tbuckley/cabot-search huggingface dataset:
MicroRNA-binding site polymorphisms in hematological malignancies
Authors: Agnieszka Dzikiewicz-Krawczyk
Journal: Journal of Hematology & Oncology (2014)

Dysregulation of microRNA networks has been implicated in hematological malignancies. One of the reasons for disturbed miRNA-mediated regulation are polymorphisms in miRNA-binding sites (miRSNPs), which alter the strength of miRNA interaction with target transcripts. In the recent years the first findings of miRSNPs associated with risk and prognosis in hematological malignancies have been reported. From the studies described in this review miRSNPs not only emerge as novel markers of risk and prognosis but can also lead to better understanding of the role of miRNAs in regulating gene expression in health and disease.
Heat-Induced Up-Regulation of NAD(P)H:Quinone Oxidoreductase Potentiates Anticancer Effects of β-Lapachone
Authors: Heon Joo Park, Eun Kyung Choi, Jihyung Choi, Ki-Jung Ahn, Eun Jung Kim, In-Mi Ji, Yeon Hee Kook, Seung-Do Ahn, Brent Williams, Robert Griffin, David A. Boothman, Chung K. Lee, Chang W. Song
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purpose of the present study was to evaluate the efficacy of mild hyperthermia to potentiate the anticancer effects of β-lapachone (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b]pyran-5,6-dione) by up-regulating NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells. Experimental Design: Effects of β-lapachone alone or in combination with mild heating on the clonogenic survival of FSaII fibrosarcoma cells of C3H mice and A549 human lung tumor cells in vitro was determined. Effects of heating on the NQO1 level in the cancer cells in vitro were assessed using Western blot analysis for NQO1 expression, biochemical determination of NQO1 activity, and immunofluorescence microscopy for NQO1 expression. Growth of FSaII tumors in the hind legs of C3H mice was determined after treating the host mice with i.p. injection of 45 mg/kg β-lapachone followed by heating the tumors at 42°C for 1 hour every other day for four times. Results: Incubation of FSaII tumor cells and A549 tumor cells with β-lapachone at 37°C reduced clonogenic survival of the cells in dose-dependent and incubation time–dependent manner. NQO1 level in the cancer cells in vitro increased within 1 hour after heating at 42°C for 1 hour and remained elevated for &amp;gt;72 hours. The clonogenic cell death caused by β-lapachone increased in parallel with the increase in NQO1 levels in heated cells. Heating FSaII tumors in the legs of C3H mice enhanced the effect of i.p.-injected β-lapachone in suppressing tumor growth. Conclusion: We observed for the first time that mild heat shock up-regulates NQO1 in tumor cells. The heat-induced up-regulation of NQO1 enhanced the anticancer effects of β-lapachone in vitro and in vivo.
Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP
Authors: L. Boeck, P. Eggimann, N. Smyrnios, H. Pargger, N. Thakkar, M. Siegemund, S. Marsch, J. Rakic, M. Tamm, D. Stolz
Journal: European Respiratory Journal (2010)

Ventilator-associated pneumonia (VAP) affects mortality, morbidity and cost of critical care. Reliable risk estimation might improve end-of-life decisions, resource allocation and outcome. Several scoring systems for survival prediction have been established and optimised over the last decades. Recently, new biomarkers have gained interest in the prognostic field. We assessed whether midregional pro-atrial natriuretic peptide (MR-proANP) and procalcitonin (PCT) improve the predictive value of the Simplified Acute Physiologic Score (SAPS) II and Sequential Related Organ Failure Assessment (SOFA) in VAP. Specified end-points of a prospective multinational trial including 101 patients with VAP were analysed. Death &lt;28 days after VAP onset was the primary end-point. MR-proANP and PCT were elevated at the onset of VAP in nonsurvivors compared with survivors (p = 0.003 and p = 0.017, respectively) and their slope of decline differed significantly (p = 0.018 and p = 0.039, respectively). Patients with the highest MR-proANP quartile at VAP onset were at increased risk for death (log rank p = 0.013). In a logistic regression model, MR-proANP was identified as the best predictor of survival. Adding MR-proANP and PCT to SAPS II and SOFA improved their predictive properties (area under the curve 0.895 and 0.880). We conclude that the combination of two biomarkers, MR-proANP and PCT, improve survival prediction of clinical severity scores in VAP.
Inhibition of type 5 phosphodiesterase counteracts β2-adrenergic signalling in beating cardiomyocytes
Authors: Andrea M. Isidori, Marisa Cornacchione, Federica Barbagallo, Antonio Di Grazia, Florencia Barrios, Lorenzo Fassina, Lucia Monaco, Elisa Giannetta, Daniele Gianfrilli, Silvio Garofalo, Xiaoxiao Zhang, Xiongwen Chen, Yang K. Xiang, Andrea Lenzi, Manuela Pellegrini, Fabio Naro
Journal: Cardiovascular Research (2015)

