tbuckley/cabot-search huggingface dataset:
Superoxide dismutase enhances ischemia-induced reactive hyperemic flow and adenosine release in dogs. A role of 5'-nucleotidase activity.
Authors: M Kitakaze, M Hori, S Takashima, K Iwai, H Sato, M Inoue, A Kitabatake, T Kamada
Journal: Circulation Research (1992)

To test the hypothesis that 5'-nucleotidase activity during ischemia is attenuated by oxygen-derived free radicals, we measured ischemia-induced reactive hyperemic flow, adenosine release, and 5'-nucleotidase activity in dogs (n = 62). A 1-minute occlusion of the coronary artery caused reactive hyperemic flow (307 +/- 5 versus 92 +/- 1 ml.100 g-1.min-1 at baseline) with increased release of adenosine (14.4 +/- 1.4 versus 0.4 +/- 0.1 nmol.100 g-1.min-1 at baseline). Superoxide dismutase augmented (p less than 0.001) both peak coronary blood flow (333 +/- 6 ml.100 g-1.min-1) and repayment (436 +/- 12 versus 320 +/- 7 ml/100 g in the untreated group). Adenosine release during reperfusion was augmented (22.7 +/- 1.9 nmol.100 g-1.min-1, p less than 0.001), and 8-phenyltheophylline completely abolished the enhanced reactive hyperemia. Enzymatic assay of 5'-nucleotidase activity revealed that the administration of superoxide dismutase increases ecto-5'-nucleotidase activity in ischemic myocardium. When an inhibitor of ecto-5'-nucleotidase, alpha, beta-methyleneadenosine 5'-diphosphate, was administered, the effects of superoxide dismutase were completely abolished. Thus, we conclude that 1) the augmentation of reactive hyperemic flow caused by superoxide dismutase is attributed to the enhanced release of adenosine and 2) the enhanced release of adenosine over the untreated controls is attributed to the protection of ecto-5'-nucleotidase activity during ischemia.
Posterior Pericardial Ascending-to-Descending Aortic Bypass
Authors: Heidi M. Connolly, Hartzell V. Schaff, Uzi Izhar, Joseph A. Dearani, Carole A. Warnes, Thomas A. Orszulak
Journal: Circulation (2001)

Coarctation of the aorta is commonly associated with recoarctation or additional cardiovascular disorders that require intervention. The best surgical approach in such patients is uncertain. Ascending-to-descending aortic bypass graft via the posterior pericardium (CoA bypass) allows simultaneous intracardiac repair or an alternative approach for the patient with complex coarctation.Between 1985 and 2000, 18 patients (13 males and 5 females, mean age 43+/-13 years) with coarctation of the aorta underwent CoA bypass through median sternotomy. Before operation, average New York Heart Association class was II (range I to IV), and 15 patients (83%) had systemic hypertension. One or more previous cardiovascular operations had been performed in 12 patients (67%); 10 patients had >/=1 prior coarctation repair. Two patients had prior noncoarctation cardiovascular surgery. Concomitant procedures performed in 14 patients (78%) included the following: aortic valve replacement in 9; coronary artery bypass surgery in 3; mitral valve repair in 2; and septal myectomy, mitral valve replacement, aortoplasty, subaortic stenosis resection, ventricular septal defect closure, and ascending aorta replacement in 1 patient each. All patients survived the operation and were alive with patent CoA bypass at a mean follow-up of 45 months. No graft-related complications occurred, and there were no instances of stroke or paraplegia. Systolic blood pressure fell from 159 mm Hg before surgery to 125 mm Hg after surgery.CoA bypass via median sternotomy can be performed with low morbidity and mortality. Although management must be individualized, extra-anatomic CoA bypass via the posterior pericardium is an excellent single-stage approach for patients with complex coarctation or recoarctation and concomitant cardiovascular disorders.
A Single Determinant Dominates the Rate of Yeast Protein Evolution
Authors: D. Allan Drummond, Alpan Raval, Claus O. Wilke
Journal: Molecular Biology and Evolution (2005)

