tbuckley/cabot-search huggingface dataset:
Effects of inhaled corticosteroids on asthmatic inflammation: The FeNOtype trial
Authors: William Anderson, Philip Short, Peter Williamson, Brian Lipworth
Journal: European Respiratory Journal (2012)

BACKGROUND: Personalised treatment for inflammatory asthma phenotypes confers superior benefits. The elevated exhaled nitric oxide (FeNO) inflammatory phenotype requires evaluation of dose-response to inhaled corticosteroids (ICS).  METHODS: Randomised, crossover trial in mild-to-moderate asthmatics receiving ICS with elevated FeNO>40ppb after ICS washout. Patients received 2 weeks of: fluticasone propionate 50ug twice-daily (FP100) or 250ug twice-daily (FP500). Primary outcome: response in diurnal domiciliary FeNO levels. Secondary outcomes included: mannitol challenge; serum eosinophilic cationic protein (ECP); blood eosinophil count; and asthma control questionnaire (ACQ).  RESULTS: 21 patients completed. We found significant dose-related reductions of diurnal FeNO compared to baseline: am FeNO: baseline=71ppb; FP100=34ppb, p  ACQ significantly improved exceeding the minimal important difference (>0.5) with values in keeping with controlled asthma (  CONCLUSION: There is significant, dose-response of diurnal FeNO to ICS in patients with a high FeNO phenotype, also associated with well controlled asthma.
Topotecan weekly versus routine 5-day schedule in patients with platinum-resistant ovarian cancer (TOWER): A randomized, two-stage phase-II study of the North-Eastern German Society of Gynaecological Oncology (NOGGO)
Authors: J. Sehouli, G. Oskay-Oezcelik, D. Stengel, A. du Bois, S. Markmann, S. Loibl, J. Wilke, A. Nugent, A. Belau, W. Lichtenegger
Journal: Journal of Clinical Oncology (2007)

5526 Background: Optimizing the therapeutic index (that is, maintaining drug effectiveness while reducing toxicity) is a major goal in chemotherapy for platinum-resistant ovarian cancer. Early phase-I/II studies suggest that weekly topotecan (T) might be effective and apparently better tolerated than the established 5-day regimen. As yet, no randomized comparison of both regimes was attempted. To prove the hypothesis of an improved therapeutic index with weekly T, we conducted a randomized, multicenter, two-stage phase-II trial, and herein present the data of the planned interim analysis. Methods: Pts with platinresistent ovarian and fallopian tube cancers or primary peritoneal carcinoma, measurable or assessable disease (GCIG-CA-125 response criteria), were eligible. Pts were randomized to receive either weekly T (d1,8,15/q28d, 4 mg/m 2 ) or T from d1–5/q21d at a dose of 1.25 mg/m 2 . According to Gehan’s two-stage-design, both arms were handled as independent studies. Overall response rate (CR + PR) was defined as primary study endpoint, secondary endpoints of the interim analysis were toxicity and safety. Results: 28 pts in the weekly and 21 pts in the conventional group, enrolled at 38 centers form the basis of this report. 230 cycles of chemotherapy were evaluated for toxicity analyses. Median age was 61 years (range, 36 - 82 years). Demographic baseline characteristics, including tumor stage and grade were well balanced between treatment arms. There were 2/28 and 5/21 responses in weekly and the conventional arm, respectively (Risk Ratio [RR] 0.30, 95% confidence interval [CI] 0.06 - 1.40, p=0.122). The risk of early treatment termination due to tumor progression (RR 1.39, 95%CI 0.75 - 2.56), haematological (RR 0.20, 95% CI 0.01 - 3.97) or non- hematological toxicities (RR 1.96, 95% CI 0.18 - 20.83) did not differ significantly between groups. The only three events of neutropenic fever occurred in the conventional arm (RR 1.70, 95% CI 0.99 - 1.16). Conclusions: Weekly T is well tolerated and potentially active. The second stage of this study will require additional 46 patients each arm. Complete enrolment is expected to be accomplished in May 2007. No significant financial relationships to disclose.
Treatment of acute lymphoblastic leukemia in adults: results of the L-10 and L-10M protocols.
Authors: P Schauer, Z A Arlin, R Mertelsmann, C Cirrincione, A Friedman, T S Gee, M Dowling, S Kempin, D J Straus, B Koziner
Journal: Journal of Clinical Oncology (1983)

