tbuckley/cabot-search huggingface dataset:
Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a <i>Bona Fide</i> PARP Inhibitor
Authors: Xuesong Liu, Yan Shi, David X. Maag, Joann P. Palma, Melanie J. Patterson, Paul A. Ellis, Bruce W. Surber, Damien B. Ready, Niru B. Soni, Uri S. Ladror, Allison J. Xu, Ramesh Iyer, John E. Harlan, Larry R. Solomon, Cherrie K. Donawho, Thomas D. Penning, Eric F. Johnson, Alexander R. Shoemaker
Journal: Clinical Cancer Research (2011)

PARP inhibitors are being developed as therapeutic agents for cancer. More than six compounds have entered clinical trials. The majority of these compounds are β-nicotinamide adenine dinucleotide (NAD(+))-competitive inhibitors. One exception is iniparib, which has been proposed to be a noncompetitive PARP inhibitor. In this study, we compare the biologic activities of two different structural classes of NAD(+)-competitive compounds with iniparib and its C-nitroso metabolite.Two chemical series of NAD(+)-competitive PARP inhibitors, iniparib and its C-nitroso metabolite, were analyzed in enzymatic and cellular assays. Viability assays were carried out in MDA-MB-436 (BRCA1-deficient) and DLD1(-/-) (BRCA2-deficient) cells together with BRCA-proficient MDA-MB-231 and DLD1(+/+) cells. Capan-1 and B16F10 xenograft models were used to compare iniparib and veliparib in vivo. Mass spectrometry and the (3)H-labeling method were used to monitor the covalent modification of proteins.All NAD(+)-competitive inhibitors show robust activity in a PARP cellular assay, strongly potentiate the activity of temozolomide, and elicit robust cell killing in BRCA-deficient tumor cells in vitro and in vivo. Cell killing was associated with an induction of DNA damage. In contrast, neither iniparib nor its C-nitroso metabolite inhibited PARP enzymatic or cellular activity, potentiated temozolomide, or showed activity in a BRCA-deficient setting. We find that the nitroso metabolite of iniparib forms adducts with many cysteine-containing proteins. Furthermore, both iniparib and its nitroso metabolite form protein adducts nonspecifically in tumor cells.Iniparib nonselectively modifies cysteine-containing proteins in tumor cells, and the primary mechanism of action for iniparib is likely not via inhibition of PARP activity.
Adiponectin: A Risk Biomarker and Attractive Target for Chemoprevention
Authors: Carol J. Fabian
Journal: Journal of Clinical Oncology (2011)

physician’s view. Ann Intern Med 154:63-64, 2011 36. Takach M: Reinventing Medicaid: State innovations to qualify and pay for patient-centered medical homes show promising results. Health Aff (Millwood) 30:13251334, 2011 37. Friedberg MW, Coltin KL, Safran DG, et al: Medical home capabilities of primary care practices that serve sociodemographically vulnerable neighborhoods. Arch Intern Med 170:938-944, 2010
Long-Term Cost Effectiveness of Early and Sustained Dual Oral Antiplatelet Therapy With Clopidogrel Given for Up to One Year After Percutaneous Coronary Intervention
Authors: Sean C. Beinart, Paul Kolm, Emir Veledar, Zefeng Zhang, Elizabeth M. Mahoney, Olivier Bouin, Sylvie Gabriel, Joseph Jackson, Roland Chen, Jaime Caro, Steven Steinhubl, Eric Topol, William S. Weintraub
Journal: Journal of the American College of Cardiology (2005)
Clinico-pathological characterization of hepatitis C virus-related B-cell non-Hodgkin’s lymphomas without symptomatic cryoglobulinemia
Authors: M. Luppi, G. Longo, M.G. Ferrari, P. Barozzi, R. Marasca, M. Morselli, C. Valenti, T. Mascia, L. Vandelli, D. Vallisa, L. Cavanna, G. Torelli
Journal: Annals of Oncology (1998)
Pseudomonas aeruginosa induces vascular endothelial growth factor synthesis in airway epithelium in vitro and in vivo
Authors: C. Martin, G. Thévenot, S. Danel, J. Chapron, A. Tazi, J. Macey, D.J. Dusser, I. Fajac, P-R. Burgel
Journal: European Respiratory Journal (2011)

