tbuckley/cabot-search huggingface dataset:
The inverse agonist propranolol does not confer steroid-sparing activity in persistent asthma
Authors: William Anderson, Philip Short, Peter Williamson, Arvind Manoharan, Brian Lipworth
Journal: European Respiratory Journal (2014)

Background: The murine asthma model shows that switching off airway beta-2 receptors with an inverse agonist may confer anti-inflammatory as well as steroid-sparing activity. We therefore assessed the putative steroid sparing effects of propranolol, an inverse agonist, by comparing propranolol plus low-dose inhaled corticosteroid (ICS) vs. higher dose ICS alone.  Methods: Randomised, double blind, placebo-controlled, crossover trial in mild-moderate persistent asthmatics. Run-in (2weeks): HFA-BDP 100μg/day. Randomised treatments (4weeks): propranolol 80mg/day + HFA-BDP 100μg/day; versus placebo + HFA-BDP 400μg/day. Propranolol up-titrated to 80mg/day over initial 2weeks. Tiotropium co-administered until 5 days pre-histamine challenge (primary outcome).  Results: 16 patients completed, mean: age 38yr; FEV 1  86·4%; Histamine PC 20  1·39mg/ml; ICS 406μg/day. Histamine PC 20  remained unchanged with propranolol + HFA-BDP100 compared to baseline (HFA-BDP100): 0·17 doubling dilution (dd) difference (95%CI -0·58-0·92). There was a significant improvement with HFA-BDP400 vs. baseline: 1·05dd (95%CI 0·43-1·66), P=0·02; and vs. propranolol + HFA-BDP100: 0·88dd (95%CI 0·45-1·30), P=0·006. Significant improvements occurred with HFA-BDP400 vs propranolol + HFA-BDP100 for FeNO, Eosinophils and ECP, and for AQLQ symptom score. Evening FEV 1  fell with propranolol: 0·22L (95%CI 0·10-0·34L), P=0·012, while ACQ and AQLQ remained unchanged.  Conclusion: The inverse agonist propranolol produced no improvements when added to low dose ICS, while further significant improvements in AHR and inflammation were demonstrated with higher dose ICS. Thus propranolol does not confer steroid-sparing activity in persistent asthma.
Prognostic significance of aneuploidy in non-small cell lung cancer (NSCLC) patients (pts)
Authors: R. Dziadziuszko, E. Wegrzynowicz, I. Kardas, J. Limon, J. Jassem
Journal: Journal of Clinical Oncology (2004)

7319 Background: DNA content abnormalities assessed with flow cytometry are linked with a poor prognosis in many cancer types, including NSCLC. The aim of this study was to determine prognostic significance of aneuploidy assessed with conventional cytogenetic analysis in NSCLC. Methods: Study group included 89 consecutive NSCLC pts (15 females and 74 males, mean age of 61 years) who underewent pulmonary resection between April 1997 and July 1999. Pathologic stage distribution was as follows: I (27 pts), II (23 pts), III (36 pts) and IV (3 pts). 54 pts had sqaumous cell carcinoma, 22 -adenocarcinoma, 6 –large cell carcinoma and 7 –mixed NSCLC. Tumor ploidy was determined by karyotyping of primary tissue culture cells derived from postoperative specimens. G-banding with Wright stain and further analysis was performed according to recommendations of the International System of Human Cytogenetics Nomenclature. Results: Aneuplody was present in 33 tumors (37%), more frequently in adenocarcinoma (25 pts, 71%) than in squamous cell carcinoma (8 pts, 15%, p<0.001). No correlation of aneuploidy with grade (p=0.70), stage (p=0.29), age (p=0.69) and sex (p=1.00) was found. Median survival of pts with and without aneuploidy was 15 and 38 months, respectively (log rank; p=0.028). In the multivariate analysis, aneuploidy was the strongest adverse factor for survival (HR=1.92, 95% CI 1.11–3.32; p=0.020), followed by tumor stage (HR=1.59, 95% CI 0.92–2.74; p=0.094). Conclusion: NSCLC aneuploidy, as evaluated by conventional cytogenetic analysis, occurs more frequently in adenocarcinoma than in squamous cell carcinoma, and is an independent predictor of poor prognosis. No significant financial relationships to disclose.
A phase II trial of denileukin difititox–in previously treated, advanced non-small cell lung cancer (NSCLC)
Authors: M. A. Gerena Lewis, R. Shukla, B. Kleykamp, A. R. Jazieh, J. Hainsworth
Journal: Journal of Clinical Oncology (2004)