Compartmentalization of cAMP and PKA activity in cardiac muscle cells plays a key role in maintaining basal and enhanced contractility stimulated by sympathetic nerve activity. In cardiomyocytes, activation of adrenergic receptor increases cAMP production, which is countered by the hydrolytic activity of selective phosphodiesterases (PDEs). The intracellular regional dynamics of cAMP production and hydrolysis modulate downstream signals resulting in different biological responses. The interplay between beta receptors (βARs) signalling and phosphodiesterase 5 (PDE5) activity remains to be addressed. Using combined strategies with pharmacological inhibitors and genetic deletion of PDEs and βAR isoforms, we revealed a specific pool of cAMP that is under dual regulation by PDE2 and, indirectly, PDE5 activity. Inhibition of PDE5 with sildenafil produces a cGMP-dependent activation of PDE2 that attenuates cAMP generation induced by βAR agonists, with concomitant modulation of stimulated contraction rate and calcium transients. PDE2 haploinsufficiency abolished the effects of sildenafil. The negative chronotropic effect of PDE5 inhibition through PDE2 activation was also observed in sinoatrial node tissue from adult mice. PDE5 inhibition selectively lowered contraction rate stimulated by β2AR, but not β1AR activation, supporting a compartmentalization of the cGMP-modulated pool of cAMP. These data identify a new effect of PDE5 inhibitors on the modulation of cardiomyocyte response to adrenergic stimulation via PDE5–PDE2-mediated cross-talk.
Autologous Transplantation for Aggressive Non-Hodgkin’s Lymphoma: Results of a Randomized Trial Evaluating Graft Source and Minimal Residual Disease
Authors: Julie M. Vose, Graham Sharp, Wing C. Chan, Craig Nichols, Kevin Loh, David Inwards, Robert Rifkin, Philip J. Bierman, James C. Lynch, Dennis D. Weisenburger, Anne Kessinger, James O. Armitage
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To determine whether the source of autologous hematopoietic stem cells altered the clinical outcomes of patients undergoing high-dose chemotherapy and hematopoietic stem-cell transplantation (HSCT) for aggressive non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Of 105 high-risk, persistent, or relapsed NHL patients slated for an autologous HSCT entered onto this trial, 93 eligible patients were randomized to receive cytokine-naive autologous bone marrow transplantation (ABMT) (n = 46) or mobilized peripheral-blood stem-cell transplantation (PBSCT) (n = 47). All patients received carmustine, etoposide, cytarabine, and cyclophosphamide as the conditioning regimen. PBSCT patients also received identical mobilization with granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/d, and both groups received G-CSF 5 μg/kg/d after the infusion of the stem-cell product until neutrophil engraftment. RESULTS: PBSCT patients had significantly faster engraftment of all cell lineages: median time to absolute neutrophil count ≥ 500/μL, 10 days versus 13 days on the ABMT arm; median time to platelet count greater than 20,000/μL untransfused, 11 days versus 15 days on the ABMT arm; and median time to RBC transfusion independence, 8 days versus 16 days on the ABMT arm. The complete response rate was 72% for PBSCT and 54% for ABMT. The death rate before posttransplant day 100 was 2% on the ABMT arm and 6% on PBSCT arm. Event-free survival was 37% for PBSCT and 37% for ABMT. However, overall survival for PBSCT was 61% compared with 43% for ABMT. CONCLUSION: Patients with aggressive NHL receiving HSCT randomized to PBSCT demonstrated improved neutrophil engraftment and platelet and RBC transfusion independence. The complete response rate and EFS were not statistically different by randomization arm. Patients whose harvests were positive for minimal residual disease by molecular analysis had poorer EFS.
Patients with non-Jo-1 anti-RNA-synthetase autoantibodies have worse survival than Jo-1 positive patients
Authors: Baptiste Hervier, Hervé Devilliers, Olivier Benveniste
Journal: Annals of the Rheumatic Diseases (2013)