Pseudomonas aeruginosa (PA) airway infection and bronchial blood vessel proliferation are features of bronchiectasis. Because vascular endothelial growth factor (VEGF)-A regulates angiogenesis, we hypothesised that PA infection induces VEGF synthesis in epithelium and peribronchial angiogenesis. Because epidermal growth factor receptor (EGFR) activation regulates VEGF synthesis in cancer, we also evaluated the roles of EGFR. Airway epithelial cells were incubated for 24 h with PA supernatants and VEGF concentrations were measured in culture medium by ELISA. C57BL/6N mice were instilled intratracheally with sterile agarose beads or with agarose beads coated with the PA strain PAO1 (mean± sem 6×10 5 ±3×10 5 cfu·animal −1 ), with or without the EGFR inhibitor AG1478 (12.5 mg·kg −1 ·day −1 intraperitoneally). Epithelial immunostaining for VEGF and phosphorylated EGFR, and peribronchial vascularity, were quantified using morphometric analysis. VEGF expression was further assessed by western blot in mouse lung homogenates. PA supernatants induced dose-dependent VEGF synthesis in cultured airway epithelial cells, effects which were prevented by EGFR antagonists. In mice, persistent PAO1 infection increased immunostaining for VEGF and phosphorylated EGFR in airway epithelium, and resulted in increased peribronchial vascularity within 7 days. These effects were reduced by EGFR inhibition. Persistent PA infection induced VEGF synthesis in airway epithelium and peribronchial angiogenesis, at least in part via EGFR-dependent mechanisms.
Third Annual Report of the Empire Rheumatism Council: To Organise Research Throughout the British Empire into the Causes, and Means of Treatment, of Rheumatic Disease
Authors: None Horder
Journal: Annals of the Rheumatic Diseases (1940)

To organise research throughout the British Empire into the causes, and means of treatment, of Rheumatic Disease) MY LORDS, LADIES AND GENTLEMEN, On account of the war, which has called away for service many of our members, and entails on most of the others difficulties in travelling, your Executive Committee considered that it would be in accordance with your wishes that the Annual Meeting should not be summoned this year.I shall not, therefore, have the pleasure of addressing you personally, but now present the Annual Report to October 31, 1939, noting that, if any member wishes to bring up a matter arising out of the Report, prompt attention will be given to it by the War Emer- gency Committee which has been constituted; and should there arise any question needing discussion at a general meeting (which I do not anticipate) a meeting will be summoned.Last year, at this time, you will recall that we were able to chronicle satisfactory progress, though the period under review had been disturbed by constant rumours of war.All hope of escaping the calamity of war has proved vain.Faced with the alternative of seeing the fabric of European civilisation destroyed piecemeal, the British Empire, side by side with France, has been compelled to take up arms.Since September your executive officers have devoted them- selves to planning how to save, as far as possible, the work of the Council from interruption and at the same time to conserve our resources so that when peace returns the campaign against rheuma- tism may be carried on again with full vigour.The need at that time will be certainly greater than heretofore.We shall, almost certainly, have to face an increased incidence of Rheumatic Disease arising not only from the war casualties but from a degree of inter- ruption of normal health services to the civil population.You will be chiefly interested in our plans for the war period; but, before referring to them, I must give a brief record of the developments of our movement up to September last.That development was so promising as to make its interruption specially tragic.First, there was manifest a strong growth of public interest in, and public determination to grapple with, the problems of Rheumatic Disease.This was shown notably at the meetings of the Rheumatism Section of the Annual Congress of the Royal In- 67 copyright.
Does the Stanford Health Assessment Questionnaire have potential as a monitoring tool for subjects with rheumatoid arthritis?
Authors: M C Greenwood
Journal: Annals of the Rheumatic Diseases (2001)

