a costimulation blockade–based protocol developed for solid organ transplantation for use in stem cell transplantation. The protocol combines donor-specific transfusion (DST) with anti-CD154 mAb. When applied to stem cell transplantation, administration of DST, anti-CD154 mAb, and allogeneic bone marrow leads to hematopoietic chimerism and central tolerance with no myeloablation and no GVHD. Tolerance in this system results from deletion of both peripheral host alloreactive CD8+ T cells and nascent intrathymic alloreactive CD8+ T cells. In the absence of large numbers of host alloreactive CD8+ T cells, the transfusion that precedes transplantation need not be of donor origin, suggesting that both allospecific and non-allospecific mechanisms regulate engraftment. Agents that interfere with peripheral transplantation tolerance impair establishment of chimerism. We conclude that robust allogeneic hematopoietic chimerism and central tolerance can be established in the absence of host myeloablative conditioning using a peripheral transplantation tolerance protocol.
Diagnosis of Metachromatic Leukodystrophy, Krabbe Disease, and Farber Disease after Uptake of Fatty Acid-labeled Cerebroside Sulfate into Cultured Skin Fibroblasts
Authors: Tooru Kudoh, David A. Wenger
Journal: Journal of Clinical Investigation (1982)

[14C]Stearic acid-labeled cerebroside sulfate (CS) was presented to cultured skin fibroblasts in the media. After endocytosis into control cells 86% was readily metabolized to galactosylceramide, ceramide, and stearic acid, which was reutilized in the synthesis of the major lipids found in cultured fibroblasts. Uptake and metabolism of the [14C]CS into cells from typical and atypical patients and carriers of metachromatic leukodystrophy (MLD), Krabbe disease, and Farber disease were observed. Cells from patients with late infantile MLD could not metabolize the CS at all, while cells from an adult MLD patient and from a variant MLD patient could metabolize ∼40 and 15%, respectively, of the CS taken up. These results are in contrast to the in vitro results that demonstrated a severe deficiency of arylsulfatase A in the late infantile and adult patient and a partial deficiency (21-27% of controls) in the variant MLD patient. Patients with Krabbe disease could metabolize nearly 40% of the galactosylceramide produced in the lysosomes from the CS. This is in contrast to the near zero activity for galactosylceramidase measured in vitro. Carriers of Krabbe disease with galactosylceramidase activity near half normal in vitro and those with under 10% of normal activity were found to metabolize galactosylceramide in cells significantly slower than controls. This provides a method for differentiating affected patients from carriers with low enzyme activity in vitro. Cells from patients with Farber disease could catabolize only ∼15% of the ceramide produced from galactosylceramide. This technique provides a method for the identification of typical and atypical patients and carriers of three genetic diseases using one substrate.
Retinol binding protein in normal human skin and in cutaneous disorders
Authors: D. BENOLDI, G. MANFREDI, E. PEZZAROSSA, F. ALLEGRA
Journal: British Journal of Dermatology (1981)

Circulating vitamin A is transported by a carrier termed retinol binding protein (RBP). Autoradiography and immunofluorescence studies showed that, in normal human skin, RBP is confirmed exclusively to the dermis. Following oral vitamin A loading, a large increase in dermal RBP but only a very small rise of serum RBP was found. Serum RBP was slightly decreased in eczema patients and markedly decreased in patients with porphyria cutanea tarda. Values in other dermatoses, including psoriasis, were normal.
High <i>EGFR</i> Gene Copy Number and Skin Rash as Predictive Markers for EGFR Tyrosine Kinase Inhibitors in Patients with Advanced Squamous Cell Lung Carcinoma
Authors: Youngjoo Lee, Hyo Sup Shim, Moo Suk Park, Joo-Hang Kim, Sang-Jun Ha, Se Hoon Kim, Byoung Chul Cho
Journal: Clinical Cancer Research (2012)