7292 Background: Prior studies have shown that the interleukin-2 receptor (IL-2r) is expressed on lung cancer cells suggesting that an IL-2r targeted therapy may have a role in the management of NSCLC. Denileukin diftitox, ONTAK®, is a chimeric protein that targets the cytocidal properties of diphtheria toxin to cells that express IL-2r and is approved for the treatment of cutaneous T-cell lymphoma. In this study, we evaluate the potential benefit of ONTAK in the treatment of advanced NSCLC. Methods: This multi-center phase II clinical trial is open for enrollment of patients with ECOG PS 0–2 and Stage IIIB/IV NSCLC who have failed at least one prior chemotherapy regimen. ONTAK is infused at 9 μg/kg on Day 1 of Cycle 1 only followed by 18 μg/kg/day Day 2–5 then every 21 days for a total of 6 cycles. Radiographic evaluation of tumor response is performed every 2 cycles. Results: Twenty patients have enrolled so far. There are 11 male and 9 female with a median age of 53 years (range 21–80). The mean number of prior treatment regimens is 2 (range 1–5). Patients received a mean of 3 (range 1–6) ONTAK cycles. There were no Grade 4 toxicities. Treatment-related Grade 3 toxicities included nausea (3), emesis (2), fever (2), fatigue (2), dehydration (2), edema (1), itching (1), pain at tumor site (1), flu-like symptoms (1), and headache (1). Symptomatic capillary leak syndrome and treatment-related death were not encountered. No patient was withdrawn due to treatment-related toxicity. Of the 20 patients enrolled, 4 are too early to evaluate for disease response, 2 had unconfirmed partial response using the RECIST criteria, 6 had stable disease, 7 had progressive disease, and 1 was not evaluable. The median time to disease progression for all evaluable patients was 1.8 months (9 days-13 months) and the median overall survival was 4.3 months (2.7 weeks–15.5 months). Conclusion: Interim analysis of the first 20 patients enrolled in this trial suggests that ONTAK has promising activity and a favorable safety profile in the management of previously treated advanced NSCLC. Further evaluation of the role of ONTAK in NSCLC is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Ligand Ligand Ligand
Prevalence of extra-pulmonary comorbidities in COPD patients and its correlation with severity of disease
Authors: Kunal Luthra, Narendra Kumar Gupta, Mahendra Kumar
Journal: European Respiratory Journal (2014)

Introduction : COPD often coexists with other diseases (comorbidities) that may have a significant impact on prognosis. Some of these arise independently of COPD, whereas others may be causally related.

Aims and objectives : To study the prevalence of extrapulmonary comorbidities in COPD patients and its correlation with severity of disease as assessed by FEV1%.

Methods : 100 patients who presented to respiratory medicine department with complains of breathlessness, cough, or sputum production and history of exposure to risk factors were enrolled for the study. After diagnosing and analysing the severity of COPD based on FEV1%, patients were screened for comorbidities - levels of Triglycerides and HDL, haemoglobin, glucose, resting systolic and diastolic blood pressure, renal function test, bone mineral density (using Ultrasound scan of calcaneum), symptoms of anxiety and depression, and 2D-Echocardiography was done.