A gene's rate of sequence evolution is among the most fundamental evolutionary quantities in common use, but what determines evolutionary rates has remained unclear. Here, we carry out the first combined analysis of seven predictors (gene expression level, dispensability, protein abundance, codon adaptation index, gene length, number of protein-protein interactions, and the gene's centrality in the interaction network) previously reported to have independent influences on protein evolutionary rates. Strikingly, our analysis reveals a single dominant variable linked to the number of translation events which explains 40-fold more variation in evolutionary rate than any other, suggesting that protein evolutionary rate has a single major determinant among the seven predictors. The dominant variable explains nearly half the variation in the rate of synonymous and protein evolution. We show that the two most commonly used methods to disentangle the determinants of evolutionary rate, partial correlation analysis and ordinary multivariate regression, produce misleading or spurious results when applied to noisy biological data. We overcome these difficulties by employing principal component regression, a multivariate regression of evolutionary rate against the principal components of the predictor variables. Our results support the hypothesis that translational selection governs the rate of synonymous and protein sequence evolution in yeast.
Association of Insulin Resistance and Inflammation With Peripheral Arterial Disease
Authors: Reena L. Pande, Todd S. Perlstein, Joshua A. Beckman, Mark A. Creager
Journal: Circulation (2008)

Although the role of inflammation in the pathophysiology of peripheral arterial disease (PAD) is well established, the contribution of insulin resistance (IR) to PAD is less clear. We hypothesized that IR is associated with PAD and that the presence of IR would influence the association between C-reactive protein (CRP) and PAD, an association established predominantly in healthy individuals.We analyzed data from 3242 adults in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004 who underwent measurement of ankle brachial index, CRP, and fasting glucose and insulin, enabling calculation of homeostasis model of IR (HOMA-IR). Odds ratios (ORs) and 95% CIs were estimated by logistic regression. The mean prevalence of PAD (defined as an ankle brachial index </=0.9) was 5.5% (SE, 0.47%). HOMA-IR was independently associated with PAD (OR, 2.06; 95% CI, 1.1 to 4.0; P=0.03 for quartile 4, P for trend across quartiles=0.047) after adjustment for age, gender, race/ethnicity, hypertension, hyperlipidemia, smoking, body mass index, chronic kidney disease, and CRP. Elevated CRP (>3 mg/L) also was strongly associated with PAD (OR, 2.2; 95% CI, 1.3 to 3.6; P=0.003 versus CRP <1 mg/L). Stratifying subjects on the basis of median HOMA-IR, we found that CRP >3 mg/L was no longer significantly associated with PAD in subjects with IR (OR, 1.3; 95% CI, 0.8 to 2.1; P=0.3, P for interaction=0.08).These findings demonstrate that IR is strongly and independently associated with PAD. Furthermore, IR modifies the association of inflammation with PAD. These data establish a role of IR in PAD and highlight the relative importance of inflammation in patients with and without IR.
NEONICOTINOID INSECTICIDE TOXICOLOGY: Mechanisms of Selective Action
Authors: Motohiro Tomizawa, John E. Casida
Journal: The Annual Review of Pharmacology and Toxicology (2004)

The neonicotinoids, the newest major class of insecticides, have outstanding potency and systemic action for crop protection against piercing-sucking pests, and they are highly effective for flea control on cats and dogs. Their common names are acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam. They generally have low toxicity to mammals (acute and chronic), birds, and fish. Biotransformations involve some activation reactions but largely detoxification mechanisms. In contrast to nicotine, epibatidine, and other ammonium or iminium nicotinoids, which are mostly protonated at physiological pH, the neonicotinoids are not protonated and have an electronegative nitro or cyano pharmacophore. Agonist recognition by the nicotinic receptor involves cation-pi interaction for nicotinoids in mammals and possibly a cationic subsite for interaction with the nitro or cyano substituent of neonicotinoids in insects. The low affinity of neonicotinoids for vertebrate relative to insect nicotinic receptors is a major factor in their favorable toxicological profile.
Hepatitis C virus and mixed cryoglobulinaemias
Authors: Massimo Galli, Giuseppe Monti, Angelo Monteverde, Fulvio Invernizzi, Maurizio Pietrogrande, Marco Di Girolamo, Cesare Mazzaro, Sergio Migliaresi, Cirillo Mussini, Elena Ossi, Piero Renoldi
Journal: The Lancet (1992)
Extracellular Matrix Metalloproteinase Inducer Up-regulates the Urokinase-Type Plasminogen Activator System Promoting Tumor Cell Invasion
Authors: Cathy Quemener, Eric E. Gabison, Benyoussef Naïmi, Géraldine Lescaille, Faten Bougatef, Marie Pierre Podgorniak, Géraldine Labarchède, Celeste Lebbé, Fabien Calvo, Suzanne Menashi, Samia Mourah
Journal: Cancer Research (2007)