To assist in the interpretation of the Stanford Health Assessment Questionnaire (HAQ) score changes for individual patients with rheumatoid arthritis (RA), by determining the minimum size of score change that can confidently be considered to reflect a significant change in disability from the patient's perspective.HAQ score changes were calculated for 40 clinic patients with RA who had reported no change to health in general over two months. These were considered to reflect both inconsistencies in questionnaire completion and any true but minor changes not considered significant enough by the patients to represent a change to their health in general. HAQ score changes over one year were also calculated for 207 clinic patients with RA.The range within which 95% of score changes would be expected to lie in the absence of significant change was estimated as +/-0.48 points (+/-2SD of the score changes) and 80% within +/-0.31 points (+/-1.29SD). A chi(2) test showed no significant association between an HAQ score increase of >0.31 over one year and decline in health related to arthritis reported by the patient over the same period.As a general guideline, an HAQ score needs to change by 0.48 points or more for 95% confidence that it reflects significant change (0.31 for 80% confidence). Although the value of HAQ as a group outcome measure is well established, this study questions the usefulness of monitoring individual HAQ scores in a clinical setting.
Smoking, Obesity, and Statin Therapy in the Prognosis of Prostate Cancer
Authors: Harry W. Daniell
Journal: Journal of Clinical Oncology (2010)

TO THE EDITOR: Gutt et al documented fewer recurrences among men with radiation-treated prostate cancer who had received statin therapy during or after their radiation therapy. They interpreted their observations to indicate a favorable influence by statins on prostate cancer behavior, a conclusion that is not appropriate unless observations are controlled for host factors that may have influenced tumor behavior. Most studies examining relationships between smoking and prostate cancer recurrence or tumor-related mortality demonstrate smoking-related increases in both, even after controlling for multiple factors including the more advanced malignant disease at presentation and the smaller prostate size characteristic of smokers. In a study similar to that of Gutt et al, Pantarotto et al reported follow-up data from 434 patients after external-beam radiation therapy with curative intent. In patients who had been current smokers at the time of therapy, they found a recurrence rate 5.2 times greater than the rate of life-long nonsmokers, and in former smokers, the recurrence rate was 2.9 times greater. Studies examining relationships between obesity and prostate cancer recurrence or tumor-related mortality have demonstrated an inconsistent pattern. Gong et al retrospectively analyzed tumor characteristics, body mass index (BMI), and smoking habits in 752 patients with prostate cancer and reported that prostate cancer–specific mortality was doubled in men with a BMI 30 kg/m compared with men who were less obese and that this mortality was 2.3 times as great in smokers compared with nonsmokers. Freedland et al reported a 2.09-fold increased risk of prostate-specific antigen failure in severely obese men (BMI 35 kg/m) and, in a recent review, concluded that obesity may reduce the risk of nonaggressive disease but increase the risk of aggressive disease, especially in those with BMI 35 kg/m. These observations suggest that if smokers in the study by Gutt et al had been less likely to receive statins either because of their lower average weight and associated lower lipid values or because of a lower level of interest in maintaining optimal health, then statin consumers would have included lower percentages of smokers, contributing to a lower frequency of tumor recurrences among them, and that the distribution of obese men might also have influenced recurrence rates. Analysis of BMI and smoking habits of their patients would increase the value of their analysis, while adding to the body of information that eventually should help to define any influence that statin therapy might have on prostate cancer behavior.
Polymorphisms in the IGF1 signalling pathway including the myostatin gene are associated with left ventricular mass in male athletes
Authors: Ruth-Jessica Karlowatz, Jürgen Scharhag, Jörg Rahnenführer, Ulrich Schneider, Ernst Jakob, Wilfried Kindermann, Klaus Dieter Zang
Journal: British Journal of Sports Medicine (2009)

Background Athlete's heart as an adaptation to long-time and intensive endurance training can vary considerably between individuals. Genetic polymorphisms in the cardiological relevant insulin-like growth factor 1 (IGF1) signalling pathway seem to have an essential influence on the extent of physiological hypertrophy. Objective Analysis of polymorphisms in the genes of IGF1, IGF1 receptor (IGF1R) and the negative regulator of the cardiac IGF1 signalling pathway, myostatin (MSTN), and their relation to left ventricular mass (LVM) of endurance athletes. Methods In 110 elite endurance athletes or athletes with a high amount of endurance training (75 males and 35 females) and 27 male controls, which were examined by echocardiographic imaging methods and ergometric exercise-testing, the genotypes of a cytosine–adenine repeat polymorphism in the promoter region of the IGF1 gene and a G/A substitution at position 3174 in the IGF1R gene were determined. Additionally, a mutation screen of the MSTN gene was performed. Results The polymorphisms in the IGF1 and the IGF1R gene showed a significant relation to the LVM for male (IGF1: p=0.003; IGF1R: p=0.01), but not for female athletes. The same applies to a previously unnoticed polymorphism in the 1 intron of the MSTN gene, whose deletion allele (AAA→AA) appears to increase the myostatic effect (p=0.015). Moreover, combinations of the polymorphisms showed significant synergistic effects on the LVM of the male athletes. Conclusions The authors' results argue for the importance of polymorphisms in the IGF1 signalling pathway in combination with MSTN on the variant degree of physiological hypertrophy of male athletes.
Potentiation of Temozolomide Cytotoxicity by Inhibition of DNA Polymerase β Is Accentuated by BRCA2 Mutation
Authors: Gregory C. Stachelek, Shibani Dalal, Katherine A. Donigan, Denise Campisi Hegan, Joann B. Sweasy, Peter M. Glazer
Journal: Cancer Research (2009)