Results : Preavalence of comorbidities ;Hypertension 58%, underweight 44%, osteoporosis 44%, depression 31%, dyslipidemia 29%, anxiety 29%, diabetes 18 %, ischemic heart disease 13%, chronic renal failure 13%,heart failure 12%, Anemia 11%,and polycythemia in 10% of patients. Prevalence of hypertension, dyslipidemia, anxiety, depression, and underweight increased with increase in severity of disease, and this correlation was statistically significant (p value < 0.05).

Conclusion : Comorbidities are very common in COPD patients. Efforts should be made to screen for comorbidity, to weigh the impact of individual comorbidities on health status and, consequently, to plan a truly multidimensional therapeutic strategy especially in patients with severe disease.
European public health policies for managing contacts of invasive meningococcal disease cases better harmonised in 2013 than in 2007
Authors: Sabine Vygen, Wiebke Hellenbrand, Pawel Stefanoff, Germaine Hanquet, Sigrid Heuberger, James Stuart
Journal: Eurosurveillance (2016)

In 2007, a European survey identified variation in country policies on public health management of invasive meningococcal disease (IMD). In 2009–10, the European Centre for Disease Prevention and Control (ECDC) published evidence-based guidance on IMD. We therefore surveyed again European countries to describe policies for managing IMD cases and contacts in 2013. We asked national IMD public health experts from 32 European countries to complete a questionnaire focusing on post-exposure prophylaxis (PEP) for IMD contacts and meningococcal vaccination. Proportions in 2007 and 2013 were compared using the chi-squared test. All 32 countries responded, with responses from two regions for Belgium and Italy; half stated having used ECDC guidance to update national recommendations. PEP was recommended to close contacts in 33 of 34 countries/regions, mainly ciprofloxacin for adults (29/32 countries) and rifampicin for children (29/32 countries). ECDC guidance for managing IMD contacts in airplanes was strictly followed by five countries/regions. Twenty-three countries/regions participated in both surveys. Compared with 2007, in 2013, more countries/regions recommended i) ceftriaxone for children (15/23 vs 6/20; p = 0.03), ii) PEP for all children in the same preschool group (8/23 vs 17/23; p = 0.02). More countries/regions recommended evidence-based measures for IMD public health management in 2013 than 2007. However, some discrepancies remain and they call for further harmonisation.
Efficiency of a DNA vaccine on allergic asthma
Authors: Adrien Tissot, Fanny Beilvert, Julie Chesné, Marie Langelot, David Lair, Marie Aude Muller, Bruno Pitard, Antoine Magnan
Journal: European Respiratory Journal (2012)

Specific immunotherapy is an attractive therapeutic option in allergic asthma. It reduces symptoms and the use of medication. Nevertheless the efficiency of immunotherapy remains limited and it may cause anaphylactic adverse effects when administrated subcutaneously. One of the new modality of immunotherapy is based on DNA vaccination which consists in the administration of DNA sequences encoding an antigen. It enables a targeted immunogenicity a Th1 bias and a good tolerance profile.

In this study we used a DNA plasmid encoding Der f 1, a major allergen from the house dust mite dermatophagoides farinae, formulated with a synthetic vector. This vaccine was tested on a murine model of allergic asthma with a prophylactic approach. We evaluated the response to treatement by airways hyperresponsiveness (AHR) measurements, and by systemic (Ig assays) and in situ (cytokine assay) immunological responses.

Vaccinated mice showed a decreased AHR. The cellularity of the bronchio-alveolar lavage (BAL) was also decreased in the vaccinated group with a decrease of neutrophils and eosinophils. IgG2a/IgG1 ratio was increased in the vaccinated group in favor of Th1 bias confirmed by increase of IFN-γ secretion by splenocytes restimulated in vitro with purified Der f 1. Analyses of cytokines in BAL showed a decrease of Th2 and Th17 cytokines and an increase of IL-10 and IFN-γ. Total IgE levels were not modified.