Two successive protocols (L-10 and L-10M) employing multidrug induction therapy with vincristine, prednisone, and doxorubicin (Adriamycin) plus an intensive consolidation phase and maintenance program have led to a significant improvement in the prognosis of adult acute lymphoblastic leukemia (ALL). The complete remission (CR) rates for the 34 patients entered on the L-10 protocol and the 38 patients entered on the L-10M protocol were 85% and 84%, respectively. The median duration of remission has not yet been reached for either the L-10 (median follow-up, 5.5 years; range, 3.5-7.5 years) or the L-10M protocol (median follow-up, 2.5 years; range, 1-3.5 years). The median survival time has not yet been reached for the L-10M protocol. Central nervous system prophylaxis with intrathecal methotrexate alone was effective in preventing central nervous system relapse. An analysis of possible prognostic factors indicated that patients less than 25 years of age had a higher CR rate than older patients (p = 0.02). Patients with an initial leukocyte count below 15,000/microL experienced longer remissions than patients with a leukocyte count above 15,000/microL (p = 0.008), and patients who achieved CR within the first month of therapy were in remission longer than those requiring a longer time to achieve CR (p = 0.04). Patients with T cell ALL did not have a poorer prognosis than other patients treated on these protocols. The L-10 and L-10M protocols were well tolerated with minimal morbidity.
Cataract Surgery Outcomes in Uveitis
Authors: H. Nida Sen, Francis M. Abreu, Thomas A. Louis, Elizabeth A. Sugar, Michael M. Altaweel, Susan G. Elner, Janet T. Holbrook, Douglas A. Jabs, Rosa Y. Kim, John H. Kempen
Journal: Ophthalmology (2015)

To assess the visual outcomes of cataract surgery in eyes that received fluocinolone acetonide implant or systemic therapy with oral corticosteroids and immunosuppression during the Multicenter Uveitis Steroid Treatment (MUST) Trial.Nested prospective cohort study of patients enrolled in a randomized clinical trial.Patients that underwent cataract surgery during the first 2 years of follow-up in the MUST Trial.Visual outcomes of cataract surgery were evaluated 3, 6, and 9 months after surgery using logarithmic visual acuity charts. Change in visual acuity over time was assessed using a mixed-effects model.Best-corrected visual acuity.After excluding eyes that underwent cataract surgery simultaneously with implant surgery, among the 479 eyes in the MUST Trial, 117 eyes (28 eyes in the systemic, 89 in the implant group) in 82 patients underwent cataract surgery during the first 2 years of follow-up. Overall, visual acuity increased by 23 letters from the preoperative visit to the 3-month visit (95% confidence interval [CI], 17-29 letters; P < 0.001) and was stable through 9 months of follow-up. Eyes presumed to have a more severe cataract, as measured by inability to grade vitreous haze, gained an additional 42 letters (95% CI, 34-56 letters; P < 0.001) beyond the 13-letter gain in eyes that had gradable vitreous haze before surgery (95% CI, 9-18 letters; P < 0.001) 3 months after surgery, making up for an initial difference of -45 letters at the preoperative visit (95% CI, -56 to -34 letters; P < 0.001). Black race, longer time from uveitis onset, and hypotony were associated with worse preoperative visual acuity (P < 0.05), but did not affect postsurgical recovery (P > 0.05, test of interaction). After adjusting for other risk factors, there was no significant difference in the improvement in visual acuity between the 2 treatment groups (implant vs. systemic therapy, 2 letters; 95% CI, -10 to 15 letters; P = 0.70).Cataract surgery resulted in substantial, sustained, and similar visual acuity improvement in the eyes of patients with uveitis treated with the fluocinolone acetonide implant or standard systemic therapy.
Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis
Authors: Christopher J.D. Wallis, Refik Saskin, Richard Choo, Sender Herschorn, Ronald T. Kodama, Raj Satkunasivam, Prakesh S. Shah, Cyril Danjoux, Robert K. Nam
Journal: European Urology (2015)