Abstract Extracellular matrix metalloproteinase inducer (EMMPRIN) is a membrane glycoprotein overexpressed in many cancer tissues and is known for its ability to stimulate MMP expression. In this work, we show that EMMPRIN is also a regulator of the urokinase-type plasminogen activation (uPA) system of serine proteases, thus participating to the increase of the overall proteolytic function of the cancer cells. Enhanced EMMPRIN expression in a tumorigenic breast epithelial cell line NS2T2A increased the levels of uPA, uPA receptor, and the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1), as measured by quantitative reverse transcription-PCR, Western blot, and plasminogen-casein zymography. This response was down-regulated by either EMMPRIN small interfering RNA or a blocking antibody to EMMPRIN. EMMPRIN-containing purified membrane fraction from Chinese hamster ovary cells when added exogenously to NS2T2A cells induced a similar activation of the uPA/PAI-1 system. Additionally, overexpression of EMMPRIN in NS2T2A cells increased uPA levels in cocultured endothelial cells, showing a paracrine regulation loop involving a tumor-stroma interaction. EMMPRIN-expressing cells also exhibited enhanced invasive potential in vitro, and the use of amiloride (uPA inhibitor) and marimastat (MMP inhibitor) showed that the two proteolytic systems reduced alone and in combination the invasive potential mediated through EMMPRIN. These data show a novel regulatory pathway for uPA activity and suggest that EMMPRIN is involved in uPA dysregulation observed in cancer. [Cancer Res 2007;67(1):9–15]
Upregulation of FcϵRI on human basophils by IgE antibody is mediated by interaction of IgE with FcϵRI
Authors: Donald MacGlashan, Lawrence M. Lichtenstein, Jane McKenzie-White, Kristin Chichester, Alistair J. Henry, Brian J. Sutton, Hannah J. Gould
Journal: Journal of Allergy and Clinical Immunology (1999)

Background: IgE is now known to upregulate the expression of FcϵRI on human basophils. It is not known which receptor on basophils mediates this process of upregulation. Objective: We sought to determine whether galectin-3, FcϵRII (CD23), or FcϵRI were involved in the upregulation of FcϵRI by IgE. Methods: The role of galectin-3 was examined by measuring the influence of α-lactose on upregulation. Basophils were examined for expression of FcϵRII (CD23) by flow cytometry and messenger (m)RNA expression. Functional discrimination between binding to FcϵRII or FcϵRI was examined through the use of mutant IgE-Fc fragments or anti-FcϵRII antibody. Results: Upregulation of FcϵRI on basophils in the presence of IgE was not altered by coincubation with α-lactose, eliminating a role for galectin-3. Basophils were not found to express FcϵRII, as determined by flow cytometry with enriched basophil preparations or RT-PCR with highly purified basophil preparations. A mutant of the Fc fragment of IgE (IgE-Fc), which binds to FcϵRI with a greater than 10-fold lower affinity than IgE or wild-type IgE-Fc but exhibits no change in affinity for FcϵRII, allowed us to distinguish between the functions of the two Fc receptors. The mutant (R334S; Henry et al 1997) was required at about 30-fold higher concentration than the wild-type IgE-Fc for the same stimulation of FcϵRI expression on basophils, thus excluding a role for FcϵRII in the response. In addition, treatment of basophils with anti-FcϵRII antibody (MHM6), which is known to be competitive with IgE, had no effect on the expression of FcϵRI or the ability of IgE to upregulate expression of FcϵRI. Conclusion: Collectively, these data indicate that IgE interacts with FcϵRI to upregulate its expression on human basophils. (J Allergy Clin Immunol 1999;104:492-8.)
Normal serum folate.
Authors: W. O. Mavor, M. P. Spence
Journal: BMJ (1968)