Abstract Purpose: This study aimed to search for predictors of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) efficacy in previously treated patients with advanced squamous cell lung carcinoma in which EGFR mutations are very rare. Experimental Design: EGFR gene copy numbers were assessed by FISH and evaluated as predictors of EGFR-TKI efficacy in 71 patients with advanced squamous cell lung cancer who received gefitinib or erlotinib as a second-line or higher therapy. The tumors were classified into EGFR/FISH-positive (high polysomy/gene amplification) and EGFR/FISH-negative (other) groups. Results: EGFR/FISH was positive in 19 (26.7%) patients. Only EGFR/FISH positive status was correlated with the EGFR-TKIs response (EGFR/FISH+ vs. EGFR/FISH−, 26.3% vs. 2.0%; P = 0.005). In a multivariate analysis, the risk of progression was lower in EGFR/FISH-positive patients (HR of EGFR/FISH+ vs. EGFR/FISH−, 0.57; P = 0.057) or patients experiencing grade 2 or more rash (HR for rash grade 2 or more vs. less than 2, 0.54; P = 0.042), compared with EGFR/FISH-negative patients or those experiencing grade of less than 2 rash, respectively. When the combined criteria of EGFR/FISH and skin rash severity were analyzed, EGFR/FISH-negative patients with grade less than 2 rash had poorer clinical outcomes than patients with positive EGFR/FISH or grade 2 or more rash, apparent as a lower response rate (0.0% vs. 21.4%; P = 0.003) and a shorter median progression-free survival (1.13 months vs. 3.90 months; P = 0.0002). Conclusions: EGFR/FISH and skin rash severity may be used to identify which patients are likely to gain a benefit from EGFR-TKIs in this population. Clin Cancer Res; 18(6); 1760–8. ©2012 AACR.
Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis
Authors: Gauri Shishodia, Shirish Shukla, Yogesh Srivastava, Shashank Masaldan, Sumita Mehta, Suresh Bhambhani, Shashi Sharma, Ravi Mehrotra, Bhudev Chandra Das, Alok Chandra Bharti
Journal: Molecular Cancer (2015)

Present study provides clinical evidence of existence of a functional loop involving miR-21 and let-7a as potential regulators of aberrant STAT3 signaling recently reported by our group in an experimental setup (Shishodia et al. BMC Cancer 2014, 14:996). The study is now extended to a set of cervical tissues that represent natural history of human papillomavirus (HPV)-induced tumorigenic transformation. Cervical tissues from histopathologically-confirmed pre-cancer (23) and cancer lesions (56) along with the normal control tissues (23) were examined for their HPV infection status, expression level of miR-21 & let-7a and STAT3 & pSTAT3 (Y705) by PCR-based genotyping, quantitative real-time PCR and immunoblotting. Analysis of cancer tissues revealed an elevated miR-21 and reduced let-7a expression that correspond to the level of STAT3 signaling. While miR-21 showed direct association, let-7a expression was inversely related to STAT3 expression and its activation. In contrast, a similar reciprocal expression kinetics was absent in LSIL and HSIL tissues which overexpressed let-7a. miR-21 was found differentially overexpressed in HPV16-positive lesions with a higher oncoprotein E6 level. Overexpression of miR-21 was accompanied by elevated level of other STAT3-regulated gene products MMP-2 and MMP-9. Enhanced miR-21 was found associated with decreased level of STAT3 negative regulator PTEN and negative regulator of MMPs, TIMP-3. Overall, our study suggests that the microRNAs, miR-21 and let-7a function as clinically relevant integral components of STAT3 signaling and are responsible for maintaining activated state of STAT3 in HPV-infected cells during cervical carcinogenesis.
Granulocyte-Macrophage Colony-Stimulating Factor Gene-Modified Autologous Tumor Vaccines in Non-Small-Cell Lung Cancer
Authors: J. Nemunaitis, D. Sterman, D. Jablons, J. W. Smith, B. Fox, P. Maples, S. Hamilton, F. Borellini, A. Lin, S. Morali, K. Hege
Journal: JNCI Journal of the National Cancer Institute (2004)

