tbuckley/cabot-search huggingface dataset:
Incidence Patterns of Spontaneous Tumors in BN/Bi Rats
Authors: J. D. Burek, C. F. Hollander
Journal: JNCI Journal of the National Cancer Institute (1977)

The occurrence of tumors in 236 female and 74 male BN/Bi rats that were allowed to live out their normal lifespans was described. For most neoplasms, the risk of a rat dying with a specific tumor increased with age. Some tumors, however, had a peak incidence; therefore, animals surviving these periods were at less risk than were their younger cohorts. The number dying with metastatic cancers was greatest in females over 30 months of age. Unexpectedly, males had a peak risk period at 25-30 months, so that males that died in older age groups had less risk of dying with a metastatic tumor. Lesions were often multiple, even in rats dying at a young age. Surprisingly, the percent dead with multiple tumors did not increase significantly with age. Some animals in every age group died without a tumor, and the percentage without neoplasms did not decrease, even in the older age groups.
Epidermal-dermal interactions regulate gelatinase activity in Apligraf®, a tissue-engineered human skin equivalent
Authors: C.S. Osborne, P. Schmid
Journal: British Journal of Dermatology (2002)

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) have important functions during skin development, repair and maintenance. MMP-2 and MMP-9 (gelatinase A and gelatinase B) are involved in regulating keratinocyte migration.To analyse whether Apligraf, a bilayered tissue-engineered human skin equivalent (HSE), produces gelatinases and TIMPs and whether or not epidermal-dermal interactions regulate MMP activity.The tissue distribution of MMP-2, MMP-9, TIMP-1, TIMP-2 and fibronectin was analysed by immunohistochemistry. Secreted MMP activity was quantified by a fluorimetric assay and gelatin zymography was used to monitor gelatinases in tissue culture supernatants.Apligraf expressed MMP-2 and MMP-9 and contained immunohistochemically detectable amounts of TIMP-1 and TIMP-2. The gelatinases were predominantly produced in the epidermis, whereas immunostaining of TIMP-1 and TIMP-2 was largely confined to the dermal component of the HSE. Fibronectin was expressed only in the dermis. Gelatin zymography demonstrated that intact Apligraf produced both MMP-2 and MMP-9, the latter predominantly in its latent form. Separation of the dermis from the epidermis resulted in an enhanced production and activation of MMP-9 by the epidermal layer, and secretion of latent and active MMP-2 by the dermal layer. Moreover, the incubation media of the separated epidermis demonstrated significantly stronger MMP activity than did intact Apligraf or its dermal component.These observations provide evidence that epidermal-dermal interactions suppress epidermal gelatinase activity. In addition, coexpression of TIMPs and fibronectin in the Apligraf dermis suggests that the product has the potential to counteract the imbalance between matrix production and degradation in chronic wounds and thus may support wound re-epithelialization.
A phase II trial of denileukin diftitox in patients with previously treated advanced non-small cell lung cancer (NSCLC)
Authors: M. A. Gerena Lewis
Journal: Journal of Clinical Oncology (2005)

7131 Background: Prior studies suggested the presence of interleukin-2 receptor (IL-2r) in NSCLC. ONTAK is a chimeric protein that targets the cytocidal properties of diphtheria toxin to cells expressing IL-2r. We evaluated the potential benefit of ONTAK in the treatment of advanced NSCLC. Methods: This multi-center phase II trial enrolled patients (pts) with ECOG PS 0–2 and stage IIIB/IV NSCLC who progressed after at least one prior chemotherapy regimen. ONTAK is infused at 9 μg/kg on Day 1 of Cycle 1 only, followed by18 μg/kg/day on Days 2–5, then every 21 days for a total of 6 cycles. Results: Forty pts were accrued with 23 males and a median age of 56 years (21–80). Mean number of prior chemotherapy regimens was 2 (1–5). Pts received a mean of 3 (1–6) cycles. Two (5%) are too early to evaluate, 2 (5%) had unconfirmed partial response by RECIST criteria, 14 (35%) had stable disease, 9 (23%) had progressive disease, and 13 (33%) were not evaluable due to clinical deterioration (8), toxicity (3), investigator’s judgment (1) and voluntary withdrawal (1). The median time to disease progression for evaluable pts was 2.6 months (1–11 months). Overall survival was 4 months (0.2 -15.6 months). One death from myocardial necrosis was attributed to treatment. Grade 3 toxicities (18) included GI, constitutional symptoms, 2 capillary leak syndrome (CLS) and one grade 4 CLS. Serial flow cytometry tests of peripheral blood lymphocytes on 11 consecutive pts showed decrease in CD8+ 25+ cells in all 5 pts with SD beyond 4 cycles compared to 2 out of 6 in pts with PD (p=0.06 by Exact Fisher Test). Conclusion: This study revealed disease control (PR + SD) of 40% in heavily pre-treated NSCLC. A better understanding of the immunomodulatory mechanism is warranted. No significant financial relationships to disclose.
Competing risk is better than composite outcome to identify renal biomarker outcome
Authors: Matthieu Jamme, Jerome Lambert
Journal: Kidney International (2015)

