tbuckley/cabot-search huggingface dataset:
Phase I/II trial of reovirus serotype 3–Dearing strain in patients with recurrent ovarian cancer.
Authors: D. E. Cohn, G. Nuovo, M. C. Coffey, D. O'Malley, M. A. Villalona-Calero, M. R. Grever, D. Deam, J. A. Zwiebel, M. A. Phelps
Journal: Journal of Clinical Oncology (2010)

TPS253 Background: The prognosis associated with recurrent ovarian cancer is poor, and palliative therapy usually involves cytotoxic chemotherapy. In an effort to increase the survival and decrease the toxicity associated with treatment, increasing attention has been paid to targeted therapies. Reovirus Serotype 3–Dearing Strain (R) is a naturally occurring human reovirus. While reovirus infection is mild, R has been shown to replicate specifically in, and be cytopathic to, transformed cells possessing an activated Ras signaling pathway. In vivo, R has been demonstrated to be effective against solid tumors when administered into a tumor as well as intravenously (IV). In nude mice, intraperitoneal (IP) ovarian cancer cells are controlled with the administration of R. Given the improved survival with the use of IP chemotherapy in ovarian cancer, we set out to assess the feasibility and toxicity of the concurrent use of IV and IP R. The trial was designed explicitly with correlative endpoints to establish the ability of IV and IP administered R to infect IP tumors and to assess the timing and method of reovirus infectivity in IP tumors. Methods: Patients with recurrent ovarian cancer are eligible for this trial, and excluded if they had received more than one prior biologic agent for treatment of their disease. Patients are treated with a fixed dose of IV R days 1-5 (3 × 1010 TCID50/day) and an escalating dose of IP R days 1-2 (1 × 109 to 1011 TCID50/day) every 28 days. The first cycle of therapy includes only IV treatment to provide the opportunity to assess the replication of R in IP tumors when the tumors are biopsied at the time of IP port placement; thereafter, each cycle includes both IV and IP administration of R. IP tumors are again biopsied before cycle 3, allowing for the assessment of replication of R after IV and IP administration. Samples of peritoneal fluid are obtained at the time of IP R for additional analysis. A planned minimum of 18 patients will be treated on the phase I study, with an additional 27 on the phase II study utilizing the MTD (primary endpoint of the phase I study) of IP R (maximum 30+40=70); to date, 8 patients have been treated. The endpoint of the phase II study is the objective response rate, utilizing a 2-stage design. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncolytics Biotech GlaxoSmithKline, KCI, Lilly Oncolytics Biotech GlaxoSmithKline, KCI, Lilly Oncolytics Biotech
Combined treatment with dendritic cell vaccine and low-dose cyclophosphamide in patients with malignant melanoma.
Authors: L. Engell-Noerregaard, E. Ellebaek, T. Zeeberg, P. thor Straten, M. H. Andersen, I. M. Svane
Journal: Journal of Clinical Oncology (2010)

e13032 Background: Cancer vaccines based on dendritic cells (DC) have been tested in several clinical trials; in general, efficacy has been low, which might be due to inefficient immune activation. Regulatory T cells (Tregs) are known to posses immunosuppressive function; in the present study we investigate the ability of cyclophosphamide (Cy) to reduce the number of Tregs and increase efficacy of DC vaccination. Methods: Patients with progressive advanced melanoma received treatment with autologous DCs pulsed with p53, survivin and telomerase derived peptides (HLA-A2+) or tumor lysate (HLA- A2−). Cy 50 mg x 2 daily for a week, every second week, celecoxib (Ce) 200 mg daily, and IL-2 2MIU day 1-5 following each vaccine, were given concomitantly. Vaccine no. 1-4 was given weekly and vaccine 5-10 biweekly. If the patient achieved stable disease (SD) vaccines was continued monthly, until progression. The aims of this nonrandomized open labeled phase II trial were to evaluate tolerability, safety and the induced clinical and immunological responses. Results: 14 of 24 patients (58%) achieved SD after 6 vaccinations and 10 progressed. One patient maintained SD for 16 vaccines (10 months). No objective responses were seen. Two patients were excluded prior to their first vaccine and 1 was excluded in SD after 4 vaccines due to anemia and refusal of blood transfusion. Those 3 patients are not included in the results. The treatment was associated with a marked increase in the proportion of Tregs from baseline to the 4th vaccine followed by a decrease from the 4th to the 6th vaccine although not to the baseline values. Conclusions: The combination of DC vaccination and Cy was well tolerated. The induction of Tregs was not decreased by adding Cy, on the contrary a higher Treg level was maintained. However, the fraction of patients who achieved SD was more than doubled as compared to a comparable cohort of patients treated with DC vaccination without Cy. No significant financial relationships to disclose.
Predictive factors of self-reported hand eczema in adult Danes: a population-based cohort study with 5-year follow-up
Authors: N.G. Heede, J.P. Thyssen, B.H. Thuesen, A. Linneberg, J.D. Johansen
Journal: British Journal of Dermatology (2016)

