tbuckley/cabot-search huggingface dataset:
Endotoxin-Induced Cardiomyopathy and Systemic Inflammation in Mice Is Prevented by Aldose Reductase Inhibition
Authors: Kota V. Ramana, Monte S. Willis, Michael D. White, Jureta W. Horton, J. Michael DiMaio, Deepak Srivastava, Aruni Bhatnagar, Satish K. Srivastava
Journal: Circulation (2006)

Sepsis is a systemic inflammatory response syndrome characterized by excessive production of inflammatory cytokines and cardiovascular collapse. Postreceptor signaling events that lead to stress responses and cytokine production are sensitive to redox changes and products of lipid peroxidation.We tested the hypothesis that inflammatory signaling and cytokine generation during sepsis depend on the activity of the enzyme aldose reductase, which catalyzes the reduction of lipid peroxidation-derived aldehydes and their glutathione conjugates. The results of the present study show that pharmacological inhibition of aldose reductase by sorbinil or knockdown of the enzyme by small interfering RNA prevents the activation of nuclear factor-kappaB and the release of tumor necrosis factor-alpha from lipopolysaccharide-stimulated RAW264.7 or H9c2 cells. Increases in serum and cardiac cytokines in response to lipopolysaccharide challenge were suppressed by inhibition of aldose reductase. Treatment with sorbinil blunted the activation of protein kinase C, c-Jun NH2-terminal kinase, and p38, as well as phosphorylation of interleukin receptor-associated kinase, IkappaB-alpha, IkappaB kinase complex-alpha/beta, and phospholipase-gamma1 and -beta1. These changes were associated with decreased myocardial nuclear factor-kappaB and activating protein-1 activity, prostaglandin E2 production, induction of cyclooxygenase 2, and inducible nitric oxide synthase. Sorbinil treatment also induced functional recovery in myocardial fractional shortening in vivo and preserved contractile function of isolated perfused hearts. Inhibition of aldose reductase increased survival in mice injected with lethal doses of lipopolysaccharide.The present demonstration that aldose reductase mediates endotoxin-induced inflammation and cardiomyopathy suggests that inhibition of this enzyme may be useful to attenuate maladaptive host responses and to treat acute cardiovascular dysfunction associated with endotoxic shock.
In Situ Vaccination With a TLR9 Agonist Induces Systemic Lymphoma Regression: A Phase I/II Study
Authors: Joshua D. Brody, Weiyun Z. Ai, Debra K. Czerwinski, James A. Torchia, Mia Levy, Ranjana H. Advani, Youn H. Kim, Richard T. Hoppe, Susan J. Knox, Lewis K. Shin, Irene Wapnir, Robert J. Tibshirani, Ronald Levy
Journal: Journal of Clinical Oncology (2010)

Combining tumor antigens with an immunostimulant can induce the immune system to specifically eliminate cancer cells. Generally, this combination is accomplished in an ex vivo, customized manner. In a preclinical lymphoma model, intratumoral injection of a Toll-like receptor 9 (TLR9) agonist induced systemic antitumor immunity and cured large, disseminated tumors.We treated 15 patients with low-grade B-cell lymphoma using low-dose radiotherapy to a single tumor site and-at that same site-injected the C-G enriched, synthetic oligodeoxynucleotide (also referred to as CpG) TLR9 agonist PF-3512676. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro restimulation with autologous tumor cells.This in situ vaccination maneuver was well-tolerated with only grade 1 to 2 local or systemic reactions and no treatment-limiting adverse events. One patient had a complete clinical response, three others had partial responses, and two patients had stable but continually regressing disease for periods significantly longer than that achieved with prior therapies. Vaccination induced tumor-reactive memory CD8 T cells. Some patients' tumors were able to induce a suppressive, regulatory phenotype in autologous T cells in vitro; these patients tended to have a shorter time to disease progression. One clinically responding patient received a second course of vaccination after relapse resulting in a second, more rapid clinical response.In situ tumor vaccination with a TLR9 agonist induces systemic antilymphoma clinical responses. This maneuver is clinically feasible and does not require the production of a customized vaccine product.
Gray platelet syndrome: natural history of a large patient cohort and locus assignment to chromosome 3p
Authors: Meral Gunay-Aygun, Yifat Zivony-Elboum, Fatma Gumruk, Dan Geiger, Mualla Cetin, Morad Khayat, Robert Kleta, Nehama Kfir, Yair Anikster, Judith Chezar, Mauricio Arcos-Burgos, Adel Shalata, Horia Stanescu, Joseph Manaster, Mutlu Arat, Hailey Edwards, Andrew S. Freiberg, P. Suzanne Hart, Lauren C. Riney, Katherine Patzel, Pranoot Tanpaiboon, Tom Markello, Marjan Huizing, Irina Maric, McDonald Horne, Beate E. Kehrel, Kerstin Jurk, Nancy F. Hansen, Praveen F. Cherukuri, Marypat Jones, Pedro Cruz, Jim C. Mullikin, Alan Nurden, James G. White, William A. Gahl, Tzippora Falik-Zaccai
Journal: Blood (2010)
The Surveillance, Epidemiology, and End-Results Program Database as a Resource for Conducting Descriptive Epidemiologic and Clinical Studies
Authors: Linda C. Harlan, Benjamin F. Hankey
Journal: Journal of Clinical Oncology (2003)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.94.023 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12805320 The Surveillance, Epidemiology, and End-Results Program Database as a Resource for Conducting Descriptive Epidemiologic and Clinical Studies Linda C. HarlanxLinda C. HarlanSearch for articles by this author , Benjamin F. HankeyxBenjamin F. HankeySearch for articles by this author Show More National Cancer Institute, Bethesda, MD https://doi.org/10.1200/JCO.2003.94.023 Full Text PDF Figures and Tables "The Surveillance, Epidemiology, and End-Results Program Database as a Resource for Conducting Descriptive Epidemiologic and Clinical Studies." Journal of Clinical Oncology, 21(12), pp. 2232–2233© 2003 by American Society of Clinical Oncology
Supplemental dietary nitrate for COPD: A randomized, double-blind, placebo-controlled, crossover trial
Authors: Conor Kerley, Kathleen Cahill, Kenneth Bolger, John Faul, Conor Burke, Liam Cormican
Journal: European Respiratory Journal (2013)