To the Editor: We read with great interest the study of Parr et al.1.Parr S.K. Clark A.J. Bian A. et al.Urinary L-FABP predicts poor outcomes in critically ill patients with early acute kidney injury.Kidney Int. 2015; 87: 640-648Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar that assesses the prognostic performance of several renal dysfunction biomarkers among critically ill patients with early acute kidney injury. Among the four candidates, when adjusting for a clinical prognosis model including age, APACHE II score, serum creatinine and sepsis, only uL-FABP was independently associated with the outcome. As stated by the authors, only modest performances have been reported in study on markers for early detection of acute kidney injury. In order to improve these performances, they suggest selecting high-risk population and using clinically meaningful endpoints. We totally share this concern but think that the chosen composite outcome, defined as doubling of serum creatinine, dialysis or death within 7 days, could precisely hamper the ability of the study to assess prognostic accuracy of these biomarkers. Though it generally increases the statistical power of a study by increasing the number of events, the use of composite outcome may be problematic.2.Cordoba G. Schwartz L. Woloshin S. et al.Definition, reporting, and interpretation of composite outcomes in clinical trials: systematic review.BMJ. 2010; 341: c3920Crossref PubMed Scopus (233) Google Scholar If we want to identify biomarkers that specifically target kidney dysfunction, it is questionable to consider patients who die from other unrelated organ dysfunctions. In the framework of survival analysis, this is known as competitive risk analysis.3.Resche-Rigon M. Azoulay E. Chevret S. Evaluating mortality in intensive care units: contribution of competing risks analyses.Crit Care. 2006; 10: R5Crossref PubMed Scopus (71) Google Scholar Dedicated techniques have been described and discrimination measures such as Area Under the Curve have been proposed in the context of competing risks.4.Wolbers M. Blanche P. Koller M.T. et al.Concordance for prognostic models with competing risks.Biostat. 2014; 15: 526-539Crossref PubMed Scopus (116) Google Scholar
Never-smoking history as a poor prognostic factor in surgically proven idiopathic pulmonary fibrosis
Authors: Tomohisa Baba, Yasunori Enomoto, Atsuto Nakazawa, Hideya Kitamura, Tsuneyuki Oda, Norikazu Matsuo, Terufumi Kato, Eri Hagiwara, Koji Okudera, Tae Iwasawa, Tamiko Takemura, Takashi Ogura
Journal: European Respiratory Journal (2013)

Objectives: Smoking is known as a risk factor of idiopathic pulmonary fibrosis (IPF), but the effect of smoking on survival has been reported variable. The objective of this study was to clarify the effect of smoking status on prognosis of IPF.  Methods: We retrospectively analyzed 92 consecutive IPF patients (never smoker 28, ever smoker 64) who underwent surgical lung biopsy from 2001 to 2009, and evaluated pulmonary function and survival time from their first visit.  Results: Twenty of 28 never smokers (71.4%) and five of 64 ever smokers (7.8%) were female (p   Conclusions: Never smokers with IPF were female predominant with high prevalence of familial history of the disease, and showed poorer prognosis. IPF in never smokers may have different pathogenic factors form that in ever smokers.
Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus
Authors: Michele Y.F. Kong, John P. Clancy, Ning Peng, Yao Li, Tomasz J. Szul, Xin Xu, Robert Oster, Wayne Sullender, Namasivayam Ambalavanan, J. Edwin Blalock, Amit Gaggar
Journal: European Respiratory Journal (2013)