massage failed to produce a palpable femoral pulse, and we assumed that the reason for this was that the grossly over-distended lungs cushioned the pressure applied to the anterior chest wall, and prevented it from being trans- mitted to the heart.In the next two cases external cardiac massage was similarly in- effective, but open massage immediately pro- duced a palpable femoral pulse and was rapidly followed by a restoration of spon- taneous cardiac pulsation in sinus rhythm.Unfortunately, in one case open cardiac massage was not started in time to prevent irreparable cerebral damage.Open cardiac massage may seem a formid- able undertaking, particularly to a physician, but it is in fact a simple procedure, and in almost every hospital the services of a sur- geon can readily be obtained to close the wound.In the light of our recent experience, which is happily not extensive, we now take the view that when a patient with status asthmaticus develops cardiac arrest in hos- pital and this is shown to be due to ventricular asystole the proper course is to under- take open cardiac massage without delay.-Weare, etc., I.
Tumor Mismatch Repair Immunohistochemistry and DNA <i>MLH1</i> Methylation Testing of Patients With Endometrial Cancer Diagnosed at Age Younger Than 60 Years Optimizes Triage for Population-Level Germline Mismatch Repair Gene Mutation Testing
Authors: Daniel D. Buchanan, Yen Y. Tan, Michael D. Walsh, Mark Clendenning, Alexander M. Metcalf, Kaltin Ferguson, Sven T. Arnold, Bryony A. Thompson, Felicity A. Lose, Michael T. Parsons, Rhiannon J. Walters, Sally-Ann Pearson, Margaret Cummings, Martin K. Oehler, Penelope B. Blomfield, Michael A. Quinn, Judy A. Kirk, Colin J. Stewart, Andreas Obermair, Joanne P. Young, Penelope M. Webb, Amanda B. Spurdle
Journal: Journal of Clinical Oncology (2013)

Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations.Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS).Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered.Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.
Congenital afibrinogenemia: mutations leading to premature termination codons in fibrinogen Aα-chain gene are not associated with the decay of the mutant mRNAs
Authors: Rosanna Asselta, Stefano Duga, Silvia Spena, Elena Santagostino, Flora Peyvandi, Gavino Piseddu, Roberto Targhetta, Massimo Malcovati, Pier Mannuccio Mannucci, Maria Luisa Tenchini
Journal: Blood (2001)
New test may improve methods for detecting recurrence of colon cancer
Authors: Scott Gottlieb
Journal: BMJ (1999)

In patients with apparently node negative colorectal cancer, the presence of a specific protein may be a more accurate marker of recurrence after surgical resection than currently used markers, according to the results of a new study.

The lead author, Dr Scott Waldman, and his colleagues at Thomas Jefferson University in Philadelphia looked at 21 patients with histologically confirmed node negative colorectal cancer who had undergone resection. Sections of paraffin-embedded lymph nodes were obtained from each patient and were pooled, and their RNA was analysed by reverse transcriptase polymerase chain reaction.

The protein known as guanylyl cyclase C messenger RNA (GCC …
Antioxidant Anti-Inflammatory Treatment in Type 2 Diabetes
Authors: Antonio Ceriello, Roberto Testa
Journal: Diabetes Care (2009)

In the last few decades, the occurrence of type 2 diabetes has rapidly increased internationally, and it has been estimated that the number of diabetic patients will more than double within 15 years (1). Type 2 diabetes is mainly characterized by the development of increased morbidity and mortality for cardiovascular disease (CVD); thus, it has been suggested that diabetes may be considered a CVD (1). However, diabetes is also characterized by dramatic microangiophatic complications, such as retinopathy, nephropathy, and neuropathy (1).