Information about predictive factors of hand eczema is crucial for primary prevention.To investigate predictive factors of hand eczema in adult Danes from the general population.Participants from a cross-sectional 5-year follow-up study in the general population, aged 18-72 years (n = 2270), completed questionnaires about skin health and were grouped into four hand eczema groups: 'never', 'incident', 'nonpersistent' and 'persistent'. Multiple logistic regression models adjusted for age group and sex were used to evaluate associations with baseline variables. The participation rate for the follow-up study was 66·5% (29·7% of the participants originally invited to the baseline study).A history of atopic dermatitis (AD) was associated with both persistent and incident hand eczema [odds ratio (OR) 9·0, 95% confidence interval (95% CI) 5·6-14·4 and OR 3·0, 95% CI 1·7-5·2, respectively]. Thus, even in adulthood, a history of AD should be considered as a predictor of incident hand eczema. While filaggrin gene (FLG) null mutations were not associated with incident hand eczema, a statistically significant association was observed with persistent hand eczema (OR 3·1, 95% CI 1·8-5·2). Finally, contact sensitization (23 allergens without nickel) was also associated with persistent hand eczema (OR 2·5, 95% CI 1·2-5·0), independently of a history of AD.This study confirms a history of AD as the strongest predictor of persistent hand eczema. We additionally found that a history of AD was associated with incident hand eczema in adults, in contrast to FLG mutations, which were associated only with persistent hand eczema in individuals with a history of AD, and not with incident hand eczema. Our study adds new knowledge to the interplay between AD, FLG mutations and hand eczema in the adult general population.
QuantiFERON-TB performance enhanced by novel <i>Mycobacterium tuberculosis</i>-specific antigens
Authors: Monica Losi, Ashley J. Knights, Francesca Mariani, Alfonso M. Altieri, Gregorino Paone, Andre G. Loxton, Novel N. Chegou, John Kenneth, Mario G. Alma, Vittorio Colizzi, Gerhard Walzl, Cesare Saltini, Jeff Boyle, Massimo Amicosante
Journal: European Respiratory Journal (2015)

One of the most significant developments in the diagnosis of tuberculosis (TB) infection has been the introduction of whole-blood based interferon-γ release assays (IGRAs) [1–3]. IGRAs, commercially available as QuantiFERON-TB Gold In-Tube test (QFT) (QIAGEN, Germantown, MD, USA) and T-SPOT.TB (Oxford Immunotec Ltd, Abingdon, UK), are based on the detection of a T-cell immune response towards RD1 antigens (ESAT-6 and CFP-10), with the addition of the TB7.7 antigen for the QFT only [1]. IGRAs are endowed with great specificity, as the antigens used are almost exclusively expressed by the Mycobacterium tuberculosis (MTB) complex, but not Mycobacterium bovis bacille Calmette–Guerin (BCG) [1–3]. However, the diagnostic sensitivity of IGRAs can be improved (75–85% in HIV-negative active TB patients) especially in countries with a high TB burden [3]. Novel Mycobacterium tuberculosis antigens from macrophage infection model improve performance of QuantiFERON-TB <http://ow.ly/TaqTO> We thank Giuseppe Liotta (Dept of Biomedicine and Prevention, University of Rome "Tor Vergata", Rome, Italy) for the support with data and statistics analysis of the study results, and Graham Lord (Dept of Experimental Immunobiology, King's College, London, UK) for the critical reading and editing of the manuscript.
Down‐regulation of the cyclin‐dependent kinase inhibitor p57 is mediated by Jab1/Csn5 in hepatocarcinogenesis
Authors: Hui Guo, Li Jing, Yangzi Cheng, Vassilis Atsaves, Yi Lv, Tao Wu, Rujuan Su, Yamin Zhang, Ronghua Zhang, Wenbin Liu, George Z. Rassidakis, Yongchang Wei, Kejun Nan, Francois X. Claret
Journal: Hepatology (2015)