Respiratory syncytial virus (RSV) infection is a potent stimulus for airway epithelial expression of matrix metalloproteinase (MMP)-9. MMP-9 activity in vivo is a predictor of disease severity in children with RSV-induced respiratory failure. Human airway epithelial cells were infected with RSV A2 strain and analysed for MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 (a natural inhibitor of MMP-9) release. In addition, endotracheal samples from children with RSV-RF and controls (non-RSV pneumonia and nonlung disease controls) were analysed for MMP-9, TIMP-1, human neutrophil elastase and myeloperoxidase activity. RSV infection of airway epithelia was sufficient to rapidly induce MMP-9 transcription and protein release. Pulmonary MMP-9 activity peaked at 48 h in infants with RSV-induced respiratory failure. In the RSV group, MMP-9 activity and MMP-9/TIMP-1 ratio imbalance predicted higher oxygen requirement and worse paediatric risk of mortality scores. The highest levels of human neutrophil elastase and myeloperoxidase activity were measured in the RSV cohort; however, unlike MMP-9, these neutrophil markers failed to predict disease severity. These results support the hypothesis that RSV is a potent stimulus for MMP-9 expression and release from human airway epithelium, and that MMP-9 is an important biomarker of disease severity in mechanically ventilated children with RSV lung infection.
The HVAD Left Ventricular Assist Device
Authors: Jeffrey J. Teuteberg, Mark S. Slaughter, Joseph G. Rogers, Edwin C. McGee, Francis D. Pagani, Robert Gordon, Eduardo Rame, Michael Acker, Robert L. Kormos, Christopher Salerno, Thomas P. Schleeter, Daniel J. Goldstein, Julia Shin, Randall C. Starling, Thomas Wozniak, Adnan S. Malik, Scott Silvestry, Gregory A. Ewald, Ulrich P. Jorde, Yoshifumi Naka, Emma Birks, Kevin B. Najarian, David R. Hathaway, Keith D. Aaronson
Journal: JACC Heart Failure (2015)
A pill in the sandwich: Covert medication in food and drink
Authors: Adrian Treloar, Barbara Beats, Michael Philpot
Journal: Journal of the Royal Society of Medicine (2000)

The covert administration of medicines in food and drink has been condemned by some and condoned by others. We used questionnaires to ascertain the views of people caring for patients with dementia in institutions and in the community. In 24 (71%) of 34 residential, nursing and inpatient units in south-east England, the respondent said that medicines were sometimes given in this way. It was often done secretly and without discussion, probably for fear of professional retribution. Few institutions had a formal policy on the matter. Of 50 people caring for demented patients in the community, 48 (96%) thought the practice sometimes justifiable, but 47 believed that doctors should consult with carers before deciding. Even if, as most carers and some authorities believe, covert medication can be justified, the poor recording and secrecy surrounding the practice in institutions are cause for concern.
Investment managers back greater transparency of clinical trials:
Authors: Nigel Hawkes
Journal: BMJ (2015)

Pension funds and asset managers with more than €3.5 trillion (£2.45trn; $3.83trn) of assets under management have put their weight behind the AllTrials (alltrials.net) campaign, which is seeking greater transparency in the conduct of clinical trials.

Arguing that investors often commit their money to drug company shares on the basis of trials completed long before the drugs are marketed, the 85 strong investor group said that clarity and transparency are vital if investors are not to be misled.

Helena Vines Fiestas, of BNP Paribas, which helped …
Special charecteristics of smoking cessation program participants in a large municipal hospital in Greece
Authors: Georgia Makrantoni, Marios Kougias, Evangelos Balis, Kostas Kotsifas, Stavroula Boulia, Maroussa Kouvela, George Tatsis
Journal: European Respiratory Journal (2011)

Introduction: Greece is the European Union country with the highest rate of tobacco consumption (more than 40%).Enforcement of laws forbidding consumption of tobacco products, combined with public awareness of the adverse effects of smoking, result in the need for efficient smoking cessation centers.

Aims: The aim of the present study is to demonstrate special characterictics of smokers addressing to the smoking cessation center of Evangelismos hospital, in Athens Greece, including dependence, motivation profile, special characteristics such as depression profile and pulmonary function testing values.