Base excision repair (BER) plays a critical role in the repair of bases damaged by oxidative metabolism or alkylating agents, such as those commonly used in cancer therapy. Incomplete BER generates intermediates that require activation of homology-dependent DNA repair to resolve. We investigated the effects of lithocholic acid (LCA), an inhibitor of the key BER enzyme DNA polymerase beta (pol beta), in cells deficient in expression of the homology-dependent repair factor BRCA2. In vitro studies show that LCA suppresses the DNA polymerase and 5'-deoxyribose phosphate lyase activities of DNA pol beta by preventing the formation of a stable pol beta-DNA complex, reducing BER effectiveness. Cytotoxicity assays based on colony formation revealed that LCA exhibits synergism with the alkylating agent temozolomide, which engages BER through DNA methylation, and that the degree of synergism is increased in cells lacking functional BRCA2. BRCA2-deficient cells also showed heightened susceptibility to both LCA and temozolomide individually. The potentiation of temozolomide cytotoxicity by LCA owes to the conversion of single-stranded DNA breaks generated through incomplete BER of methylated nucleotides into double-stranded breaks during DNA replication, as indicated by gammaH2AX immunofluorescence. Death seems to be induced in cotreated cells through an accumulation of persistent double-stranded DNA breaks. Mutations of the BRCA2 gene have been extensively characterized and are present in various cancers, implying that inhibition of BER may offer a means to augment tumor selectivity in the use of conventional cancer therapies.
NEK8 Mutations Affect Ciliary and Centrosomal Localization and May Cause Nephronophthisis
Authors: Edgar A. Otto, Melissa L. Trapp, Ulla T. Schultheiss, Juliana Helou, Lynne M. Quarmby, Friedhelm Hildebrandt
Journal: Journal of the American Society of Nephrology (2008)

Nephronophthisis, an autosomal recessive kidney disease, is the most frequent genetic cause of chronic renal failure in the first 3 decades of life. Causative mutations in 8 genes (NPHP1-8) have been identified, and homologous mouse models for NPHP2/INVS and NPHP3 have been described. The jck mouse is another model of recessive cystic kidney disease, and this mouse harbors a missense mutation, G448V, in the highly conserved RCC1 domain of Nek8. We hypothesized that mutations in NEK8 might cause nephronophthisis in humans, so we performed mutational analysis in a worldwide cohort of 588 patients. We identified 3 different amino acid changes that were conserved through evolution (L330F, H425Y, and A497P) and that were absent from at least 80 ethnically matched controls. All 3 mutations were within RCC1 domains, and the mutation H425Y was positioned within the same RCC1 repeat as the mouse jck mutation. To test the functional significance of these mutations, we introduced them into full-length mouse Nek8 GFP-tagged cDNA constructs. We transiently overexpressed the constructs in inner medullary collecting duct cells (IMCD-3 cell line) and compared the subcellular localization of mutant Nek8 to wild-type Nek8. All mutant forms of Nek8 showed defects in ciliary localization to varying degrees; the H431Y mutant (human H425Y) was completely absent from cilia and the amount localized to centrosomes was decreased. Overexpression of these mutants did not affect overall ciliogenesis, mitosis, or centriole number. Our genetic and functional data support the assumption that mutations in NEK8 cause nephronophthisis (NPHP9), adding another link between proteins mutated in cystic kidney disease and their localization to cilia and centrosomes.
Antihypertensive Therapy and the Risk of New-Onset Diabetes
Authors: Panteleimon A. Sarafidis, George L. Bakris
Journal: Diabetes Care (2006)