To date, there is no Level 1 evidence comparing the efficacy of radical prostatectomy and radiotherapy for patients with clinically-localized prostate cancer.To conduct a meta-analysis assessing the overall and prostate cancer-specific mortality among patients treated with radical prostatectomy or radiotherapy for clinically-localized prostate cancer.We searched Medline, EMBASE, and the Cochrane Library through June 2015 without year or language restriction, supplemented with hand search, using Preferred Reporting Items for Systematic Reviews and Meta-Analysis and Meta-analysis of Observational Studies in Epidemiology guidelines. We used multivariable adjusted hazard ratios (aHRs) to assess each endpoint. Risk of bias was assessed using the Newcastle-Ottawa scale.Nineteen studies of low to moderate risk of bias were selected and up to 118 830 patients were pooled. Inclusion criteria and follow-up length varied between studies. Most studies assessed patients treated with external beam radiotherapy, although some included those treated with brachytherapy separately or with the external beam radiation therapy group. The risk of overall (10 studies, aHR 1.63, 95% confidence interval 1.54-1.73, p<0.00001; I(2)=0%) and prostate cancer-specific (15 studies, aHR 2.08, 95% confidence interval 1.76-2.47, p < 0.00001; I(2)=48%) mortality were higher for patients treated with radiotherapy compared with those treated with surgery. Subgroup analyses by risk group, radiation regimen, time period, and follow-up length did not alter the direction of results.Radiotherapy for prostate cancer is associated with an increased risk of overall and prostate cancer-specific mortality compared with surgery based on observational data with low to moderate risk of bias. These data, combined with the forthcoming randomized data, may aid clinical decision making.We reviewed available studies assessing mortality after prostate cancer treatment with surgery or radiotherapy. While the studies used have a potential for bias due to their observational design, we demonstrated consistently higher mortality for patients treated with radiotherapy rather than surgery.
Psychiatric correlates of incest in childhood
Authors: E F Pribor, S H Dinwiddie
Journal: American Journal of Psychiatry (1992)

The purpose of the study was to describe more precisely the type of psychiatric illness associated with incest during childhood.The Diagnostic Interview Schedule was administered to 52 adult women who had been victims of incest during childhood and to 23 age- and race-matched comparison subjects from local self-help agencies.The prevalence of 19 psychiatric disorders was higher in the incest group than base population rates. Rates of anxiety disorders (panic disorder, agoraphobia, social and simple phobia), major depression, and alcohol abuse and dependence were significantly higher in the incest group than in the comparison group. More severe types of incestuous abuse were associated with a higher risk for the development of psychiatric disorders.There was an association between incest and psychiatric disorders in this community-based treatment population. All patients, especially those who present with these specific psychiatric disorders, should be queried about childhood sexual abuse during the history.
Mechanism of enzymatic activation and epigenetic function of the automodification reaction catalyzed by PARP-1
Authors: Rafael Alvarez-Gonzalez, Hilda Mendoza-Alvarez
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2780 

We have determined the kinetics of PARP-1 automodification and the possible epigenetic function of the auto-poly(ADP-ribosyl)ation reaction catalyzed by PARP-1 [EC [2.4.2.30][1]] in transcriptional eukaryotic regulation by p53, a tumor suppressor protein. Enzymatic analysis of PARP-1 initial automodification reaction rates with the Hanes-Wilkinson plot was consistent with a sequential-ordered kinetic mechanism. Formation of the catalytically competent enzyme complex favored DNA-binding and PARP-1 dimerization first, followed by βNAD+ binding. The reaction rate also increased with characteristic substrate saturation kinetics as a function of nicked double stranded (ds) DNA. Saturating levels of nicked dsDNA resulted in a higher enzymatic efficiency, e.g., kcat/km , due to both, an increase in the rate constant ( kcat ) and a decrease in the binding affinity for βNAD+ (kNAD ). Therefore, we conclude that nicked ds DNA is a hetero-allosteric activator of PARP-1 dimerization and auto-poly(ADP-ribosyl)ation. Furthermore, in the presence of wild type p53, we observed that the automodification reaction of PARP-1, as well as the covalent poly(ADP-ribosyl)ation of the tumor suppressor protein reduced the ability of the heterologous polypeptide acceptor to recognize its DNA sequence-specific binding site as judged by Electrophoretic Mobility Shift Assays. In light of the high frequency of p53 single point mutations in different types of cancer, one must carefully evaluate the molecular interplay between PARP-1 and p53, two different DNA strand break sensors that are subject to epigenetic poly(ADP-ribosyl)ation. How these two “guardian angels” of genomic integrity, one constitutive (PARP-1) and one inducible (p53) gene products, regulate gene expression in immortally transformed cells, should open interesting avenues for tumor-specific chemotherapy. In summary, our results are consistent with the conclusion that the kinetic pathway to the formation of a catalytically competent quaternary complex of PARP-1 (kinetic mechanism) determines the poly(ADP-ribose) protein acceptor specificity, the efficiency of protein-bound ADP-ribose polymerization, and the regulation of maintenance of genomic integrity and transcriptional epigenetic regulation of p53-dependent gene expression.