This formulation of DNA vaccination induces cellular and humoral specific response with a pro-Th1 bias accompanied by a decrease of the Th17 and Th2 responses. It enables an improvement of lung cellular infiltrate and airway hyperresponsiveness. DNA vaccination seems therefore promising to prevent allergy.
Abstract 9861: Caveolin 1-Regulated Src-dependent Cardiac Connexin 43 Degradation Mediates Renin-Angiotensin System Activation-Induced Arrhythmias
Authors: Kai-Chien Yang, Cody A Rutledge, Mao Mao, Farnaz R Bakhshi, An Xie, Hong Liu, Marcelo G Bonini, Hemal H Patel, Richard D Minshall, Samuel C Dudley
Journal: Circulation (2013)

Background: Activation of the cardiac renin-angiotensin system (RAS) is associated with increased risk of ventricular arrhythmia and sudden cardiac death. Increased cardiac RAS activity leads to conduction block and spontaneous ventricular arrhythmias as a result of connexin 43 (Cx43) degradation mediated by the activation of redox-sensitive tyrosine kinase c-Src signaling. The molecular mechanism of c-Src activation downstream of RAS signaling remains elusive. Results: Using a transgenic mouse model of cardiac-specific overexpression of angiotensin converting enzyme (ACE8/8) and a heterologous expression system, we uncovered a ~50% reduction in the binding of c-Src to caveolin 1 (Cav1) and subsequent c-Src activation as a result of S-nitrosylation of Cav-1 at Cys156 (Cav1-SNO) upon enhanced RAS signaling. RAS-induced Cav1-SNO and Src activation was mediated by eNOS-derived NO in response to increased mitochondrial oxidative stress. Knockout of Cav1 (but not caveolin 3) resulted in activation of c-Src, degradation of Cx43 (42% reduction from WT level), reduced cardiac conduction velocity (by 30%), and increased arrhythmic risk (75% Cav1-/- vs. 0% WT mice showed induced ventricular arrhythmia). Arrhythmic risk in Cav1-/- mice was mitigated by pharmacological inhibition of c-Src. Conclusions: Cav1 S-nitrosylation plays a critical role in mediating RAS-induced arrhythmias by increasing c-Src activity. Oxidative stress-induced Cav1 S-nitrosylation in response to cardiac RAS signaling promotes Src-dependent disruption of Cx43 hemichannels and ventricular arrhythmia. These findings may explain the genetic association of Cav1 with arrhythmias and suggests that targeted regulation of Cav1 or antioxidant therapy may reduce arrhythmic risk during RAS activation.
Questions your patients may have about Zika virus
Authors: Zosia Kmietowicz
Journal: BMJ (2016)

The BMJThe World Health Organization has declared the Zika virus a public health emergency.The agency said that the evidence for a link between the virus and the increase in cases of babies with microcephaly and a spike in cases of Guillain-Barré syndrome was growing. 1 Here is advice you can use to answer questions your patients may have about Zika virus.
A New Breast Carcinoma Antigen Defined by a Monoclonal Antibody2
Authors: Steven A. Stacker, Christopher Thompson, Clare Riglar, Ian F. C. McKenzie
Journal: JNCI Journal of the National Cancer Institute (1985)

