tbuckley/cabot-search huggingface dataset:
Impaired Fasting Glucose and Risk of Cardiovascular Disease in Korean Men and Women
Authors: Hong-Kyu Kim, Chul-Hee Kim, Eun Hee Kim, Sung Jin Bae, Jaewon Choe, Joong-Yeol Park, Seong-Wook Park, Young Duk Yun, Soo-Jin Baek, Yejin Mok, Sun Ha Jee
Journal: Diabetes Care (2012)

OBJECTIVE The relationship between impaired fasting glucose (IFG) and risk of cardiovascular disease (CVD) or ischemic heart disease (IHD) varies widely according to sex and ethnicity. We evaluated the relationship between IFG and CVD or IHD among Korean men and women. RESEARCH DESIGN AND METHODS A total of 408,022 individuals who underwent voluntary private health examinations in 17 centers in South Korea were followed for 10 years. Data regarding CVD or IHD events were obtained from the Korean National Health Insurance database. IFG was categorized as grade 1 (fasting glucose 100–109 mg/dL) or grade 2 (110–125 mg/dL). RESULTS Incidence rates of CVD (per 100,000 person-years) were 2,203 for diabetes. Age-adjusted hazard ratios (HRs) for CVD were 1.17 (95% CI 1.13–1.20) for grade 1 IFG, 1.30 (1.24–1.35) for grade 2 IFG, and 1.81 (1.75–1.86) for diabetes. The increased risk for women was similar to that of men. Age-adjusted HRs for IHD and ischemic stroke were also significantly increased for men and women with IFG and diabetes. After multivariate adjustment of conventional risk factors (hypertension, dyslipidemia, smoking, obesity, and family history of CVD), the overall risk of CVD was greatly attenuated in all categories. However, the HRs for IHD and ischemic stroke remained significantly increased in men for grade 2 IFG but not in women. CONCLUSIONS In Korea, grade 2 IFG is associated with increased risk of IHD and ischemic stroke, independent of other conventional risk factors, in men but not in women.
Management of residual thymic cysts in patients treated for mediastinal Hodgkin's disease.
Authors: A M el-Sharkawi, B Patel
Journal: Thorax (1995)

The pathogenesis of residual thymic cysts after treatment for mediastinal Hodgkin9s disease is uncertain. Their presence after adequate treatment often presents the oncologist and the thoracic surgeon with a therapeutic dilemma. Two patients with residual thymic cysts after curative treatment for mediastinal Hodgkin9s disease are described and the management discussed.
Synergy between the NAMPT Inhibitor GMX1777(8) and Pemetrexed in Non–Small Cell Lung Cancer Cells Is Mediated by PARP Activation and Enhanced NAD Consumption
Authors: Manuel Chan, Michel Gravel, Alexandre Bramoullé, Gaëlle Bridon, Daina Avizonis, Gordon C. Shore, Anne Roulston
Journal: Cancer Research (2014)

Abstract GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway–related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non–small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC. Cancer Res; 74(21); 5948–54. ©2014 AACR.
Regulation of Renal Calcium Receptor Gene Expression by 1,25-Dihydroxyvitamin D3 in Genetic Hypercalciuric Stone-Forming Rats
Authors: Jim J. Yao, Shaochun Bai, Alexander J. Karnauskas, David A. Bushinsky, Murray J. Favus
Journal: Journal of the American Society of Nephrology (2005)

Hypercalciuria in inbred genetic hypercalciuric stone-forming (GHS) rats is due, in part, to a decrease in renal tubule Ca reabsorption. Activation of the renal Ca receptor (CaR) may decrease renal tubule Ca reabsorption and cause hypercalciuria through suppression of Ca-sensitive potassium channel activity. Because the rat renal CaR gene is regulated by extracellular calcium and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and GHS rats have increased renal vitamin D receptor content, the current study was undertaken to determine the level of CaR gene expression in GHS rat kidney and whether CaR gene expression is regulated by 1,25(OH)2D3. Male GHS and normal control (NC) rats were fed a Ca-sufficient diet (0.6% Ca). Western blotting revealed a four-fold increase in CaR protein in GHS rat renal tissue, and 1,25(OH)2D3 administration increased renal CaR in both GHS and NC rats. Northern blot analysis of extracts of renal cortical tissue from GHS and NC rats revealed a major 7-kb transcript of CaR and a more modest 4-kb transcript, both of which were readily detectable. Both Northern blotting and real-time reverse transcription-PCR revealed increased basal CaR mRNA expression levels in GHS rat kidney. 1,25(OH)2D3 administration increased renal CaR mRNA levels 2.0- and 3.3-fold in GHS and NC rats, respectively. Despite the greater incremental increase by 1,25(OH)2D3 in NC rats, CaR mRNA levels remained higher in GHS rat kidney, and the elevation was more sustained. 1,25(OH)2D3 increased CaR mRNA through both elevated CaR gene expression and prolonged tissue half-life. These results demonstrate that GHS rats have high levels of CaR gene expression and CaR protein that may contribute to the hypercalciuria and calcium nephrolithiasis.
Self-regulation in hospital waiting lists
Authors: Dominic P Smethurst, Hywel C Williams
Journal: Journal of the Royal Society of Medicine (2002)