Down-regulation of p57 (KIP2) cyclin-dependent kinase inhibitors accelerates the growth and invasion of hepatocellular carcinoma (HCC), suggesting that p57 may play an important role in liver carcinogenesis. However, the mechanism or oncogenic signal leading to p57 down-regulation in HCC remains to be determined. Herein, we demonstrated that Jab1/Csn5 expression is negatively correlated with p57 levels in HCC tissues. Kaplan-Meier analysis of tumor samples revealed that high Jab1/Csn5 expression with concurrent low p57 expression is associated with poor overall survival. The inverse pattern of Jab1 and p57 expression was also observed during carcinogenesis in a chemically induced rat HCC model. We also found that mechanistically, Jab1-mediated p57 proteolysis in HCC cells is dependent on 26S-proteasome inhibitors. We further demonstrated that direct physical interaction between Jab1 and p57 triggers p57 down-regulation, independently of Skp2 and Akt pathways, in HCC cells. These data suggest that Jab1 is an important upstream negative regulator of p57 and that aberrant expression of Jab1 in HCC could lead to a significant decrease in p57 levels and contribute to tumor cell growth. Furthermore, restoration of p57 levels induced by loss of Jab1 inhibited tumor cell growth and further increased cell apoptosis in HCC cells. Moreover, silencing Jab1 expression further enhanced the antitumor effects of cisplatin-induced apoptosis in HCC cells.Jab1-p57 pathway confers resistance to chemotherapy and may represent a potential target for investigational therapy in HCC.
Gait speed is a predictor of readmission following hospitalisation for acute exacerbations of COPD
Authors: Samantha Kon, Sarah Jones, Susie Schofield, Jane Canavan, Claire Nolan, Mandy Dickson, Brigitte Haselden, Michael Polkey, Paul Cullinan, William Man
Journal: European Respiratory Journal (2014)

Background: Hospitalisation for acute exacerbations of COPD (AECOPD) is associated with high risk of readmission. Physical performance is potentially amenable to treatment and may help stratify patients at risk of early hospital readmission.

Aim: The aim of this study was to evaluate the ability of the 4-metre gait speed (4MGS) measured at hospital discharge to predict risk of future readmission.

Methods: 4MGS was measured in 213 patients admitted to hospital with a primary diagnosis of AECOPD at discharge. Data on all-cause non-elective hospital readmissions at 90 and 30 days was obtained.

Results: Baseline characteristics: mean age 72.1,FEV135%pred,52% male. Mean(SD) 4MGS was 0.61m/s(0.26). Patients with 4MGS <0.40ms-1 (Q1) had significantly increased rates of all-cause readmission at 90 and 30 days compared with 4MGS ≥0.80ms-1 (Q4):(48.2vs11.5%;p<0.001 and 31.4%vs7.4%;p<0.001). Gait speeds <0.40ms-1 were associated with a greater odds of all cause readmission at 90 and 30 days (age adjusted odds ratio (OR 95%CI) 5.32 (1.87to15.13) and 4.24 (1.23to14.55). Each 0.1ms-1 decline in 4MGS resulted in higher odds of readmission at 90 days (OR1.24 (1.08 to 1.42)). The association between 4MGS and readmission was seen in older patients only.

![Figure][1] 



Conclusion: The 4MGS is a simple measure of physical performance that independently predicts the risk of readmission in older patients hospitalised for acute exacerbation of COPD.

 [1]: pending:yes
Abstract MP078: Endothelial Function and Arterial Stiffness Associated with the Extent of Brain White Matter Disease
Authors: Dhananjay Vaidya, Paul Nyquist, Brian G Kral, Lisa R Yanek, Taryn F Moy, Lewis C Becker, Diane M Becker
Journal: Circulation (2012)