A new monoclonal antibody (MoAb), 3E1-2, to human breast carcinoma cells was made. With the use of the immunoperoxidase technique, 3E1-2 was tested on Formalin-fixed and fresh sections of 27 normal and 81 neoplastic tissues, including 37 carcinomas of the breast, 15 lung tumors, 5 colon tumors, and other tumors. Strong uniform staining of the cytoplasm and membrane occurred with the breast carcinoma, whereas with normal breast tissue less intense staining of the luminal membrane was seen; not all cells were reactive with the MoAb. Most other human tumors (with the exception of some lung, kidney, and uterine carcinomas) were nonreactive, and few normal tissues were reactive. The unique features of this new MoAb are: a) reaction with Formalin-fixed as well as fresh tissue; b) lack of a reaction with the cell surface of 43 established cell lines, including 10 lines derived from breast carcinoma cultures; c) variable staining patterns in different breast carcinomas, varying from all cells staining to dense cytoplasmic staining to minimal membrane staining of a few cells; d) a great differential in staining patterns between normal and neoplastic tissue (nonetheless, some normal tissues were 3E-1.2+). The antibody does not detect a tumor-specific antigen, but has a high carcinoma-to-normal breast ratio of staining. In addition, preliminary studies on the sera of 20 patients with carcinoma of the breast have shown that the antigen detected by 3E1-2 is elevated in their serum; 3E1-2 thus has the potential to be used for diagnosis of this disease.
Clinical trial of sequential N-phosphonacetyl-L-aspartate, thymidine, and 5-fluorouracil in advanced colorectal carcinoma.
Authors: M J O'Connell, C G Moertel, J Rubin, R G Hahn, L K Kvols, A J Schutt
Journal: Journal of Clinical Oncology (1984)

Preclinical studies have demonstrated enhanced cytotoxic effects of 5-fluorouracil (5-FU) when given in conjunction with N-phosphonacetyl-L-aspartate (PALA) or thymidine in several murine systems. Early clinical studies have demonstrated significant delayed depletion of pyrimidine nucleotides in tumor biopsy specimens following systemic PALA administration and prolonged serum levels of 5-FU after thymidine administration. Each of these biochemical effects would be anticipated to augment the cytotoxic activity of 5-FU. A phase II trial of a timed sequential administration schedule of PALA, thymidine, and 5-FU was conducted in 37 patients with advanced measurable colorectal cancer. Ten of 37 patients (27%) experienced objective tumor responses with a median response duration of 22 weeks, and 18 patients (49%) had stable disease for a median duration of 20 weeks. Six of 13 patients (46%) with anaplastic histology and/or rapidly progressive tumors experienced high-quality tumor responses. Leukopenia and neurologic side effects were the primary toxicities, including one death caused by sepsis. This regimen has demonstrated striking alteration in the 5-FU dose-effect relationship and definite antitumor activity in patients with advanced colorectal cancer. Further trials in patients with anaplastic carcinomas of the colon or other anatomic sites should be considered.
Smoking habits and psychological stress of patients with COPD
Authors: Birgit Schwaighofer, Danijel Jelusic, Michael Wittmann, Michael Schuler, Konrad Schultz
Journal: European Respiratory Journal (2014)

Introduction: relations between smoking habits & psychological stress (PS) are proven. So far no systematic data was collected whether these results apply to patients with COPD, and if there are indications as a negative predictor for tobacco dehabituation in context of inpatient pulmonary rehabilitation (PR).

Objectives: The aim of this research was to determine whether there is a difference in PS between smokers & ex-smokers and between smokers who refrained from smoking during PR and those who continued.

Methods: From Feb13-Jan14 353 patients with COPD were screened via PHQ-9 & GAD-7 in terms of symptoms of depression & anxiety and interviewed towards their smoking habits at admission (T0) & dismissal (T1).

Results: At T0 37.7% of the participants were smokers; at T1 the % dropped to 18% (51.9% refrained from smoking). A sig. higher PS, in terms of higher test scores in PHQ-9 & GAD-7, at T0 was observed in both groups in comparison to T1. No differences between smokers & ex-smokers were found regarding PS at T0 & T1. Patients who refrained from smoking during PR as well as those who were still smoking showed sig. lower scores in PHQ-9 & GAD-7 at T1 in comparison to T0. No difference between those who refrained from smoking during PR and those who still smoked were found at T0 & T1.

![Figure][1] 



Conclusions: A sig. reduction of PS within 3 weeks PR was shown. In contradiction to results found in literature, no difference between PS & smoking habits were found.