Numerous studies have consistently demonstrated that certain classes of antihypertensive medications have differential effects on carbohydrate and lipid metabolism in humans. In general, higher doses of thiazide diuretics (i.e., ≥25 mg/day hydrochlorothiazide) and β-blockers, at any antihypertensive dose, worsen glycemic control, with β-blockers worsening insulin sensitivity (1). Conversely, ACE inhibitors, angiotensin II receptor blockers, and calcium channel blockers (CCBs) have neutral or beneficial effects on these variables (2,3). It is noteworthy, however, that not all drugs within the same class have similar effects on insulin sensitivity. This is exemplified by the effects of vasodilating β-blockers failing to worsen insulin resistance and consequently having neutral effects on glycemic control (4,5).

These aforementioned observations are evident in 11 randomized clinical outcome trials where development of new-onset diabetes was evaluated as a secondary end point (Table 1) (6–11). In contrast to this general trend, the STOP-2 (Swedish Trial in Old Patients with Hypertension 2) reported no difference in diabetes incidence between conventional treatment (β-blockers or diuretics) and either ACE inhibitor–or CCB-based treatment (12). Moreover, in addition to prospective randomized trials, some long-term epidemiological studies, such as the ARIC (Atherosclerosis Research in Communities) study, have linked different classes of antihypertensive agents with development of new-onset diabetes (13).

All of these studies, however, have limitations to their conclusions. First, all had cardiovascular outcomes rather than incidence of new-onset diabetes as a primary end point. Second, it is difficult to assess the effects of a single class of agents since many studies …
Negative Regulation of Immunoglobulin E–dependent Allergic Responses by Lyn Kinase
Authors: Sandra Odom, Gregorio Gomez, Martina Kovarova, Yasuko Furumoto, John J. Ryan, Harry V. Wright, Claudia Gonzalez-Espinosa, Margaret L. Hibbs, Kenneth W. Harder, Juan Rivera
Journal: The Journal of Experimental Medicine (2004)

A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn−/− bone marrow–derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn−/− mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn−/− mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcεRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcεRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn−/− mice because both lyn−/− and lyn−/− fyn−/− mice showed high IgE levels. Thus, lyn−/− mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.
Second World Congress on the Insulin Resistance Syndrome
Authors: Zachary T. Bloomgarden
Journal: Diabetes Care (2005)

This is the third and final installment in a series of articles on the Second World Congress on the Insulin Resistance Syndrome, Universal City, California, 18–20 November 2004.

At a symposium on insulin resistance, hypertension, and cardiovascular disease (CVD) cosponsored by the European Group for the Research of Obesity, Hypertension, and Insulin Resistance, Albert P. Rocchini (Ann Arbor, MI) discussed the relationship of hypertension and insulin resistance in obesity. Potential explanations for the frequency with which insulin resistance and hypertension are associated could be the coincidence of two common abnormalities, the causation of one by the other, or, intriguingly, the existence of a common underlying factor. The first explanation appears unlikely, with a preponderance of evidence suggesting that the two conditions are related (1). It also appears unlikely that hypertension causes insulin resistance, as glucose uptake is not affected in experimental renovascular hypertension and because lowering blood pressure in individuals with hypertension does not necessarily improve glucose uptake. There is, however, greater forearm vascular resistance in obese than in nonobese adolescents, with glucose uptake across this tissue inversely related to vascular resistance, suggesting that vascular resistance may play a role in some aspects of insulin action (2). The converse, that insulin resistance may cause hypertension, appears more likely to be a factor. Fasting insulin levels correlate with systolic blood pressure, and the drop in blood pressure following weight loss is related to the improvement in insulin sensitivity. Interestingly, in hypertensive obese individuals, somatostatin decreases both the insulin level and blood pressure, suggesting an effect of hyperinsulinemia. Insulin can lead to sodium retention (3) and angiotensin II–mediated aldosterone production, can change vascular structure and function, can alter cation flux, and can activate the sympathetic nervous system. In both obese and nonobese individuals during water diuresis, however, sodium excretion decreases with a …