Background: Subclinical white matter disease of the brain is presumed to be of vascular origin. However associations with important facets of arterial structure and function have not been well studied. Methods: We examined 381 participants in GeneSTAR (57% female, 63% white, 37% black, age 51.6±10.5), a study of subclinical vascular disease in apparently asymptomatic individuals from families with early coronary artery disease (CAD). Volumetric measurement of white matter hyperintensities (lesion volume as a percent of brain volume, WMHV) was acquired from T3 magnetic resonance images. Ultrasound imaging of the brachial artery at rest and during hyperemia induced by 5 minutes of forearm ischemia was used to determine (1) the distensibility coefficient (DC) of the brachial artery at rest and (2) endothelial function as the percentage hyperemic flow mediated dilation (FMD). Mixed model analyses correcting for intrafamilial correlations, adjusting for age, sex, race, total and HDL-cholesterol, diabetes, hypertension, and current smoking, was used to test the association of WMHV with DC and FMD. Results: The unadjusted Spearman correlation of WMHV with FMD was -0.19 (p&lt;0.001) and with DC was -0.11 (p=0.030). In adjusted analysis, every 10% higher FMD was associated with 0.1% lower WMHV (p=0.028) and every 10% higher DC was associated with 3.3% lower WMHV (p=0.025). When both arterial measures were included in the same regression model, the association of FMD remained significant (p=0.037), while DC remained at the borderline (p=0.052). Conclusion: Two different facets of arterial function, (a) distensibility at rest, which is a material property of vessel walls, and (b) endothelial function resulting in functional reactivity to stimuli, are independently associated with subclinical white matter disease in the brain. This study reinforces the contention that white matter disease of the brain is of vascular origin.
Cux1 Enables Interhemispheric Connections of Layer II/III Neurons by Regulating Kv1-Dependent Firing
Authors: Fernanda M. Rodríguez-Tornos, Carlos G. Briz, Linnea A. Weiss, Alvaro Sebastián-Serrano, Saúl Ares, Marta Navarrete, Laura Frangeul, Maria Galazo, Denis Jabaudon, José A. Esteban, Marta Nieto
Journal: Neuron (2016)
Efficacy of erlotinib in the treatment of patients with brain metastasis from non small cell lung cancer
Authors: D. Abigerges, R. Khater, W. Mokadem, S. Chammas
Journal: Journal of Clinical Oncology (2006)

17149 Background: Erlotinib has shown good activity in lung cancer.Brain metastases remain a major problem in lung cancer treatment because of the blood brain barrier.We report three cases of adenocarcinoma of the lung metastatic to the brain treated with erlotinib100 mg daily. Methods: Two males (age 54 and 57 years) and one female (age 50 years). The two male patients received combination chemotherapy for stage IV disease (carboplatine, gemcitabine, docetaxel) and recurred after initial response. Both have been irradiated to brain with relapse. The female patient received adjuvant chemotherapy (carboplatine and gemcitabine) and adjuvant radiation to the mediastinum and presented one month after the end of radiation with right upper limb paralysis and clonic crisis. Results: The three patients presented very rapid response to erlotinib, with almost disappearance of neurological signs within the first two weeks. MRI of the brain showed partial response after 15 days in two patients and after one month in the third. The female patient is still responding and well doing after four months on erlotinib without radiation nor corticosteroids or antiepileptics, the later treatments being refused by the patient. One male patient died from pulmonary embolism 40 days after the initiation of erlotinib while he was still presenting tumor response. The other two patients are still alive with partial response and no neurological symptoms, four months after the initiation of erlotinib. Conclusions: We believe that erlotinib deserves further evaluation in non small cell lung cancer metastatic to the brain. The very quick response to treatment can select responders very early because of the cost of the drug. No significant financial relationships to disclose.
Introduction to the Analysis of Survival Data in the Presence of Competing Risks
Authors: Peter C. Austin, Douglas S. Lee, Jason P. Fine
Journal: Circulation (2016)

Competing risks occur frequently in the analysis of survival data. A competing risk is an event whose occurrence precludes the occurrence of the primary event of interest. In a study examining time to death attributable to cardiovascular causes, death attributable to noncardiovascular causes is a competing risk. When estimating the crude incidence of outcomes, analysts should use the cumulative incidence function, rather than the complement of the Kaplan-Meier survival function. The use of the Kaplan-Meier survival function results in estimates of incidence that are biased upward, regardless of whether the competing events are independent of one another. When fitting regression models in the presence of competing risks, researchers can choose from 2 different families of models: modeling the effect of covariates on the cause-specific hazard of the outcome or modeling the effect of covariates on the cumulative incidence function. The former allows one to estimate the effect of the covariates on the rate of occurrence of the outcome in those subjects who are currently event free. The latter allows one to estimate the effect of covariates on the absolute risk of the outcome over time. The former family of models may be better suited for addressing etiologic questions, whereas the latter model may be better suited for estimating a patient’s clinical prognosis. We illustrate the application of these methods by examining cause-specific mortality in patients hospitalized with heart failure. Statistical software code in both R and SAS is provided.
The prognostic factor in patients with myositis-associated interstitial lung disease
Authors: Akira Shiraki, Morihide Ando, Takashi Abe, Harunori Nakashima, Michiko Hibi, Joe Shindo
Journal: European Respiratory Journal (2014)

