tbuckley/cabot-search huggingface dataset:
Abstract 241: A mutant DNA polymerase-delta associated with increased tumor progression causes random deletions in DNA
Authors: Lawrence A. Loeb, Michael W. Schmitt, Ranga N. Venkatesan, Marie-Jeanne Pillaire, Jean-Se'bastien Hoffmann
Journal: Cancer Research (2010)

Abstract For many years, we have advanced the hypothesis that cancers exhibit a mutator phenotype. Recent support for this concept was gained by the increased frequency of random single-base substitutions measured in human tumors as well as by the large numbers of clonal mutations detected by DNA sequencing in a variety of human cancers. While these findings indicate that cancer cells accumulate large numbers of mutations, it remains unclear what types of alterations in the fidelity of DNA synthesis contribute most to the evolution of a tumor. In order to delineate the types of mutations that have the greatest impact on accelerating tumorigenesis, we studied the consequences of altered accuracy of synthesis by mutant DNA polymerases. DNA polymerase δ (Pol δ) is responsible for replication of the lagging DNA strand during replication and functions in multiple DNA repair pathways. Based on homology to substitutions known to induce error-prone synthesis in other DNA polymerases, we constructed a series of single base substitutions at position L606 in the catalytic domain of human Pol δ. We found that Pol δ L606G introduces a high frequency of point mutations into DNA in vitro, but heterozygous mice expressing L606G do not exhibit a cancer phenotype. In contrast, Pol δ L606K synthesizes DNA in vitro with high accuracy; yet heterozygous mice expressing this mutant exhibit enhanced rates of tumor progression. Compared to either the wild type or L606G, the L606K mutant is defective in lesion bypass; cells expressing this mutant exhibit a decrease in the rate of fork progression. In addition, L606K cells exhibit an increase in spontaneous chromosomal aberrations, and comparative genomic hybridization analysis reveals an increased frequency of random deletions in tumors from mice expressing Pol δ L606K. These results indicate that mutations in a major replicating DNA polymerase can result in random deletions throughout the genome that have the potential to affect tumor progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 241.
P100 The Clinical COPD Questionnaire: Response to Pulmonary Rehabilitation: Abstract P100 Table 1
Authors: D Dilaver, MM Peasey, AL Clark, MGS Ng, M Mittal, SSC Kon, JL Canavan, SE Jones, MI Polkey, WDC Man
Journal: Thorax (2012)

<h3>Background</h3> The Clinical COPD Questionnaire (CCQ) is a 10-item health status instrument which has been shown to be reliable and valid in COPD. It takes only two minutes to complete and is simple to score, ranging from 0 (best) – 6 (worst health status). A change in the total CCQ score of 0.4 or more is considered clinically significant <i>(Kocks et al Respir Res 2006)</i>. There is a relative paucity of data assessing the responsiveness of the CCQ to pulmonary rehabilitation (PR). We hypothesised that the CCQ would be responsive to PR and that changes would correlate with changes in other well established health status instruments (Chronic Respiratory Questionnaire: CRQ, St George’s Respiratory Questionnaire: SGRQ and the COPD Assessment Test: CAT). <h3>Methods</h3> 75 consecutive COPD patients referred to an 8-week outpatient PR programme were recruited. The CCQ, along with the CRQ, SGRQ, CAT, and incremental shuttle walk (ISW), were measured before and after PR. Paired t-test was used to compare outcomes before and after PR, whilst Spearman’s rank correlation was used to assess association between change in CCQ with change in other health status questionnaires. <h3>Results</h3> 53 patients completed PR. Baseline characteristics were 33 Male:20 Female, mean (standard deviation) age 68.5(9.9) years, FEV1% predicted 58 (27) and ISW 224 (178) metres. There was a significant reduction (improvement) in CCQ following PR (Pre: 2.9 (1.3) versus Post: 2.1 (1.2); 95% confidence interval –0.4 to –1.0). Significant improvements were also seen in ISW, CRQ domains, SGRQ and CAT with PR. Changes in CCQ correlated significantly with changes in the other health status instruments (see table 1). <h3>Conclusion</h3> The CCQ is responsive to PR and a practical alternative to longer-established health status instruments.
Cultural and Linguistic Barriers to Mental Health Service Access: The Deaf Consumer's Perspective
Authors: Annie G. Steinberg, Vicki Joy Sullivan, Ruth C. Loew
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: The authors investigated knowledge, attitudes, and beliefs about mental illness and providers held by a group of deaf adults. METHOD: The American Sign Language interviews of 54 deaf adults were analyzed. RESULTS: Recurrent themes included mistrust of providers, communication difficulty as a primary cause of mental health problems, profound concern with communication in therapy, and widespread ignorance about how to obtain services. CONCLUSIONS: Deaf consumers' views need due consideration in service delivery planning. Outreach regarding existing programs is essential. (Am J Psychiatry 1998; 155:982–984)
Reduced Cortisol Metabolism during Critical Illness
Authors: Eva Boonen, Hilke Vervenne, Philippe Meersseman, Ruth Andrew, Leen Mortier, Peter E. Declercq, Yoo-Mee Vanwijngaerden, Isabel Spriet, Pieter J. Wouters, Sarah Vander Perre, Lies Langouche, Ilse Vanhorebeek, Brian R. Walker, Greet Van den Berghe
Journal: New England Journal of Medicine (2013)

Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.
Shaping the sperm head: an ER enzyme leaves its mark
Authors: Angshumoy Roy, Yi-Nan Lin, Martin M. Matzuk
Journal: Journal of Clinical Investigation (2006)

Lipid storage diseases are debilitating inherited metabolic disorders that stem from the absence of specific lysosomal enzymes that degrade selected lipids. Most characteristically, these disorders affect the nervous and the reticulo-endothelial systems, with massive organomegaly resulting from the presence of engorged, lipid-laden macrophages. In this issue of the JCI, Yildiz et al. describe the role of the ER-resident enzyme β-glucosidase 2 (GBA2) in mice (see the related article beginning on page 2985). Surprisingly, GBA2 deficiency leaves bile acid and cholesterol metabolism intact, instead causing lipid accumulation in the ER of testicular Sertoli cells, round-headed sperm (globozoospermia), and impaired male fertility.
Cost of temozolomide therapy and global care for recurrent malignant gliomas followed until death
Authors: Jean-Blaise Wasserfallen, Sandrine Ostermann, Serge Leyvraz, Roger Stupp
Journal: Neuro-Oncology (2005)

Effectiveness and costs of care and treatment of recurrent malignant gliomas are largely unknown. In this study, 49 patients (32 males, 17 females; mean age, 49; age range, 23-79) were treated with temozolomide (TMZ) for recurrent or progressive malignant gliomas after standard radiation therapy. Cost assessment (payer's perspective) singled out treatment for first recurrence and all costs of care until death. We computed personnel costs as wages; drugs, imaging, and laboratory tests as prices; and hospitalizations as day rates. Patients were administered a median of five TMZ cycles at recurrence. Drug acquisition costs amounted to euro 2206 per cycle (76% of total costs). Seven patients showed no second recurrence (two are still alive), 16 received no further chemotherapy and died after 3.9 months, and 26 received second-line chemotherapy. After the second progression, median survival was 4.0 months (95% confidence interval, 1.8-6.1). Overall monthly costs of care varied between euro 2450 and euro 3242 among the different groups, and median cost-effectiveness and cost utility ranged from euro 28,817 to euro 38,450 and from euro 41,167 to euro 53,369 per life of year and per quality-adjusted life-year gained, respectively. We conclude that despite high TMZ drug acquisition costs, care of recurrent malignant gliomas is comparable to other accepted therapies.
Familial deficiency of dihydropyrimidine dehydrogenase. Biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity.
Authors: R B Diasio, T L Beavers, J T Carpenter
Journal: Journal of Clinical Investigation (1988)