 [1]: pending:yes
Comparison of Age-Specific Mortality From Breast Cancer in Males in the United States and Japan 2
Authors: Suresh H. Moolgavkar, John A. H. Lee, R. Douglas Hade
Journal: JNCI Journal of the National Cancer Institute (1978)

Journal Article Comparison of Age-Specific Mortality From Breast Cancer in Males in the United States and Japan Get access Suresh H. Moolgavkar, M.D., Ph. D., Suresh H. Moolgavkar, M.D., Ph. D. 4 4Address reprint requests to Dr. Moolgavkar at his present address: The Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pa. 19111. Search for other works by this author on: Oxford Academic PubMed Google Scholar John A. H. Lee, M.D., John A. H. Lee, M.D. Search for other works by this author on: Oxford Academic PubMed Google Scholar R. Douglas Hade, B.S. R. Douglas Hade, B.S. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 60, Issue 6, June 1978, Pages 1223–1225, https://doi.org/10.1093/jnci/60.6.1223 Published: 01 June 1978 Article history Received: 04 May 1977 Accepted: 08 January 1978 Published: 01 June 1978
Abstract 13438: Aortic Valve Adaptation to Aortic Root Dilatation: Insights into the Mechanism of Functional Aortic Regurgitation from Three-Dimensional Cardiac Computed Tomography
Authors: Dae-Hee Kim, Mark D. Handschumacher, Robert A. Levine, Byung Joo Sun, Jeong Yoon Jang, Dong Hyun Yang, Joon-Won Kang, Jong-Min Song, Duk-Hyun Kang, Tae-Hwan Lim, Jae-Kwan Song
Journal: Circulation (2013)

Dae- Hee Kim, 2013 Finalist and Presenting Author
Side effects and efficacy of thalidomide and low dose dexamethasone combination in newly diagnosed symptomatic multiple myeloma patients in India—A pilot study
Authors: P. Jain, V. R. Pai, K. Prabhash, S. Gupta, P. M. Parikh
Journal: Journal of Clinical Oncology (2008)

19530 Background: The standard schedule of thalidomide and dexamethasone combination in untreated myeloma includes three pulses (each of four days with 40 mg per day) of dexamethasone and thalidomide 200 mg/day every 28 days. Poor tolerance to this schedule, low feasibility of stem cell transplant, uncertain access to myeloma care resources and higher rate of infections and hyperglycemia are the limitations in our clinical setting. We undertook a phase II, one stage study of low dose dexamethasone and thalidomide as initial treatment of myeloma with the primary end point of establishing the adverse effect profile of this combination. The secondary end point was evaluation of efficacy. Methods: Twenty consecutive patients of untreated myeloma were treated with thalidomide 200 mg/day with dexamethasone 40 mg per day D1 to D4 every 21 days. Patients were evaluated after 3rd and 6th cycles. Zolendronic acid was given monthly. Antithrombotic prophylaxis and erythropoietin were not routinely used. Patients were monitored for thrombosis, neuropathy and other known adverse effects. Results: There was no occurrence of thrombosis, skin rash, bradycardia or deaths. There were no grade 3 or 4 toxicities except one patient who had grade 3 constipation after 6 cycles. All patients (100%) had grade 2 constipation at the end of three cycles and 13/20 (65 %) after 6 cycles. At the end of 3rd and 6th cycles, 50 % of patients had grade 2 sensory neuropathy and 95 % developed grade 2 fatigue. Sixteen of the 20 patients (80%) had a response to therapy after 3 cycles and 19 of the 20 patients (95%) after 6 cycles. At the completion of 6 cycles, four patients (20 %, 95% CI 2 -37 %) had CR, six had VGPR (30 %, 95% CI 1 -50 %) and PR was seen in nine patients (45%, 95 % CI 23 to 66%). Conclusions: For the initial treatment of myeloma low dose dexamethasone with thalidomide seems well tolerated with minimal grade 3 and 4 toxicities. It is effective and feasible in our patient population. It merits further study with and formal comparison with high dose dexamethasone regimen. No significant financial relationships to disclose.