There is evidence that hospital waiting lists in the UK are resistant to shortening because reductions in length generate increases in referrals. We explored this concept by examining outpatient data for eight specialties in a large hospital centre over 17 months. Correlation coefficients were calculated by regressing waiting list density (numbers waiting more than 26 weeks) against referral rate.In three of the eight specialties, with the longest waiting lists, referral rates were significantly related, after one month's delay, to waiting list density (P<0.01)—dermatology, R=0.68; ear-nose-throat R=0.78; trauma/orthopaedics (R=0.64). These were the three with the longest lists.These results help to explain why initiatives to shorten waiting lists are commonly ineffective in the long term.
Patterns of Gene Expression in Different Histotypes of Epithelial Ovarian Cancer Correlate with Those in Normal Fallopian Tube, Endometrium, and Colon
Authors: Rebecca T. Marquez, Keith A. Baggerly, Andrea P. Patterson, Jinsong Liu, Russell Broaddus, Michael Frumovitz, Edward N. Atkinson, David I. Smith, Lynn Hartmann, David Fishman, Andrew Berchuck, Regina Whitaker, David M. Gershenson, Gordon B. Mills, Robert C. Bast, Karen H. Lu
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Epithelial ovarian cancers are thought to arise from flattened epithelial cells that cover the ovarian surface or that line inclusion cysts. During malignant transformation, different histotypes arise that resemble epithelial cells from normal fallopian tube, endometrium, and intestine. This study compares gene expression in serous, endometrioid, clear cell, and mucinous ovarian cancers with that in the normal tissues that they resemble. Experimental Design: Expression of 63,000 probe sets was measured in 50 ovarian cancers, in 5 pools of normal ovarian epithelial brushings, and in mucosal scrapings from 4 normal fallopian tube, 5 endometrium, and 4 colon specimens. Using rank-sum analysis, genes whose expressions best differentiated the ovarian cancer histotypes and normal ovarian epithelium were used to determine whether a correlation based on gene expression existed between ovarian cancer histotypes and the normal tissues they resemble. Results: When compared with normal ovarian epithelial brushings, alterations in serous tumors correlated with those in normal fallopian tube (P = 0.0042) but not in other normal tissues. Similarly, mucinous cancers correlated with those in normal colonic mucosa (P = 0.0003), and both endometrioid and clear cell histotypes correlated with changes in normal endometrium (P = 0.0172 and 0.0002, respectively). Mucinous cancers displayed the greatest number of alterations in gene expression when compared with normal ovarian epithelial cells. Conclusion: Studies at a molecular level show distinct expression profiles of different histologies of ovarian cancer and support the long-held belief that histotypes of ovarian cancers come to resemble normal fallopian tube, endometrial, and colonic epithelium. Several potential molecular markers for mucinous ovarian cancers have been identified.
Differential Sensitivity of Malignant Glioma Cells to Methylating and Chloroethylating Anticancer Drugs: p53 Determines the Switch by Regulating <i>xpc, ddb2</i>, and DNA Double-Strand Breaks
Authors: Luís F.Z. Batista, Wynand P. Roos, Markus Christmann, Carlos F.M. Menck, Bernd Kaina
Journal: Cancer Research (2007)