Severe neurotoxicity due to 5-fluorouracil (FUra) has previously been described in a patient with familial pyrimidinemia. We now report the biochemical basis for both the pyrimidinemia and neurotoxicity in a patient we have recently studied. After administration of a "test" dose of FUra (25 mg/m2, 600 microCi[6-3H]FUra by intravenous bolus) to a patient who had previously developed neurotoxicity after FUra, a markedly prolonged elimination half-life (159 min) was observed with no evidence of FUra catabolites in plasma or cerebrospinal fluid and with 89.7% of the administered dose being excreted into the urine as unchanged FUra. Using a sensitive assay for dihydropyrimidine dehydrogenase in peripheral blood mononuclear cells, we demonstrated complete deficiency of enzyme activity in the patient and partial deficiency of enzyme activity in her father and children consistent with an autosomal recessive pattern of inheritance. Patients who are deficient in this enzyme are likely to develop severe toxicity after FUra administration.
Aberrant production of leukotriene C4 by macrophages from autoimmune-prone mice.
Authors: T J Santoro, D H Morris, R C Murphy, R C Baker
Journal: The Journal of Experimental Medicine (1988)

Eicosanoids have been implicated in the pathogenesis of autoimmune diseases. In this study, peritoneal macrophages from autoimmune-prone mice were examined for their capacity to produce proinflammatory 5-lipoxygenase metabolites. The results indicate that enhanced production of leukotriene C4 is a common feature of murine autoimmunity and suggest further that aberrations in 5-lipoxygenase activity may play a role in the development of lupus.
Effects of recombinant human interleukin-12 on eosinophils, airway hyper-responsiveness, and the late asthmatic response
Authors: Shannon A Bryan, Brian J O'Connor, Salah Matti, Margaret J Leckie, Varsha Kanabar, Jamey Khan, Steven J Warrington, Louis Renzetti, Alexis Rames, Juergen A Bock, Malcolm J Boyce, Trevor T Hansel, Stephen T Holgate, Peter J Barnes
Journal: The Lancet (2000)
Thrombocytosis as a presenting feature of acute lymphoblastic leukemia in childhood
Authors: Julie Blatt, Lila Penchansky, Marianna Horn
Journal: American Journal of Hematology (1989)

To determine the incidence of thrombocytosis at presentation in acute lymphoblastic leukemia (ALL), medical records of all children diagnosed at the Children's Hospital of Pittsburgh from 1980 to 1987 were reviewed. Out of 217 such patients, 7 (3.2%) had platelet counts greater than 400,000/mm3. All of the seven were boys compared with a male:female ration of 1.4:1 in the entire ALL population. Other than sex, no characteristics were clearly associated with thrombocytosis, including white blood cell count, hemoglobin, lymphoblast morphology, and immunologic or chromosomal markers. Apart from ALL, no inflammatory or infectious process which might have caused a thrombocytosis, was detected in any of these patients. The period of induction therapy was notable for the preservation of platelet counts greater than 20,000/mm3 in all patients. However, of the seven children with thrombocytosis, two had major induction complications: one, a cavernous sinus thrombosis; and the other, gastrointestinal bleeding with duodenal perforation. We conclude that thrombocytosis at diagnosis can be seen in children, particularly boys, with ALL. Based on small numbers, this group of patients may be at risk for major events during induction therapy. Large numbers, longer follow-up, and platelet function studies on similar patients will be of interest.
Nephropathy and Elevated BP in Mice with Podocyte-Specific NADPH Oxidase 5 Expression
Authors: Chet E. Holterman, Jean-François Thibodeau, Chelsea Towaij, Alex Gutsol, Augusto C. Montezano, Robin J. Parks, Mark E. Cooper, Rhian M. Touyz, Christopher R.J. Kennedy
Journal: Journal of the American Society of Nephrology (2013)

NADPH oxidase (Nox) enzymes are a significant source of reactive oxygen species, which contribute to glomerular podocyte dysfunction. Although studies have implicated Nox1, -2, and -4 in several glomerulopathies, including diabetic nephropathy, little is known regarding the role of Nox5 in this context. We examined Nox5 expression and regulation in kidney biopsies from diabetic patients, cultured human podocytes, and a novel mouse model. Nox5 expression increased in human diabetic glomeruli compared with nondiabetic glomeruli. Stimulation with angiotensin II upregulated Nox5 expression in human podocyte cultures and increased reactive oxygen species generation. siRNA-mediated Nox5 knockdown inhibited angiotensin II-stimulated production of reactive oxygen species and altered podocyte cytoskeletal dynamics, resulting in an Rac-mediated motile phenotype. Because the Nox5 gene is absent in rodents, we generated transgenic mice expressing human Nox5 in a podocyte-specific manner (Nox5(pod+)). Nox5(pod+) mice exhibited early onset albuminuria, podocyte foot process effacement, and elevated systolic BP. Subjecting Nox5(pod+) mice to streptozotocin-induced diabetes further exacerbated these changes. Our data show that renal Nox5 is upregulated in human diabetic nephropathy and may alter filtration barrier function and systolic BP through the production of reactive oxygen species. These findings provide the first evidence that podocyte Nox5 has an important role in impaired renal function and hypertension.
Efficacy and Safety of Low-Carbohydrate Diets
Authors: Dena M. Bravata, Lisa Sanders, Jane Huang, Harlan M. Krumholz, Ingram Olkin, Christopher D. Gardner, Dawn M. Bravata
Journal: JAMA (2003)