Methods: Three hundred (300) smokers of mean age of 48.47±11.42 years, smoking 38.97±22,87 packyears participated in Evangelismos Hospital smoking cessation program during the last two years. A thorough medical history was obtained focusing on dependence and motivation for quitting.Pulmonary function testing, including spirometry was performed in all individuals.Statistical analysis was performed using the non parametric test for sign values.

Results: Men smoke more than women (47.52±26.61 vs 35,33±22.05).One the other hand Greek women present more motivated to quit smoking than men (16,26±11.32 vs 10.08±12.08).In addition pulmonary function testing reveals high percentage of abnormalities cuased by smoking,such as small airway disease. Abandoning the cessation program is significantly ralated (p<0.05) with a depressive profile of the participant.

Conclusions: Smoking cessation programs reveal interesting profiles of the Greek population, concerning the smoking habit,pulmonary function teting abnormalities and factors related to abandoning a smoking cessation program.
Adult asthma incidence and long term exposure to air pollution in six European cohorts: The European study of cohorts for air pollution effects (ESCAPE)
Authors: Benedicte Jacquemin, Valérie Siroux, Margaux Sanchez, Anne-Elie Carsin, Martin Adam, Anna Buschka, Françoise Clavel-Chapelon, Christophe Declercq, Anna Hansel, Dirk Keidel, Ursula Krämer, Alessandro Marcon, Nicole Probst-Hensch, Tamara Schikowski, Christian Schindler, Morgane Stempfelet, Jordi Sunyer, Andrea Vierkötter, Cai Yutong, Nino Künzli, Francine Kauffmann
Journal: European Respiratory Journal (2013)

It is still unclear if air pollutants play a role in asthma development in adults. The aim was to assess the impact of long-term exposure to air pollution on adult onset asthma in 6 European cohorts (ECRHS, EGEA, E3N, NSHD, SALIA, SAPALDIA) using standardized ESCAPE exposure estimates.

Annual concentrations of NO2 and particulate matter (PM10 and PM2.5) at home addresses were estimated using land-use regression models. To assess incidence, asthma definition was developed being specific at baseline and sensitive at follow-up. Logistic regression models were adjusted for age, sex, BMI, education and smoking. Cohort-specific results were meta-analysed.

23701 subjects with NO2 and 16662 subjects with PM exposure estimates were included. Asthma incident cases were 1257. Incidence rates varied between 2.9 and 8.3/1000/year in SAPALDIA and EGEA respectively. The meta-analyses did not show significant associations between air pollution and asthma incidence (OR:1.05 (95%CI:0.97,1.14) per 10μg/m3 of NO2 and 1.04 (95%CI:0.88,1.22) per 10μg/m3 PM10). EGEA was the only cohort showing a significant positive association (OR:1.36 (95%CI:1.07,1.72) per 10μg/m3 of NO2).

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The point estimates were lower than the ones previously published and the meta-analysis did not show statistically significant associations between air pollution and adult onset-asthma.

Funds: ESCAPE EC-FP7-GA 211250.

 [1]: pending:yes
Educational, occupational, and insurance status of childhood cancer survivors in their fourth and fifth decades of life.
Authors: D M Hays, J Landsverk, S E Sallan, K D Hewett, A F Patenaude, D Schoonover, S L Zilber, K Ruccione, S E Siegel
Journal: Journal of Clinical Oncology (1992)

PURPOSE Survivors of childhood cancer who are now greater than or equal to 30 years of age are available for study in significant numbers for the first time. An evaluation of their educational achievement, current employment status, frequency of problems in the work-place, and ability to obtain affordable health and life insurance was the aim of this study. PATIENTS AND METHODS This was a case-control study of 219 childhood cancer survivors with individually matched controls from two tertiary-care pediatric centers. Telephone interviews were used and drew on a 356-item basic instrument for both subjects and controls. Medical (including intensity of therapy), marital, and psychosocial areas were included in the survey, but statistical comparisons concentrated on educational and economic issues. RESULTS The overall current status of survivors and controls in the relevant areas, ie, education, employment, and insurance, was similar. A history of employment discrimination for entry into the uniformed services and in other special situations, and life insurance discrimination during the initial years after the completion of therapy was noted. Survivors experienced few problems in the work-place. Survivors of CNS tumors were unique, with problems in many of the areas studied, although there were notable individual exceptions. CONCLUSION With the exception of those individuals with CNS tumor histories, survivors who were treated in the era of 1945 to 1975 had few economic sequelae of cancer or its therapy that extended beyond the first decades after treatment.
Chemokine (C‐X‐C motif) ligand 13 promotes intrahepatic chemokine (C‐X‐C motif) receptor 5+ lymphocyte homing and aberrant B‐cell immune responses in primary biliary cirrhosis
Authors: Yongyin Li, Weibin Wang, Libo Tang, Xuanqiu He, Xin Yan, Xiaoyong Zhang, Youfu Zhu, Jian Sun, Yongquan Shi, Xiong Ma, Ian R. Mackay, M. Eric Gershwin, Ying Han, Jinlin Hou
Journal: Hepatology (2015)