Abstract Glioblastoma multiforme is the most severe form of brain cancer. First line therapy includes the methylating agent temozolomide and/or the chloroethylating nitrosoureas [1-(2-chloroethyl)-1-nitrosourea; CNU] nimustine [1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea; ACNU], carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea; BCNU], or lomustine [1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; CCNU]. The mechanism of cell death after CNU treatment is largely unknown. Here we show that ACNU and BCNU induce apoptosis in U87MG [p53 wild-type (p53wt)] and U138MG [p53 mutant (p53mt)] glioma cells. However, contrary to what we observed previously for temozolomide, chloroethylating drugs are more toxic for p53-mutated glioma cells and induce both apoptosis and necrosis. Inactivation of p53 by pifithrin-α or siRNA down-regulation sensitized p53wt but not p53mt glioma cells to ACNU and BCNU. ACNU and BCNU provoke the formation of DNA double-strand breaks (DSB) in glioma cells that precede the onset of apoptosis and necrosis. Although these DSBs are repaired in p53wt cells, they accumulate in p53mt cells. Therefore, functional p53 seems to stimulate the repair of CNU-induced cross-links and/or DSBs generated from CNU-induced lesions. Expression analysis revealed an up-regulation of xpc and ddb2 mRNA in response to ACNU in U87MG but not U138MG cells, indicating p53 regulates a pathway that involves these DNA repair proteins. ACNU-induced apoptosis in p53wt glioma cells is executed via both the extrinsic and intrinsic apoptotic pathway, whereas in p53mt glioma cells, the mitochondrial pathway becomes activated. The data suggest that p53 has opposing effects in gliomas treated with methylating or chloroethylating agents and, therefore, the p53 status should be taken into account when deciding which therapeutic drug to use. [Cancer Res 2007;67(24):11886–95]
High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration
Authors: K Paulsson, M Heidenblad, B Strömbeck, J Staaf, G Jönsson, Å Borg, T Fioretos, B Johansson
Journal: Leukemia (2006)
Response to eczema and cancer risk: a critical appraisal and review of the literature
Authors: C.Y. Hwang, Y.J. Chen, H.N. Liu, Y.T. Chang
Journal: British Journal of Dermatology (2011)

Wedgeworth et al.1 have written a critical appraisal of our study2 on cancer risk in atopic patients. They have performed a very comprehensive literature review on the topic of eczema and cancer risk. This work provides further information to enable both researchers and clinicians to understand how the immune system interacts with oncogenesis of different organs. In response to their appraisal, we would like to take this opportunity to present our comments. Validation of diagnosis is one of the most difficult problems for researchers using electronic claims and medical record databases as the research material. It is even more challenging for dermatologists, because many dermatological diseases are not specified in the current ICD‐9‐CM codes. We were aware that ICD‐9‐CM code 691.0 does not belong to eczema, so only those with ICD‐9‐CM codes 691 and 691.8 were included as our eczema cohort. Although no study has been performed to validate the diagnoses of atopic dermatitis in the National Health Insurance Research Database (NHIRD) before, a recent study showed that the accuracy of the NHIRD in recording ischaemic stroke diagnosis was high.3
Determinants of improvement of quality of life in persistent atrial fibrillation: Data from the RACE study
Authors: Vincent E. Hagens, Adelita V. Ranchor, Eric Van Sonderen, Jan H. Kingma, Hans A. Bosker, Otto Kamp, Tsjerk Kingma, Harry J. Crijns, Isabelle C. Van Gelder
Journal: Journal of the American College of Cardiology (2003)
Lansley reforms will destroy NHS, leading doctors say
Authors: A. O'Dowd
Journal: BMJ (2010)

More than 200 leading doctors have attacked the plans of England’s health secretary, Andrew Lansley, to reform the NHS, saying that they will destroy the health service.

Policy experts have also questioned the wisdom of the changes, given a newly published social attitudes survey of Britain, which rates current public satisfaction with the NHS at a record high.

A joint letter signed by 206 medical professionals published in the Times newspaper on 13 December says that the health secretary’s desire to put patients at the heart of care and involve clinicians in decisions about service provision could be achieved without the “massive structural upheaval” of abolishing primary care trusts and strategic health authorities. …
Hyperpolarized 13C Spectroscopy Detects Early Changes in Tumor Vasculature and Metabolism after VEGF Neutralization
Authors: Sarah E. Bohndiek, Mikko I. Kettunen, De-en Hu, Kevin M. Brindle
Journal: Cancer Research (2012)