Context Low-carbohydrate diets have been popularized without detailed evidence of their efficacy or safety. The literature has no clear consensus as to what amount of carbohydrates per day constitutes a low-carbohydrate diet. Objective To evaluate changes in weight, serum lipids, fasting serum glucose, and fasting serum insulin levels, and blood pressure among adults using low-carbohydrate diets in the outpatient setting. Data Sources We performed MEDLINE and bibliographic searches for English-language studies published between January 1, 1966, and February 15, 2003, with key words such as low carbohydrate , ketogenic , and diet . Study Selection We included articles describing adult, outpatient recipients of low-carbohydrate diets of 4 days or more in duration and 500 kcal/d or more, and which reported both carbohydrate content and total calories consumed. Literature searches identified 2609 potentially relevant articles of low-carbohydrate diets. We included 107 articles describing 94 dietary interventions reporting data for 3268 participants; 663 participants received diets of 60 g/d or less of carbohydrates—of whom only 71 received 20 g/d or less of carbohydrates. Study variables (eg, number of participants, design of dietary evaluation), participant variables (eg, age, sex, baseline weight, fasting serum glucose level), diet variables (eg, carbohydrate content, caloric content, duration) were abstracted from each study. Data Extraction Two authors independently reviewed articles meeting inclusion criteria and abstracted data onto pretested abstraction forms. Data Synthesis The included studies were highly heterogeneous with respect to design, carbohydrate content (range, 0-901 g/d), total caloric content (range, 525-4629 kcal/d), diet duration (range, 4-365 days), and participant characteristics (eg, baseline weight range, 57-217 kg). No study evaluated diets of 60 g/d or less of carbohydrates in participants with a mean age older than 53.1 years. Only 5 studies (nonrandomized and no comparison groups) evaluated these diets for more than 90 days. Among obese patients, weight loss was associated with longer diet duration ( P = .002), restriction of calorie intake ( P = .03), but not with reduced carbohydrate content ( P = .90). Low-carbohydrate diets had no significant adverse effect on serum lipid, fasting serum glucose, and fasting serum insulin levels, or blood pressure. Conclusions There is insufficient evidence to make recommendations for or against the use of low-carbohydrate diets, particularly among participants older than age 50 years, for use longer than 90 days, or for diets of 20 g/d or less of carbohydrates. Among the published studies, participant weight loss while using low-carbohydrate diets was principally associated with decreased caloric intake and increased diet duration but not with reduced carbohydrate content.
Lost Opportunities: Physicians' Reasons and Disparities in Breast Cancer Treatment
Authors: Nina A. Bickell, Felice LePar, Jason J. Wang, Howard Leventhal
Journal: Journal of Clinical Oncology (2007)