 [1]: pending:yes
Distribution of natural resistance to NS3 protease inhibitors in hepatitis C genotype 1a separated into clades 1 and 2 and in genotype 1b of HIV-infected patients
Authors: S. Bagaglio, C. Uberti-Foppa, E. Messina, M. Merli, H. Hasson, A. Andolina, A. Galli, A. Lazzarin, G. Morsica
Journal: Clinical Microbiology and Infection (2015)
Abstract 13377: Predictors of High Operator Radiation Exposure During Cardiac Catheterization: Insights From the Radicure (Radiation Reduction During Cardiac Catheterization Using Real-time Monitoring) Study
Authors: Georgios Christopoulos, Aristotelis C Papayannis, Mohammed Alomar, Anna P Kotsia, Tesfaldet T Michael, Bavana V Rangan, Michele Roesle, Deborah Shorrock, Lorenza Makke, Spyros Maragkoudakis, Atif Mohammad, Karan Sarode, Charles E Chambers, Subhash Banerjee, Emmanouil S Brilakis
Journal: Circulation (2014)

Background: The RadiCure study examined the impact of real-time radiation monitoring on patient and operator exposure during cardiac catheterization. We sought to identify the factors associated with increased radiation exposure of the first operator. Methods: We studied the baseline clinical characteristics and procedural outcomes of 505 patients that were enrolled in the RadiCure study from January 2012 to May 2014. Multivariable analysis of high (above median or &gt;1.0 mrem) exposure of the first operator was performed. Variables with a significant (p&lt;0.10) association on univariable analysis were included in the multivariable model. Results: Mean age was 65±8 years and most patients were men (99%) with a high prevalence of diabetes mellitus (54%), and prior coronary artery bypass graft surgery (30%). Median procedure time was 27 (14-51) minutes; radial access was used in 18% of cases and chronic total occlusion (CTO) interventions constituted 7% of the procedures. Median fluoroscopy time was 6.2 (2.5-12.5) minutes; median patient Air Kerma (AK) radiation exposure was 0.908 (0.602-1.636) Gray; and median first operator exposure was 1.0 (0.5-2.2) mrem. On multivariable analysis, radial access (Odds ratio [OR] 6.62, 95% Confidence Interval [CI] 3.13-14.76), followed by CTO intervention (OR 5.53, 95% CI 1.73-20.71) and patient AK radiation exposure &gt; 0.9 Gray (OR 4.56, 95% CI 2.32-9.19) were found to be the strongest independent predictors of high first operator exposure. Real-time radiation exposure monitoring and use of a radioabsorbent drape were shown to have a significant protective effect (OR 0.33, 95% CI 0.19-0.57; and OR 0.38, 95% CI 0.18-0.77; respectively) (Figure 1). Conclusions: In the RadiCure study, high patient AK exposure, radial access and CTO intervention were associated with high first operator exposure. Real-time radiation monitoring and use of a radioabsorbent drape were independently associated with lower operator radiation exposure.
Closed suction system versus open system
Authors: Ahmed Elmansoury, Hedya Said
Journal: European Respiratory Journal (2014)

Background:catheter suction are used to remove tracheal secretions through the endotracheal tube in mechanically ventilated patients, which may be either closed suction system (css) or open one. In css the catheter is a part of ventilator circuit and there is no need disconnect the ventilator and it seems that the css prevent soiling and spraying of respiratory secretion into the ICU. Objective: to compare css system in comparison with an open tracheal suction system in adult patients receiving mechanical ventilation for more than 24 hours in terms of VAP incidence, length of stay in the intensive care unit and mortality. Method: We prospectively recruited all mechanically ventilated patient in our general ICU, Darelshefa hospital between January 2012 and January 2013. Group A are those with open tracheal suction system (OTSS) and group B with closed tracheal suction system (CTSS), comparing VAP incidence, length of stay in the intensive care unit and mortality between the two groups. Results group A (OTSS) where the incidence of VAP was30.13/1000 ventilator days not statistically significant in comparison with patients in group B with CTSS with VAP incidence 17.48/1000 ventilator days. Conclusion:There is no difference in the incidence of ventilator associated pneumonia and mortality rates between the two groups. The average length of stay declined in patients with OTSS group.
Mutations of the p53 gene and microsatellite inestability (MSI) as prognostic factors in metastatic colorectal cancer (CRC)
Authors: B. Calvo, N. Fuente, U. Aresti, M. S. Jangi, S. Carrera, A. Buque, A. Sancho, P. Garrido, A. Ruiz de Lobera, A. Muñoz
Journal: Journal of Clinical Oncology (2008)