Recent evidence suggests that glucose overload may damage the cells through oxidative stress (2). This is currently the basis of the “unifying hypothesis” that hyperglycemia-induced oxidative stress may account for the pathogenesis of all diabetic complications (2).

It has been suggested that the following four key biochemical changes induced by hyperglycemia are all activated by a common mechanism—overproduction of superoxide radicals (2): 1 ) increased flux through the polyol pathway (in which glucose is reduced to sorbitol, reducing levels of both NADPH and reduced glutathione); 2 ) increased formation of advanced glycation end products (AGEs); 3 ) activation of protein kinase C (with effects ranging from vascular occlusion to expression of proinflammatory genes), and 4 ) increased shunting of excess glucose through the hexosamine pathway (mediating increased transcription of genes for inflammatory cytokines). Excess plasma glucose drives excess production of electron donors (mainly -NADH/H+) from the tricarboxylic acid cycle; in turn, this surfeit results in the transfer of single electrons (instead of the usual electron pairs) to oxygen, producing superoxide radicals and other reactive oxygen species (instead of the usual H2O end product). The superoxide anion itself inhibits the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GADPH), and consequently, glucose and glycolytic intermediates spill into the polyol and hexosamine pathways, as well as additional pathways that culminate in protein kinase …
Effects of the Flt3 ITD on response to chemotherapy in a murine model of acute myeloid leukemia
Authors: T. S. Pardee, J. Zuber, S. W. Lowe
Journal: Journal of Clinical Oncology (2009)

7060 Background: Acute myeloid leukemia (AML) is an aggressive, genetically heterogeneous malignancy. This heterogeneity is thought to underlie the divergent responses to treatment observed and contribute to relapse. The Flt3 receptor tyrosine kinase containing an internal tandem duplication (Flt3 ITD) is a common mutation in AML and associated with a poor prognosis; however, its effect on chemotherapy response is currently unknown. Methods: Murine AML was generated by retroviral transduction of an MLL-ENL fusion protein into fetal liver cells and subsequent transplantation into syngeneic mice. Blasts were harvested from moribund animals and myeloid lineage confirmed by immunophenotyping. Flt3 ITD sequence was inserted into a GFP tagged vector. Blasts were infected with Flt3 ITD or control virus. For competition assays mixtures of infected and uninfected blasts were exposed to chemotherapy for 72 hours. Among the remaining viable cells, percentages of infected blasts were determined by flow cytometry. For in vivo competition assays animals were injected with mixtures of blasts, treated with chemotherapy and percentages of Flt3 ITD positive blasts as well as total leukemic burden in femoral bone marrow was assessed. Results: Presence of the Flt3 ITD confers an advantage to doxorubicin (dox) in vitro. After exposure to dox at 5ng/mL more infected blasts remained viable when compared to controls (p = 0.0001). Presence of the Flt3 ITD increased sensitivity to cytarabine (Ara-C). After exposure to 50 nM Ara-C fewer Flt3 ITD blasts remained viable (p = 0.0293). Flt3 ITD confers sensitivity to Ara-C in vivo. Bl6 mice were injected with 1x10 6 blasts, 10% containing Flt3 ITD. After 12 days mice were treated for 5 days with either Ara-C at 200mg/kg, dox at 3mg/kg or observation. Ara-C treated animals had fewer Flt3 ITD blasts than controls (p = 0.0030) or dox treated animals (p &lt; 0.0001) and lower leukemic burden (p &lt; 0.0001). In contrast there was no difference in leukemic burden between Ara-C treated, dox treated or control animals in AML without Flt3 ITD (p = 0.2833). Conclusions: The Flt3 ITD confers resistance to doxorubicin in vitro and sensitivity to Ara-C in vitro and in vivo. These results suggest AML patients with Flt3 ITD may benefit more from high-dose cytarabine regimens then anthracyclines. No significant financial relationships to disclose.