To evaluate the feasibility, safety, and efficacy of vaccination with autologous tumor cells genetically modified with an adenoviral vector (Ad-GM) to secrete human granulocyte–macrophage colony-stimulating factor (GM-CSF), we conducted a phase I/II multicenter trial in patients with early and advanced stage non–small-cell lung cancer (NSCLC). Vaccines were generated from autologous tumor harvests. Intradermal injections were given every 2 weeks for a total of three to six vaccinations. Tumors were harvested from 83 patients, 20 with early-stage NSCLC and 63 with advanced- stage NSCLC; vaccines were successfully manufactured for 67 patients, and 43 patients were vaccinated. The most common toxicity was a local injection-site reaction (93%). Three of 33 advanced-stage patients, two with bronchioloalveolar carcinoma, had durable complete tumor responses (lasting 6, 18, and ≥22 months). Longer survival was observed in patients receiving vaccines secreting GM-CSF at more than 40 ng/24 h per 106 cells (median survival = 17 months, 95% confidence interval [CI] = 6 to 23 months) than in patients receiving vaccines secreting less GM-CSF (median survival = 7 months, 95% CI = 4 to 10 months) (P = .028), suggesting a vaccine dose–related survival advantage.
Effects of Fosinopril and Pravastatin on Cardiovascular Events in Subjects With Microalbuminuria
Authors: Folkert W. Asselbergs, Gilles F.H. Diercks, Hans L. Hillege, Ad J. van Boven, Wilbert M.T. Janssen, Adriaan A. Voors, Dick de Zeeuw, Paul E. de Jong, Dirk J. van Veldhuisen, Wiek H. van Gilst
Journal: Circulation (2004)

Microalbuminuria is associated with increased risk of cardiovascular events. We assessed whether therapeutic intervention aimed at lowering urinary albumin excretion would reduce cardiovascular events in microalbuminuric subjects (15 to 300 mg/24 hours).From the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort (n=8592), 1439 subjects fulfilled the inclusion criteria of the PREVEND Intervention Trial (PREVEND IT). Of these subjects, 864 were randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality and hospitalization for cardiovascular morbidity. Mean age was 51+/-12 years; 65% of subjects were male, and 3.4% had a previous cardiovascular event. Mean cholesterol level was 5.8+/-1.0 mmol/L, mean systolic/diastolic blood pressure was 130+/-18/76+/-10 mm Hg, and median urinary albumin excretion was 22.8 (15.8 to 41.3) mg/24 hours. The primary end point occurred in 45 subjects (5.2%). Fosinopril reduced urinary albumin excretion by 26% (P<0.001). Subjects treated with fosinopril showed a 40% lower incidence of the primary end point (hazard ratio 0.60 [95% CI 0.33 to 1.10], P=0.098, log-rank). Pravastatin did not reduce urinary albumin excretion, and subjects treated with pravastatin showed a 13% lower incidence of the primary end point than subjects in the placebo group (0.87 [0.49 to 1.57], P=0.649, log-rank).In microalbuminuric subjects, treatment with fosinopril had a significant effect on urinary albumin excretion. In addition, fosinopril treatment was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.
Hepatitis C virus reinfection after sustained virological response in HIV-infected patients with chronic hepatitis C
Authors: Juan A. Pineda, Rocio Núñez-Torres, Francisco Téllez, María Mancebo, Federico García, Nicolás Merchante, Montserrat Pérez-Pérez, Karin Neukam, Juan Macías, Luis M. Real
Journal: Journal of Infection (2015)
Inhaled and nasal corticosteroids: safety aspects*
Authors: G. Passalacqua, M. Albano, G. W. Canonica, C. Bachert, P. Van Cauwenberge, R. J. Davies, S. R. Durham, K. Kontou‐Fili, F. Horak, H.‐J. Malling
Journal: Allergy (2000)
Diversity in Mitochondrial Function Explains Differences in Vascular Oxygen Sensing
Authors: Evangelos D. Michelakis, Vaclav Hampl, Ali Nsair, XiCheng Wu, Gwyneth Harry, Al Haromy, Rachita Gurtu, Stephen L. Archer
Journal: Circulation Research (2002)