Introduction: Nitric oxide (NO) is an important systemic and pulmonary arterial vasodilator. The conversion of nitrite (derived from dietary nitrate) to nitric oxide can occur independent of nitric oxide synthase in a process that is upregulated in hypoxic conditions. Since COPD patients commonly suffer hypoxaemia during exercise, we hypothesized that dietary nitrate supplementation might acutely improve exercise capacity in hypoxic COPD patients through enhanced production of nitric oxide.

Aims & objectives: We wanted to compare the effect of a single drink of beetroot juice (containing 14 mmol of nitrate) on exercise capacity (incremental shuttle walk test) and arterial blood pressure (BP) in COPD patients compared to a matched placebo drink (containing less than 0.5mmol of dietary nitrate).

Methods: Twelve subjects (6 male) with COPD were recruited. Plasma nitrate and BP were assessed. Oximetry and self-reported dysnoea (Borg scale) were assessed pre- and post-incremental shuttle walk test (ISWT). Subjects were then randomized to drink beetroot juice or a matched placebo and the protocol was repeated 3 hours later. After a 7-day washout period, the protocol was repeated with the crossover beverage.

Results: COPD subjects who took dietary nitrate walked significantly further than when they took placebo (+23 ± 9 vs. -13 ± 5 metres; p < 0.01) and had a reduction in systolic BP (-13 ± 5 vs. 0 ± 1 mmHg; p < 0.05)

Conclusion: Acute consumption of dietary nitrate can improve exercise tolerance and lower blood pressure in COPD patients.
Cardiac A2 adenosine receptors - influence of ischaemia
Authors: R. Zucchi, S. Ronca-Testoni, P. Galbani, G. Yu, M. Mariani, G. Ronca
Journal: Cardiovascular Research (1992)

Objective: The aim was to detect cardiac A2 adenosine receptors through radioligand binding, and to assess the effect of ischaemia on these receptors. Methods: Isolated working rat hearts were subjected either to aerobic perfusion or to global ischaemia. A membrane fraction was prepared from ventricular tissue, and 3H-5'-N-ethylcarboxamide adenosine (NECA) binding was determined in the presence of N6-cyclopentyl adenosine (CPA). A2 binding was calculated as the fraction of NECA binding displaced by 100 μM CPA but not displaced by 50 nM CPA. Results: Analysis of A2 NECA binding according to single binding site model yielded Kd=22.0 nM, Bmax=34.0 fmol·mg−1 in control hearts; Kd=49.7 nM, Bmax=44.3 fmol·mg−1 in hearts subjected to 30 min ischaemia (p<0.05 for difference in Kd). In the control group a two site model provided a significantly (p<0.05) better fit (Kd=5.6 and 183.7 nM, Bmax=9.5 and 64.4 fmol·mg−1 for the high and low affinity sites respectively). The high affinity component of A2 NECA binding disappeared in the presence of the GTP analogue guanyl-5'-yl imidodiphosphate, suggesting the existence of multiple coupling states of the receptor. In the ischaemic group no significant improvement in data fitting was obtained with the two site model. Conclusions: The results provide evidence of the existence of cardiac A2 adenosine receptors. Ischaemia modifies receptor properties and appears to affect chiefly the high affinity component of A2 binding, possibly by preventing receptor interaction with membrane G proteins.
Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.
Authors: F C Schmalstieg, W J Leonard, M Noguchi, M Berg, H E Rudloff, R M Denney, S K Dave, E G Brooks, A S Goldman
Journal: Journal of Clinical Investigation (1995)