We read with interest the manuscript by Aggarwal et al 1 entitled ‘ Patients with non-Jo-1 anti-RNA-synthetase autoantibodies have worse survival than Jo-1 positive patients ’. This large cohort study provides important information on outcomes for patients with antisynthetase syndrome (ASS), based on the specificity of the anti-RNA-synthetase autoantibody subtypes. Interestingly, the authors decided to include patients with anti-glycyl (EJ), anti-isoleucyl (OJ) and anti-asparagyl (KS)-tRNA-synthetase autoantibodies, something which had not yet been done in the previous studies,2 ,3 due to …
Health-related quality of life in COPD patients with chronic respiratory failure
Authors: M. L. Duiverman, J. B. Wempe, G. Bladder, H. A. M. Kerstjens, P. J. Wijkstra
Journal: European Respiratory Journal (2008)

The Maugeri Respiratory Failure (MRF-28) and Severe Respiratory Insufficiency (SRI) questionnaires were recently developed to assess health-related quality of life (HRQoL) in patients with chronic respiratory failure, although not exclusively in chronic obstructive pulmonary disease (COPD) patients. The aim of the present study was to investigate whether the MRF-28 and SRI are reliable and valid HRQoL questionnaires in COPD patients with chronic hypercapnic respiratory failure (CHRF). In total, 72 COPD patients with CHRF underwent pulmonary function and exercise testing, and completed the MRF-28, the SRI, the Chronic Respiratory Questionnaire (CRQ), the Hospital Anxiety and Depression Scale, the Groningen Activity and Restriction Scale and two dyspnoea indexes. Physical domain scores of the questionnaires correlated with exercise tolerance, dyspnoea and daily activities, while psychological domains correlated strongly with anxiety and depression. Anxiety scores accounted for 51 and 56% of the total explained variance in total CRQ and SRI scores, respectively. The emphasis of the MRF-28 was restrictions in activities of daily living (52% of total variance). In conclusion, the present study showed that the Maugeri Respiratory Failure and Severe Respiratory Insufficiency questionnaires were reliable and valid questionnaires in chronic obstructive pulmonary disease patients with chronic hypercapnic respiratory failure. While the emphasis in the Maugeri Respiratory Failure questionnaire is on activities of daily living, the Severe Respiratory Insufficiency questionnaire, like the Chronic Respiratory Questionnaire, is more related to anxiety and depression.
Prospective Validation of a New Method of Monitoring Minimal Residual Disease in Childhood Acute Myelogenous Leukemia
Authors: Daniel Steinbach, Peter Bader, Andre Willasch, Stephan Bartholomae, Klaus-Michael Debatin, Martin Zimmermann, Ursula Creutzig, Dirk Reinhardt, Bernd Gruhn
Journal: Clinical Cancer Research (2014)

Abstract Purpose: This study evaluated the prognostic impact of a novel, simple, and standardized assay for monitoring minimal residual disease (MRD) in pediatric acute myelogenous leukemia (AML). Experimental Design: The expression of seven leukemia-associated genes (WT1, PRAME, CCL23, GAGED2, MSLN, SPAG6, and ST18) was measured by TaqMan Low Density Arrays in 112 patients and 52 healthy controls. Patients were treated according to the multicenter study AML-BFM 2004. Samples were collected prospectively at standard time points. The laboratory that measured MRD was blinded to patient outcome. Results: Relapse-free survival (RFS) was 95% (N = 19; SE = 5%) if expression of all genes was down to normal on day 15, 63% (N = 41; SE = 8%) if expression was normalized on day 28, and 38% (N = 21; SE = 11%) in patients who still showed elevated expression on day 28. The prognostic impact of MRD remained significant (P = 0.002) when patients were stratified for the AML-BFM 2004 risk group. Multivariate analysis identified the MRD risk group and day 28 cytology as the only independent prognostic factors. Patients with a cytologic nonremission on day 28, which was confirmed by MRD, had a dismal prognosis. Only 1 out of 8 patients survived without relapse. Conclusions: This novel method of monitoring MRD has a strong prognostic impact that is independent from established risk factors in childhood AML. Clin Cancer Res; 21(6); 1353–9. ©2014 AACR.
Classic of Operative Gynaecology
Authors: J. C. Moir
Journal: BMJ (1975)