Renal arteries (RAs) dilate in response to hypoxia, whereas the pulmonary arteries (PAs) constrict. In the PA, O 2 tension is detected by an unidentified redox sensor, which controls K + channel function and thus smooth muscle cell (SMC) membrane potential and cytosolic calcium. Mitochondria are important regulators of cellular redox status and are candidate vascular O 2 sensors. Mitochondria-derived activated oxygen species (AOS), like H 2 O 2 , can diffuse to the cytoplasm and cause vasodilatation by activating sarcolemmal K + channels. We hypothesize that mitochondrial diversity between vascular beds explains the opposing responses to hypoxia in PAs versus RAs. The effects of hypoxia and proximal electron transport chain (pETC) inhibitors (rotenone and antimycin A) were compared in rat isolated arteries, vascular SMCs, and perfused organs. Hypoxia and pETC inhibitors decrease production of AOS and outward K + current and constrict PAs while increasing AOS production and outward K + current and dilating RAs. At baseline, lung mitochondria have lower respiratory rates and higher rates of AOS and H 2 O 2 production. Similarly, production of AOS and H 2 O 2 is greater in PA versus RA rings. SMC mitochondrial membrane potential is more depolarized in PAs versus RAs. These differences relate in part to the lower expression of proximal ETC components and greater expression of mitochondrial manganese superoxide dismutase in PAs versus RAs. Differential regulation of a tonically produced, mitochondria-derived, vasodilating factor, possibly H 2 O 2 , can explain the opposing effects of hypoxia on the PAs versus RAs. We conclude that the PA and RA have different mitochondria.
Epitope mapping of inhibitory antibodies against platelet glycoprotein Ibα reveals interaction between the leucine-rich repeat N-terminal and C-terminal flanking domains of glycoprotein Ibα
Authors: Nancy Cauwenberghs, Karen Vanhoorelbeke, Stephan Vauterin, Douwe F. Westra, Gabriel Romo, Eric G. Huizinga, José A. Lopez, Michael C. Berndt, Jolàn Harsfalvi, Hans Deckmyn
Journal: Blood (2001)
Value of C reactive protein in the assessment of erosive osteoarthritis of the hand
Authors: L Punzi
Journal: Annals of the Rheumatic Diseases (2005)

To investigate the value of serum C reactive protein (CRP) as a marker of erosive osteoarthritis (EOA) of the hand.Ninety eight patients, 67 with EOA and 31 with non-EOA of the hand, were included in the study and analysed for radiographic score (RS), number of erosions, and joint count (JC) at clinical observation and at bone scintigraphy. CRP was assayed in a serum sample by a highly sensitive immunonephelometric method.The median (interquartile range) CRP level was 4.7 (2.4-6.9) mg/l in the EOA and 2.1 (0.5-4.9) mg/l in the non-EOA group (p = 0.001). In all patients, CRP correlated with RS (r(s) = 0.43, p<0.001), and mainly with JC at clinical observation (r(s) = 0.72, p<0.001) and at bone scintigraphy (r(s) = 0.47, p<0.001). The correlation of CRP with RS and JC was confirmed at clinical observation and at bone scintigraphy in the EOA subgroup, but only with JC at clinical observation in the non-EOA subgroup.CRP levels are higher in EOA than in non-EOA patients. These levels probably reflect the disease activity of EOA, as suggested by correlations between CRP and JC at clinical observation and at bone scintigraphy.