Clinical and immunologic features of a recently recognized X-linked combined immunodeficiency disease (XCID) suggested that XCID and X-linked severe combined immunodeficiency (XSCID) might arise from different genetic defects. The recent discovery of mutations in the common gamma chain (gamma c) gene, a constituent of several cytokine receptors, in XSCID provided an opportunity to test directly whether a previously unrecognized mutation in this same gene was responsible for XCID. The status of X chromosome inactivation in blood leukocytes from obligate carriers of XCID was determined from the polymorphic, short tandem repeats (CAG), in the androgen receptor gene, which also contains a methylation-sensitive HpaII site. As in XSCID, X-chromosome inactivation in obligate carriers of XCID was nonrandom in T and B lymphocytes. In addition, X chromosome inactivation in PMNs was variable. Findings from this analysis prompted sequencing of the gamma c gene in this pedigree. A missense mutation in the region coding for the cytoplasmic portion of the gamma c gene was found in three affected males but not in a normal brother. Therefore, this point mutation in the gamma c gene leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID.
Age-related differences in the pathogenesis of chronic rhinosinusitis
Authors: Seong H. Cho, Seung J. Hong, Brian Han, Sun H. Lee, Lydia Suh, James Norton, David Lin, David B. Conley, Rakesh Chandra, Robert C. Kern, Bruce K. Tan, Atsushi Kato, Anju Peters, Leslie C. Grammer, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2012)
Initial Steroid Sensitivity in Children with Steroid-Resistant Nephrotic Syndrome Predicts Post-Transplant Recurrence
Authors: Wen Y. Ding, Ania Koziell, Hugh J. McCarthy, Agnieszka Bierzynska, Murali K. Bhagavatula, Jan A. Dudley, Carol D. Inward, Richard J. Coward, Jane Tizard, Christopher Reid, Corinne Antignac, Olivia Boyer, Moin A. Saleem
Journal: Journal of the American Society of Nephrology (2014)

Of children with idiopathic nephrotic syndrome, 10%-20% fail to respond to steroids or develop secondary steroid resistance (termed initial steroid sensitivity) and the majority progress to transplantation. Although 30%-50% of these patients suffer disease recurrence after transplantation, with poor long-term outcome, no reliable indicator of recurrence has yet been identified. Notably, the incidence of recurrence after transplantation appears reduced in patients with steroid-resistant nephrotic syndrome (SRNS) due to monogenic disorders. We reviewed 150 transplanted patients with SRNS to identify biomarkers that consistently predict outcome of SRNS after transplantation. In all, 25 children had genetic or familial SRNS and did not experience post-transplant recurrence. We reviewed phenotypic factors, including initial steroid sensitivity, donor type, age, ethnicity, time to ESRD, and time on dialysis, in the remaining 125 children. Of these patients, 57 (45.6%) developed post-transplant recurrence; 26 of 28 (92.9%) patients with initial steroid sensitivity recurred after transplantation, whereas only 26 of 86 (30.2%) patients resistant from the outset recurred (odds ratio, 30; 95% confidence interval, 6.62 to 135.86; P<0.001). We were unable to determine recurrence in two patients (one with initial steroid sensitivity), and nine patients did not receive initial steroids. Our data show that initial steroid sensitivity is highly predictive of post-transplant disease recurrence in this pediatric patient population. Because a pathogenic circulating permeability factor in nephrotic syndrome remains to be confirmed, we propose initial steroid sensitivity as a surrogate marker for post-transplant recurrence.
Upregulation of atrial natriuretic peptide gene expression in remnant kidney of rats with reduced renal mass.
Authors: K Totsune, H S Mackenzie, H Totsune, J L Troy, J Lytton, B M Brenner
Journal: Journal of the American Society of Nephrology (1998)