This is a neat pocket-size book, with much of the material in tabular or note form.Presumably for economy reasons there are no plates or illustrations.It is one of the first textbooks of geriatrics confined to disease of one system.With few exceptions, all diseases found in textbooks of general medicine occur in old age.The difficulty in writing a geriatric textbook is to avoid a recapitulation of general medicine.A reason- able section must always be given to the physiology and anatomy of ageing, followed by emphasis on the peculiarities of disease in the old.Much of the necessary information
High-dose VP-16-213 and autologous bone marrow transplantation for refractory malignancies: a phase I study.
Authors: S N Wolff, M F Fer, C M McKay, K R Hande, J D Hainsworth, F A Greco
Journal: Journal of Clinical Oncology (1983)

VP-16-213, a congener of epipodophyllotoxin, is a useful chemotherapeutic agent especially against small-cell carcinoma of the lung, germ cell carcinoma, and lymphoma. The standard dose of this drug is limited by myelosuppression. Autologous transplantation of cryopreserved bone marrow assures the restoration of hematopoiesis after marrow ablative cytotoxic therapy. By using this technique, VP-16-213 was dose-escalated using a Fibonacci scheme from the previous highest dose administered to humans (1,500 mg/m2) to 2,700 mg/m2 (900 mg/m2 per day for three consecutive days). At 2,700 mg/m2, severe extramedullary toxicity of the mucous membranes was observed in three of three courses. At the next highest dose (2,400 mg/m2), two of 18 courses (11%, p less than 0.01) resulted in severe mucositis, thus defining this dose as the maximally tolerated dose based on extramedullary toxicities. As anticipated, myelotoxicity was severe but based on the kinetics of marrow recovery, VP-16-213 in these doses appeared not to be marrow ablative. Based on responses observed in this study, high-dose VP-16-213 should be explored in phase II studies or used in combination chemotherapy.
Inhibition of Hepatic Stellate Cell Proliferation and Activation by the Semisynthetic Analogue of Fumagillin TNP-470 in Rats
Authors: Yan Qing Wang, Kazuo Ikeda, Takashi Ikebe, Kosei Hirakawa, Michio Sowa, Kazuki Nakatani, Norifumi Kawada, Kenji Kaneda
Journal: Hepatology (2000)

Proliferation and activation of hepatic stellate cells (HSCs) are critical steps for the development of postnecrotic fibrosis in the liver. The present study aimed to reveal the inhibitory effect of the semisynthetic analogue of fumagillin TNP-470 on these events for its possible use as an antifibrogenic agent. Rat models of carbon tetrachloride (CCl(4))- and dimethylnitrosamine-induced hepatic fibrosis were used for an in vivo study. In both models, the fibrotic area was considerably decreased by concurrent repetitive subcutaneous injections of 30 mg/kg body weight of TNP-470. In CCl(4)-induced fibrosis, factor VIII-related antigen-positive blood vessels, desmin-, or alpha-smooth muscle actin (alphaSMA)-positive mesenchymal cells, bromodeoxyuridine (BrdU)-positive mesenchymal cells also decreased in number by treatment with TNP-470. In in vitro experiments, a supplement of 1,000 ng/mL TNP-470 suppressed BrdU incorporation and cyclins D1, D2, and E expression by cultured HSCs in the absence and/or presence of platelet-derived growth factor (PDGF). Expression of HSC activation markers, i.e., alphaSMA and PDGF receptor beta, was also suppressed. The present results indicate that TNP-470 inhibits HSC proliferation by blocking the cell-cycle transition from G1 to S and HSC activation, and, as the consequence, prevents the progression of hepatic fibrosis, probably being coupled with its antiangiogenic effect.
Weight, Weight Gain, and Survival After Breast Cancer Diagnosis
Authors: Candyce H. Kroenke, Wendy Y. Chen, Bernard Rosner, Michelle D. Holmes
Journal: Journal of Clinical Oncology (2005)