The serological hallmark of primary biliary cirrhosis (PBC) is the presence of high titer and specific antimitochondrial antibodies (AMAs). Although there is no global immune defect in patients with PBC, there is widespread dysregulated B‐cell function, including increased sera levels of immunoglobulin M and enhanced B‐cell responses to cytosine‐phosphate‐guanine stimulation. The mechanisms involved in this B‐cell dysfunction have remained unknown. To address this issue, we focused on identifying the frequencies of B‐cell subsets in patients with PBC and the mechanisms that lead to B‐cell dysregulation, including the relationships with chemokine (C‐X‐C motif) receptor 5 (CXCR5) + CD4 + T cells. Herein, we report that elevations of both serum and intrahepatic interleukin‐21 (IL‐21) were found in patients with PBC and, in particular, promoted B‐cell proliferation, signal transducer and activator of transcription 3 phosphorylation and AMA production in vitro . More important, upon stimulation with recombinant E2 subunit of pyruvate dehydrogenase complex, CXCR5 + CD4 + T cells in PBC produced higher levels of IL‐21 than healthy controls. Additionally, sorted CXCR5 + CD4 + T cells increased production of AMAs by autologous CD19 + B cells. Indeed, elevated expression of intrahepatic chemokine (C‐X‐C motif) ligand 13 (CXCL13), a key chemokine of CXCR5 + cells, was uniquely found within the portal tracts in PBC, accompanied by infiltrates of CD4 + , CXCR5 + , CD19 + , and CD38 + cells. Conclusion : CXCL13 promotes aggregation of CD19 + B cells and CXCR5 + CD4 + T cells, which directs the aberrant AMA response by IL‐21. These data have implications for potential immunotherapy and also reflect the unique lymphoid biology in liver of PBC. (H epatology 2015;61:1998‐2007)
Airborne transmission of respiratory syncytial virus (RSV) infection
Authors: Hemant Kulkarni, Claire Smith, Robert Hirst, Norman Baker, Andrew Easton, Chris O'Callaghan
Journal: European Respiratory Journal (2011)

Introduction: RSV is a highly contagious pathogen and spreads among groups of young children, within families and between patients in hospital. RSV is thought to spread predominantly by hands contaminated with infectious respiratory secretions [1]. However, it remains unclear if RSV can be spread by aerosol. Knowledge of this is important as it is assumed in many hospitals that aerosol transmission of RSV does not occur.

Aim: To determine if patients with RSV bronchiolitis produce aerosolised particles containing RSV capable of infecting human respiratory epithelial cells (A549).

Method: 18 infants with “RSV Bronchiolitis” were recruited. An Andersen microbial impactor was placed 100cm from the head of the patient and run for 30min fractionating collected particles into different aerosol size distributions. Room air was impacted into 20ml of RPMI growth media and its infectivity of A549 was determined using plaque assays. Immunofluorescence staining of the infected A549 cells was used to confirm RSV infection.

Results: 17 infants produced infectious airborne particles less than 4.7μ. We estimated the number of infectious RSV within aerosols of less than 4.7μ produced from 12/17 patients to be 188.5±68 (mean ± SEM, range 2.4 to 4044) in 10 litres of air. This volume would be inhaled by a 3.1kg baby in 10 minutes (respiratory rate 40/min; tidal volume 8ml/kg).

Conclusion: Infants with RSV bronchiolitis produce aerosols that contain infectious RSV in aerosols small enough to deposit in the lower airways. These findings may influence infection control strategies to prevent aerosol transmission of RSV in a hospital setting.

Reference: 

*   1. Goldmann DA. Pediatric Infectious Disease Journal 2000;19(10 Suppl).