Atrial natriuretic peptide (ANP) is synthesized in the kidney but its physiologic significance there is unclear. To determine whether renal expression of the ANP gene is regulated, renal ANP mRNA expression was assessed in remnant kidneys after 5/6 nephrectomy in Munich-Wistar rats. In normal sodium intake groups, ANP mRNA expression in the remnant kidney was significantly increased by 5.0 +/- 0.8-fold (n = 7, mean +/- SEM) at 4 d when compared with sham-operated controls (n = 6, all sham-operated groups) (*P < 0.001 by Scheffe's test) and by 28.3 +/- 5.1-fold at 14 d. This latter response was markedly diminished to 7.6 +/- 2.1-fold (n = 7, versus sham) in rats maintained on a low sodium diet. At 4 d, on the other hand, no significant downregulation was observed with dietary sodium restriction. Because natriuretic peptides have previously been shown by us to play a major role in the adaptive responses of remnant nephrons to renal mass ablation, these data suggest that ANP of renal origin may contribute to the overall mechanism for enhancing sodium excretion in the face of declining nephron number.
Chemical Probes of Endocannabinoid Metabolism
Authors: Jacqueline L. Blankman, Benjamin F. Cravatt
Journal: Pharmacological Reviews (2013)

The endocannabinoid signaling system regulates diverse physiologic processes and has attracted considerable attention as a potential pharmaceutical target for treating diseases, such as pain, anxiety/depression, and metabolic disorders. The principal ligands of the endocannabinoid system are the lipid transmitters <i>N</i>-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which activate the two major cannabinoid receptors, CB1 and CB2. Anandamide and 2-AG signaling pathways in the nervous system are terminated by enzymatic hydrolysis mediated primarily by the serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. In this review, we will discuss the development of FAAH and MAGL inhibitors and their pharmacological application to investigate the function of anandamide and 2-AG signaling pathways in preclinical models of neurobehavioral processes, such as pain, anxiety, and addiction. We will place emphasis on how these studies are beginning to discern the different roles played by anandamide and 2-AG in the nervous system and the resulting implications for advancing endocannabinoid hydrolase inhibitors as next-generation therapeutics.
Primary human CD34+ hematopoietic stem and progenitor cells express functionally active receptors of neuromediators
Authors: Ulrich Steidl, Simone Bork, Sebastian Schaub, Oliver Selbach, Janette Seres, Manuel Aivado, Thomas Schroeder, Ulrich-Peter Rohr, Roland Fenk, Slawomir Kliszewski, Christian Maercker, Peter Neubert, Stefan R. Bornstein, Helmut L. Haas, Guido Kobbe, Daniel G. Tenen, Rainer Haas, Ralf Kronenwett
Journal: Blood (2004)
Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: Evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis
Authors: Michel Niederberger, Pere Ginès, Phoebe Tsai, Pierre-Yves Martin, Kenneth Morris, André Weigert, Ivan McMurtry, Robert W. Schrier
Journal: Hepatology (1995)