Introduction :   Anti-aminoacyl-transfer RNA synthetase antibodies (anti-ARS-abs) are most common antibodies in patients with polymyositis (PM) /dermatomyositis (DM). Anti-melanoma differentiation-associated gene 5 antibody (Anti-MDA5-ab) is a marker for rapidly progressive and poor prognostic interstitial lung disease (ILD) with amyopathic DM.   Objectives:   To evaluate the prognosis markers in patients with ILDs associated to PM/DM.   Methods :   We reviewed clinical (C-reactive protein, Krebs von den Lungen-6, anti-ARS-abs, anti-MDA5-ab, lymphocytes in bronchial lavage, amyopatic DM) and radiological data of the 51 consecutive patients with ILDs related to PM/DM, retrospectively. Anti-ARS-abs and anti-MDA5-ab were screened out by immunoprecipitation techniques in Department of Dermatology, Kanazawa University and ELISA method in Department of Dermatology, Nagoya University.   Results :   Median age was 61 years old and male gender was 25%. 23 patients had anti-ARS-abs and 9 patients had anti-MDA5 ab. 19 patients had neither of them. 6 patients (26%) with anti-ARS-abs, 5 (56%) with anti-MDA5-ab and 5 (26%) with double negative died in follow up period (45 months, median). C-reactive protein (CRP) g 1.0 (p=0.031, OR 1.91) was the only significant factor between overall survivors and non-survivors. On the other hand, anti-ARS-abs positive (p=0.031, OR 0.54) and anti-MDA5-ab positive (p=0.005, OR 2.04) were significant factors between 1 year survivors and non-survivors. Amyopathic DM was not risk factor on both long and short-term survivals.   Conclusion:   Anti-MDA5-ab was a risk factor on short-term survivals and CRP value was related to long-term prognosis in this cohort.
Improving inhalation parameters through dry powder inhalers (DPIs) after an acute asthma exacerbation
Authors: Wahida Azouz, Mokhtar El-Soussi, Henry Chrystyn
Journal: European Respiratory Journal (2012)

All DPIs are passive inhalers because they require the generation of an internal energy (P) from an interaction between the patient9s inhalation and the device9s resistance to deaggregate the formulation in the metered dose. During acute exacerbations patient inspiratory effort will be reduced and thus P will be reduced. We have measured the inhalation profiles of 18 asthmatics, mean(SD) age 42.0(11.8) years, on days 1-4 following their admission with an acute exacerbation. These measurements have been made using a Diskus (DKS), Easyhaler (EASY) and Turbuhaler (TBH) - inhalers with medium, medium/high and high resistance.  All parameters improved. PIF should not be considered in isolation and provides the wrong message, especially for high resistance DPIs, as PP and ACC are more important. The significance of the IV results needs to be investigated.
New method of evaluation of β-receptors' affinity and expression
Authors: Olga Agapova, Kirill Zykov, Yuri Skoblov
Journal: European Respiratory Journal (2014)

β-active drugs[ may change the affinity and the expression of β-receptors. This may reduce efficacy and safety of the treatment in patients with cardiorespiratory diseases. Receptors' affinity and expression can be assessed by radioligand method on lymphocytes and extrapolated on the bronchial smooth muscles, but this method is not appropriate for clinic.

Objective : Evaluate the change of relative activity of β-receptors in patients receiving β-active drugs using a new optimized radioligand method.

Methods : We provide an optimized method to determine β-receptors on T-lymphocytes' surface. This method is based on detection of the change in the amount of 125I-cyanopindolol in presence of specific β1 and β2 ligands. Method does not determine the amount of ligand binding sites but evaluates the changes of β-receptor relative potency occurring under the influence of β-blockers/agonists. Patients with or without bronchial asthma (BA) and arterial hypertension (AH) were enrolled.

Results : 6 patients without BA and AH aged 35,1±7,8 initially had specific β2-receptor binding 0,73±0,51 fmol/109 and β2 specific binding in percents of common binding 57,9±9,8%; after 30 min of inhalation of a short-β2-agonist–1,52±0,87fmol/109 (52,3±4,4%), after 2 hours–0,72±0,5fmol/109 (46,5±5,4%). 5 patients with AH and BA aged 54,6±6,7 initially had 1,14±0,39fmol/109 (46,8±12,4%), after 30 min-1,32±0,46fmol/109 (55,8±9,9%), after 2 hours–1,29±0,42fmol/109 (50,8±13,8%).

Conclusion : This method enables to assess relative activity of T-cells' β-receptors. Further research is needed to establish the validity of this method to identify receptors' changes and its association with clinical features during treatment with β-active drugs.