Abstract No clinically validated biomarkers exist to image tumor responses to antiangiogenic therapy. Here, we report the utility of hyperpolarized 13C magnetic resonance spectroscopy (MRS) to detect the early effects of anti-VEGF therapy. In two colorectal cancer xenograft models, displaying differential sensitivity to VEGF blockade, we compared hyperpolarized MRS with measurements of tumor perfusion using dynamic contrast agent–enhanced (DCE)-MRI and tumor cellularity using diffusion-weighted MRI of the apparent diffusion coefficient (ADC) of tissue water. In tumors sensitive to anti-VEGF therapy, 13C flux between hyperpolarized [1-13C]pyruvate and [1-13C]lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4-13C2]malate from hyperpolarized [1,4-13C2]fumarate increased in parallel with tumor cell necrosis, preceding any change in tumor ADC. In contrast, tumors that were less sensitive to anti-VEGF therapy showed an increase in 13C flux from hyperpolarized [1-13C]pyruvate and an increase in uptake of a gadolinium contrast agent, whereas tumor ADC decreased. Increased label flux could be explained by vascular normalization after VEGF blockade, increasing delivery of hyperpolarized [1-13C]pyruvate as observed. Despite the minimal response of these tumors to treatment, with only a minor increase in necrosis observed histologically, production of [1,4-13C2]malate from hyperpolarized [1,4-13C2]fumarate in therapy-resistant tumors also increased. Together, our findings show that hyperpolarized 13C MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death. Cancer Res; 72(4); 854–64. ©2012 AACR.
TRPV4 Dysfunction Promotes Renal Cystogenesis in Autosomal Recessive Polycystic Kidney Disease
Authors: Oleg Zaika, Mykola Mamenko, Jonathan Berrout, Nabila Boukelmoune, Roger G. O'Neil, Oleh Pochynyuk
Journal: Journal of the American Society of Nephrology (2013)

The molecular mechanism of cyst formation and expansion in autosomal recessive polycystic kidney disease (ARPKD) is poorly understood, but impaired mechanosensitivity to tubular flow and dysfunctional calcium signaling are important contributors. The activity of the mechanosensitive Ca2+-permeable TRPV4 channel underlies flow-dependent Ca2+ signaling in murine collecting duct (CD) cells, suggesting that this channel may contribute to cystogenesis in ARPKD. Here, we developed a method to isolate CD-derived cysts and studied TRPV4 function in these cysts laid open as monolayers and in nondilated split-open CDs in a rat model of ARPKD. In freshly isolated CD-derived cyst monolayers, we observed markedly impaired TRPV4 activity, abnormal subcellular localization of the channel, disrupted TRPV4 glycosylation, decreased basal [Ca2+]i, and loss of flow-mediated [Ca2+]i signaling. In contrast, nondilated CDs of these rats exhibited functional TRPV4 with largely preserved mechanosensitive properties. Long-term systemic augmentation of TRPV4 activity with a selective TRPV4 activator significantly attenuated the renal manifestations of ARPKD in a time-dependent manner. At the cellular level, selective activation of TRPV4 restored mechanosensitive Ca2+ signaling as well as the function and subcellular distribution of TRPV4. In conclusion, the functional status of TRPV4, which underlies mechanosensitive Ca2+ signaling in CD cells, inversely correlates with renal cystogenesis in ARPKD. Augmenting TRPV4 activity may have therapeutic potential in ARPKD.
MDM2 Regulates Dihydrofolate Reductase Activity through Monoubiquitination
Authors: Maria Maguire, Paul C. Nield, Timothy Devling, Rosalind E. Jenkins, B. Kevin Park, Radosław Polański, Nikolina Vlatković, Mark T. Boyd
Journal: Cancer Research (2008)

Abstract MDM2 is a ubiquitin ligase that is best known for its essential function in the negative regulation of p53. In addition, MDM2 expression is associated with tumor progression in a number of common cancers, and in some cases, this has been shown to be independent of p53 status. MDM2 has been shown to promote the degradation of a number of other proteins involved in the regulation of normal cell growth and proliferation, including MDM4 and RB1. Here, we describe the identification of a novel substrate for the MDM2 ubiquitin ligase: dihydrofolate reductase (DHFR). MDM2 binds directly to DHFR and catalyses its monoubiquitination and not its polyubiquitination. In addition, MDM2 expression reduces DHFR activity in a p53-independent manner, but has no effect upon the steady-state level of expression of DHFR. We show that changes in MDM2 expression alter folate metabolism in cells as evidenced by MDM2-dependent alteration in the sensitivity of cells to the antifolate drug methotrexate. Furthermore, we show that the ability of MDM2 to inhibit DHFR activity depends upon an intact MDM2 RING finger. Our studies provide for the first time a link between MDM2, an oncogene with a critical ubiquitin ligase activity and a vital one-carbon donor pathway involved in epigenetic regulation, and DNA metabolism, which has wide ranging implications for both cell biology and tumor development. [Cancer Res 2008;68(9):3232–41]
Enhancement of in vitro and in vivo antigen-specific antibody responses by interleukin 11.
Authors: T G Yin, P Schendel, Y C Yang
Journal: The Journal of Experimental Medicine (1992)