22088 Background: Several genetic changes have been described associated with CRC, but the prognostic significance of most of them remains controversial. We analysed the distribution and the association with survival of some molecular markers in CCR tissues. Methods: From March-04 to June-05 73 patients were included with recent diagnosis of CRC: 53M/20F with a mean age of 70y (46–88). There were 25 rectal tumors (34%) and stage distribution was I:11, IIA:24, IIB:2, IIIA:3, IIIB:9, IIIC:8 and IV:16. During the anatomopathologic exam of the resected specimens, fresh samples were obtained (tumoral tissue and normal tissue), and they were stored in freezer vials at −86°C. In every sample all the following analysis were performed: LOH of the APC and DCC genes, MSI and Kras mutations using different biological techniques, and mutations of the p53 gene (exons 5 to 9) by sequence analysis. Results: LOH of DCC was found in 62% of the tumors, LOH of APC in 46% and MSI in 22% (MSI-LOW in 12 patients and MSI-HIGH in 4). Fifty one percent of the patients showed p53 mutations, mainly at the exons 5 (32%) and 8 (30%), and 38% carried a mutation in Kras (27 at the codon 12 and 1 at the codon 13). LOH of DCC was seen more frequently in older patients (p=0.045) and it showed associated with the presence of p53 mutations (p=0.005). In loco-regional stages (I-III), Kras was more frequently mutated in patients without node involvement (stages I-II vs III, p=0.012). In advanced disease, point mutations of p53 (p=0.031) and the abscence of MSI (p=0.022) were associated with a significant worse survival at multivariate analysis, even when clinical variables (age, gender, tumor location, palliative chemotherapy) were included in the model (p53: p=0.023; MSI: p=0.015). Conclusions: In our cohort of patients, mutations of the p53 supressor gene and the absence of MSI in the primary tumor are independent prognostic factors in patients with ACRC at the moment of diagnosis. No significant financial relationships to disclose.
A Novel Approach Using Sorafenib in Alpha Fetoprotein–Producing Hepatoid Adenocarcinoma of the Lung
Authors: Tatjana Gavrancic, Yeun-Hee Anna Park
Journal: Journal of the National Comprehensive Cancer Network (2015)

Hepatoid adenocarcinoma of the lung (HAL) is an extremely rare cancer without clear treatment guidance and with a poor prognosis. This report discusses a 64-year-old man who presented with complaints of hemoptysis and was found to have a right upper lobe (RUL) lung mass on chest CT with presence of a right hilar mass and retrocaval lymphadenopathy, and metastasis to the vertebral spine and rib. The patient was diagnosed with T2N2M1 (stage IV) unresectable disease. A biopsy of the RUL mass revealed hepatoid variant adenocarcinoma. Immunohistochemical stains showed tumor cells positive for CK7, AFP, Hep Par 1, napsin A, and cytoplasmic TTF-1 staining. In contrast, CK5, CK6, and CK20 were negative, and EGFR was wild-type. Serum alpha fetoprotein (AFP) level was elevated at 181 ng/mL. The patient was treated with platinum-based doublet chemotherapy and sorafenib, and his AFP level decreased to 25 ng/mL. This case report presents the novel use of sorafenib in combination with platinum-based doublet chemotherapy in EGFR wild-type HAL, which led to a partial response. Single-agent sorafenib led to stable disease overall, achieving a survival among the longest reported for unresectable stage IV, all while maintaining an ECOG performance status of 0 to 1.
Keeping up the balance: role of HDACs in cardiac proteostasis and therapeutic implications for atrial fibrillation
Authors: Deli Zhang, Xu Hu, Robert H. Henning, Bianca J.J.M. Brundel
Journal: Cardiovascular Research (2015)

Cardiomyocytes are long-lived post-mitotic cells with limited regenerative capacity. Proper cardiomyocyte function depends critically on the maintenance of a healthy homeostasis of protein expression, folding, assembly, trafficking, function, and degradation, together commonly referred to as proteostasis. Impairment of proteostasis has a prominent role in the pathophysiology of ageing-related neurodegenerative diseases including Huntington's, Parkinson's, and Alzheimer's disease. Emerging evidence reveals also a role for impaired proteostasis in the pathophysiology of common human cardiac diseases such as cardiac hypertrophy, dilated and ischaemic cardiomyopathies, and atrial fibrillation (AF). Histone deacetylases (HDACs) have recently been recognized as key modulators which control cardiac proteostasis by deacetylating various proteins. By deacetylating chromatin proteins, including histones, HDACs modulate epigenetic regulation of pathological gene expression. Also, HDACs exert a broad range of functions outside the nucleus by deacetylating structural and contractile proteins. The cytosolic actions of HDACs result in changed protein function through post-translational modifications and/or modulation of their degradation. This review describes the mechanisms underlying the derailment of proteostasis in AF and subsequently focuses on the role of HDACs herein. In addition, the therapeutic potential of HDAC inhibition to maintain a healthy proteostasis resulting in a delay in AF onset and progression is discussed.