Women with breast cancer do not consistently receive adjuvant treatments that have been shown to increase survival. Acquiring an understanding of the reasons for these lost opportunities may inform strategies for quality improvement.Interviews were conducted with surgeons treating 119 women who did not receive guideline-recommended adjuvant therapy to ascertain reasons underlying treatment omission. Primary reason for underuse was categorized as not recommended, recommended but declined, or system failure (treatment recommended, not refused but did not ensue). Logistic regression identified patient characteristics, and surgeons' practice and referral patterns associated with underuse.Surgeons did not recommend adjuvant treatment for 41 (34%) of 119 women, most often because perceived risks exceeded benefits (37 of 119; 31%); unawareness of treatment benefits was rare (four of 119; 3%). Among the 78 (66%) of 119 for whom surgeons recommended treatment, 37 (31%) declined therapy; 41 (34%) system failures occurred. System failures occurred more commonly among minority than white women (73% v 54%; P < .01), and more commonly in women who were receiving Medicaid or were uninsured than those with Medicare or commercial insurance (54% v 19%; P < .01). Women treated by a surgeon who works closely with oncologists were less likely to experience a system failure (84% v 68%; P < .05).One third of underuse episodes were attributable to surgeons' perceptions that treatment was not indicated, one third because women did not accept recommendations, and one third were the result of system failures. Reasons for underuse of adjuvant breast cancer treatments appear multifactorial and this heterogeneity suggests the need for simultaneous development of different strategies to improve care.
Role of Cytoskeletal Organization in the Regulation of Adenylate Cyclase-Cyclic Adenosine Monophosphate by Hormones
Authors: U. ZOR
Journal: Endocrine Reviews (1983)

AGENERATION ago, in the United States, Rail et al. (1) suggested that the newly discovered cAMP is a second messenger of hormonal action, while in England, Sir Rudolph Peters (2) hypothesized that hormones act through the reorientation of the cytoskeletal (CSK) system. The gap between the two groups of researchers at that time was even greater, since Rall and Sutherland discovered that adrenaline stimulates the generation of cAMP followed by activation of phosphorylase in broken cell preparations (1, 3), while Peters (2) emphasized the whole (intact) cell and not a specific enzyme as the target for hormonal action. The aim of this review is to try to narrow the gap between the ideas of the two schools and demonstrate that the hormonal stimulation of cAMP production and its biochemical actions are controlled by the CSK system. The field of membrane-bound adenylate cyclase (AC) and cyclic nucleotide research had been developing rapidly and is summarized in a few books (3–5), series of international conferences (6) and the Journal of Cyclic Nucleotide Research.
ApoE Plasma Levels and Risk of Cardiovascular Mortality in Old Age
Authors: Simon P Mooijaart, Jimmy F. P Berbée, Diana van Heemst, Louis M Havekes, Anton J. M de Craen, P. Eline Slagboom, Patrick C. N Rensen, Rudi G. J Westendorp
Journal: PLoS Medicine (2006)

Background The ε2, ε3, and ε4 alleles of the apolipoprotein E gene (APOE) encode three isoforms, apoE2, E3, and E4, respectively. The apoE isoforms circulate in different plasma concentrations, but plasma concentrations of the same isoform also differ between individuals. Whereas the isoforms have been associated with cardiovascular disease, the relation between plasma apoE levels and cardiovascular disease is unknown. Methods and Findings We assessed APOE genotypes, plasma levels of apoE, cardiovascular risk factors, and mortality in a population-based sample of 546 individuals aged 85 y who participated in the Leiden 85-plus Study and were prospectively followed for specific causes of death for 5 y. Participants in the highest tertile of apoE levels suffered a twofold-increased risk of cardiovascular mortality (hazard ratio compared to lowest tertile, 2.08; 95% confidence interval [CI], 1.30 to 3.33). Among the 324 participants with the ε3ε3 genotype, the hazard from cardiovascular disease was threefold increased (highest versus lowest tertile 3.01; 95% CI 1.60 to 5.66), with similar estimates for men and women. Other causes of death were not increased significantly. Plasma levels of apoE in ε3ε3 participants were positively correlated with total cholesterol ( p < 0.001), low-density lipoprotein cholesterol ( p < 0.001) and triglycerides ( p < 0.001) and negatively with high-density lipoprotein cholesterol levels ( p = 0.010). Adjustment for plasma lipids did not change the hazard ratios, whereas interaction was absent. The risk associated with high levels of apoE, however, was strongest in participants from the lowest tertile of C-reactive protein (CRP) levels and absent in those from the highest tertile ( pinteraction < 0.001). Among participants from the lowest tertile of CRP levels, those with a high apoE levels had a significantly steeper increase in CRP than those with low apoE levels ( p = 0.020). Similar cardiovascular mortality risks as in ε3ε3 participants were found in ε2 and ε4 carriers. Conclusions In old age, high plasma apoE levels precede an increase of circulating CRP and strongly associates with cardiovascular mortality, independent of APOE genotype and plasma lipids.