Arterial vasodilation is considered to be the key factor in the development of sodium and water retention leading to ascites formation in cirrhosis. To determine if nitric oxide (NO) is involved in the pathogenesis of arterial vasodilation in cirrhosis, we measured the concentration of cyclic guanosine monophosphate (cGMP), the second messenger of NO, in arterial tissue from rats with carbon tetrachloride-induced cirrhosis. Aortic cGMP concentration was markedly increased in cirrhotic rats, particularly in those with ascites (ascites, 826 +/- 70; no ascites, 597 +/- 48; controls, 331 +/- 25 fmol/mg, ANOVA F = 23.1, P < .0001), and correlated inversely with arterial pressure (r = -.56, P < .0001) and systemic vascular resistance (r = -.69, P = .014) and directly with cardiac index (r = .74, P < .01). The chronic administration of the NO synthesis inhibitor NG-nitro-L-arginine-methyl-ester (L-NAME) (10 mg/kg/day for 7 days) induced a marked reduction in aortic cGMP concentration in cirrhotic rats with ascites to similar values obtained in L-NAME-treated control rats (86 +/- 14 vs. 89 +/- 8 fmol/mg, respectively, NS), indicating that the high-aortic cGMP content in cirrhotic rats was caused by an increased NO synthesis. Mean arterial pressure after L-NAME treatment increased to similar values in both groups of animals. These results suggest that in cirrhosis there is an increased vascular production of NO that may play a role in the pathogenesis of arterial vasodilation.
Effect of BRCA1 and BRCA2 on the Association Between Breast Cancer Risk and Family History
Authors: E. B. Claus, J. Schildkraut, E. S. Iversen, D. Berry, G. Parmigiani
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: The discovery of BRCA1 and BRCA2 has led to a reassessment of the association between family history of breast/ovarian cancer and breast cancer risk after controlling for carrier status for mutations in the BRCA1 and BRCA2 genes. We examined whether family history of breast cancer remains a predictive risk factor for this disease after carrier status for BRCA1 and/or BRCA2 mutations is taken into consideration. Methods: The data are from 4730 case subjects with breast cancer and 4688 control subjects enrolled in the Cancer and Steroid Hormone Study. The probability of being a BRCA1 and/or BRCA2 gene carrier was calculated for each woman. Among predicted noncarriers, logistic regression was used to assess the relationship (odds ratios and 95% confidence intervals [CIs]) between case or control status and family history of breast or ovarian cancer. Estimates of age-specific breast cancer risk are presented by predicted carrier status. Results: Among predicted noncarriers, case subjects were 2.06 times (95% CI = 1.69-2.50) and 1.24 times (95% CI = 1.17-1.32) more likely to report a firstdegree or second-degree family history of breast cancer, respectively, than were control subjects. Case subjects were 1.99 times (95% CI = 1.63-2.44), 1.66 times (95% CI = 1.18-2.38), and 2.23 times (95% CI = 0.21-24.65) more likely to report an affected mother, sister, or both, respectively, than were control subjects. A family history of ovarian cancer was not statistically significantly associated with breast cancer risk. Noncarriers were predicted to have a lifetime risk of 9% of developing breast cancer compared with a 63% risk for carriers. Conclusions: Among women with a moderate family history of breast cancer, i.e., predicted noncarriers of BRCA1 and/or BRCA2 mutations, family history remains a factor in predicting breast cancer risk. In families with breast and ovarian cancers, the aggregation of these two cancers appears to be explained by BRCA1/BRCA2 mutation-carrier probability.
Permuted tRNA Genes in the Nuclear and Nucleomorph Genomes of Photosynthetic Eukaryotes
Authors: S. Maruyama, J. Sugahara, A. Kanai, H. Nozaki
Journal: Molecular Biology and Evolution (2009)

Transfer RNA (tRNA) is a central genetic element in the decoding of genome information for all of Earth's life forms. Nevertheless, there are a great number of missing tRNAs that have been left without examination, especially in microbial genomes. Two tRNA gene families remarkable in their structure and expression mechanism have been reported: split and permuted tRNAs. Split tRNAs in archaea are encoded on the genome as two or three fragmented genes and then processed into single tRNA molecules. Permuted tRNAs are organized with the 5' and 3' halves of the gene positioned in reverse on the genome and hitherto have been found only in one tiny red alga. Here we reveal a wide-ranging distribution of permuted tRNA genes in the genomes of photosynthetic eukaryotes. This includes in the smallest eukaryotic genome known to date, the nucleomorph genome of the chlorarachniophyte alga Bigelowiella natans. Comparison between cDNA and genomic DNA sequences of two nucleomorph-encoded tRNA(Ser) genes confirms that precursors are circularized and processed into mature tRNA molecules in vivo. In the tRNA(Ser)(AGA), adenine at the wobble position of the codon is likely modified to inosine to expand capacity of the codon recognition. We also show the presence of permuted tRNAs in the ultrasmall free-living green algae Ostreococcus and Micromonas, which are closely related to the B. natans nucleomorph. Conserved intron/leader sequence structures in the intron-containing and permuted tRNAs suggest the ancient origin of the splicing machinery in the common ancestor of eukaryotes and archaea. Meanwhile, a wide but patchy distribution of permuted tRNA genes in the photosynthetic eukaryotes implies that extant permuted tRNAs might have emerged multiple times. Taken together, our data demonstrate that permuted tRNA is an evolutionarily conserved and fundamental element in tiny eukaryotic genomes.
A Sex-Specific Marker Reveals Male Heterogamety in European Tree Frogs
Authors: L. Berset-Brandli
Journal: Molecular Biology and Evolution (2006)

Most amphibians examined so far show undifferentiated sex chromosomes. The heterogametic sex's identity, usually revealed through indirect means, often varies among closely related species or even populations (as do sex-linkage groups), suggesting great evolutionary instability of the sex-determining genes. Here we take advantage of a sex-specific marker that amplifies in several related species of European tree frogs (Hyla arborea group) to disclose a homogeneous pattern of male heterogamety. Besides relevance for evolutionary studies of sex determination in amphibians, our results have potential for addressing practical issues in conservation biology because sex reversal by anthropogenic endocrine disruptors is considered one possible cause of amphibian decline.