Purpose To determine whether weight prior to diagnosis and weight gain after diagnosis are predictive of breast cancer survival. Methods Patients included 5,204 Nurses' Health Study participants diagnosed with incident, invasive, nonmetastatic breast cancer between 1976 and 2000; 860 total deaths, 533 breast cancer deaths, and 681 recurrences (defined as secondary lung, brain, bone, or liver cancer, and death from breast cancer) accrued to 2002. We computed the change in body mass index (BMI) from before to the first BMI reported ≥ 12 months after the date of diagnosis. Cox proportional hazards models were used to evaluate associations of categories of BMI before diagnosis and of BMI change with time to event. We stratified by smoking, menopausal status, and breast cancer–related variables. Results In multivariate-adjusted analyses, weight before diagnosis was positively associated with breast cancer recurrence and death, but this was apparent only in never smokers. Similarly, among never-smoking women, those who gained between 0.5 and 2.0 kg/m 2 (median gain, 6.0 lb; relative risk [RR], 1.35; 95% CI, 0.93 to 1.95) or more than 2.0 kg/m 2 (median gain, 17.0 lb; RR, 1.64; 95% CI, 1.07 to 2.51) after diagnosis had an elevated risk of breast cancer death during follow-up (median, 9 years), compared with women who maintained their weight (test for linear trend, P = .03). Associations with weight were stronger in premenopausal than in postmenopausal women. Similar findings were noted for breast cancer recurrence and all-cause mortality. Conclusion Weight and weight gain were related to higher rates of breast cancer recurrence and mortality, but associations were most apparent in never-smoking women.
Smoking status, prevalence of smoking-related diseases and their impact on costs in patients hospitalized in the thoracic units of a tertiary hospital in Brazil
Authors: Anna Miethke Morais, Elisa Maria Siqueira Lombardi, Gustavo F. Prado, Stella R. Martins, Renato Paceli, Mário Terra-Filho, Ubiratan de Paula Santos
Journal: European Respiratory Journal (2013)

Introduction: Smoking is the leading global risk factor of preventable death, with high costs for the Health-Care System. Aims: To evaluate the prevalence of smoker status and to assess the portion of hospitalizations due to smoking-related diseases, as well as their impact on the total hospitalization costs in our thoracic units. Methods: Patients hospitalized in the Pulmonary Medicine, Thoracic Surgery and Lung Transplantation divisions between February and July 2012 were interviewed about demographics and smoking. Data on the diagnosis and hospitalization costs were supplemented by the hospital’s information sector. A descriptive analysis of the data was performed. Results: 281 patients were interviewed and 344 admissions were recorded. The sample contained 157 never smokers (55,9%), 111 former smokers (39,5%) and 13 smokers (4,6%). Among never smokers and former smokers, 82% and 96%, respectively, had environmental tobacco exposure. Smoking-related diseases were responsible for 45% of all admissions (59% of smokers’ and former smokers’; 35% of never smokers’). Most common smoking related diseases were neoplasms (42,6%; 59% of them were lung cancer), tobacco-related-ILDs (13,5%) and COPD (12,3%). Hospitalizations for smoking-related diseases were responsible for 33% of total costs. Conclusions: This study points to the high prevalence of ever-smokers and environmental tobacco smoke, as well as the high proportion of hospitalizations for smoking-related diseases, even among never smokers. Also alerts to the significant portion of hospital costs for tobacco-related diseases in our thoracic units.
Efficacy and safety of tofacitinib, an oral Janus kinase inhibitor, in the treatment of psoriasis: a Phase 2b randomized placebo-controlled dose-ranging study
Authors: K.A. Papp, A. Menter, B. Strober, R.G. Langley, M. Buonanno, R. Wolk, P. Gupta, S. Krishnaswami, H. Tan, J.A. Harness
Journal: British Journal of Dermatology (2012)

Tofacitinib is a novel, oral Janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.This Phase 2b, 12-week, dose-ranging study (A3921047, NCT00678210) aimed to characterize the exposure-response, efficacy and safety of tofacitinib vs. placebo in patients with moderate-to-severe chronic plaque psoriasis.One hundred and ninety-seven patients were randomized. The primary endpoint was the proportion of patients achieving a ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12.At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25·0% (2 mg; P < 0·001), 40·8% (5 mg; P < 0·0001) and 66·7% (15 mg; P < 0·0001), compared with placebo (2·0%). Significant increases in the proportion of PASI 75 responses were seen by week 4 and were maintained at week 12. Exposure-response over the 0-15 mg tofacitinib twice-daily dose range was successfully characterized. PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib vs. placebo. The most frequently reported adverse events (AEs) were infections and infestations: 22·4% (2 mg twice daily), 20·4% (5 mg twice daily), 36·7% (15 mg twice daily) and 32·0% (placebo). Discontinuations due to AEs were 6·0%, 2·0%, 4·1% and 6·1% of patients in the placebo, and 2, 5 and 15 mg twice-daily tofacitinib groups, respectively. Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in haemoglobin and neutrophils were observed.Short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well tolerated.