The availability of large quantities of highly purified recombinant interleukin 11 (rhuIL-11) has allowed us to investigate the effects of rhuIL-11 on sheep red blood cell (SRBC)-specific antibody responses in the murine system. The results showed that rhuIL-11 was effective in enhancing the generation of mouse spleen SRBC-specific plaque-forming cells (PFC) in the in vitro cell culture system in a dose-dependent manner. These effects of rhuIL-11 were abrogated completely by the addition of anti-rhuIL-11 antibody, but not by the addition of preimmunized rabbit serum. Cell-depletion studies revealed that L3T4 (CD4)+ T cells, but not Lyt-2 (CD8)+ T cells, are required in the rhuIL-11-stimulated augmentation of SRBC-specific antibody responses. The effects of rhuIL-11 on the SRBC-specific antibody responses in vivo were also examined. RhuIL-11 administration to normal C3H/HeJ mice resulted in a dose-dependent increase in the number of spleen SRBC-specific PFC as well as serum SRBC-specific antibody titer in both the primary and secondary immune responses. In mice immunosuppressed by cyclophosphamide treatment, rhuIL-11 administration significantly augmented the number of spleen SRBC-specific PFC as well as serum SRBC-specific antibody titer when compared with the cyclophosphamide-treated mice without IL-11 treatment. These results demonstrated that IL-11 is a novel cytokine involved in modulating antigen-specific antibody responses in vitro as well as in vivo.
USEFULNESS OF CREATINE-KINASE MYOCARDIAL BAND IN THE DIAGNOSIS OF ACUTE MYOCARDIAL INFARCTION AFTER THE ADVENT OF HIGH-SENSITIVITY CARDIAC TROPONINS
Authors: Mikkel M. Schoos, Martin Nielsen, Jørgen Thode, Steen Hansen, Kasper Iversen, Peter Clemmensen, Rolf Steffensen
Journal: Journal of the American College of Cardiology (2013)
Lost in translation: Does radiological evidence of right ventricular strain in acute pulmonary embolism trigger echocardiographic follow-up?
Authors: Claire McBrien, Diana Slim, O'Sullivan Laura, Simon Message, Raghuram Ananthakrishnan
Journal: European Respiratory Journal (2013)

Introduction: Pulmonary Hypertension (PH) is defined as raised Pulmonary Arterial Systolic Pressure ≥25mmHg at rest on Right Heart Catheterisation (ESC/ERS, 2009). Chronic Thromoboembolic Pulmonary Hypertension (CTEPH) is a complication of pulmonary embolism (PE), with a reported cumulative incidence of 3.1% at 1 year (Pengo et al, 2004). Patients with evidence of PH or Right Ventricular Dysfunction (RVD) during admission should undergo echocardiography after discharge (usually after 3-6 months) to establish PH resolution (ESC/ERS, 2009)  Objective: To assess if radiological evidence of RVD affects follow-up after PE.  Methods: Retrospective analysis of all patients diagnosed with PE on Computed Tomography Pulmonary Angiography (CTPA) in 2010 in a single Trust. CTPA reports were stratified according to presence or absence of RVD and echocardiography reports reviewed for signs of PH.  Results: 19.3%(329/1702) of CTPA scans revealed PE: Central (28.6%); Submassive (28.0%); Peripheral (44.4%). Figure 1 summarises the main findings.  Conclusions: RV strain is often not commented on in CTPA reports. Despite low numbers in some groups, it seems radiological evidence of RVD may be useful in deciding which patients need echocardiography after acute PE.
Base rates in the applied domain of accounting
Authors: Lisa Koonce
Journal: Behavioral and Brain Sciences (1996)

Abstract Koehler's call for a reanalysis of the base rate fallacy is particularly important in the applied domain of accounting, since base rate data appear to be an important input for many accounting tasks. In this commentary I discuss the use of base rates in accounting and explain why more flexible standards of performance are important when judging the use of base rates.