tbuckley/cabot-search huggingface dataset:
Gemcitabine plus docetaxel (GD) versus capecitabine plus docetaxel (CD) for anthracycline-pretreated metastatic breast cancer (MBC) patients (pts): Results of a European phase III study
Authors: S. Chan, G. Romieu, J. Huober, T. Delozier, M. Tubiana –Hulin, A. Lluch, A. Schneeweiss, A. Llombart, E. Carrasco, P. Fumoleau
Journal: Journal of Clinical Oncology (2005)

581 Background: CD has shown to have higher efficacy when compared with D alone in MBC. GD has shown to be efficacious and safe in MBC even in anthracycline-pretreated pts; gemcitabine was recently approved in this setting. This study compared GD with CD as first- or second-line treatment in MBC pts pretreated with an anthracycline. Primary objective was progression-free survival (PFS); secondary objectives were overall response rate (ORR), time to treatment failure (TtTF), overall survival (OS), toxicity, and quality of life (QOL). Methods: Pts with histologically confirmed MBC who relapsed after an anthracycline-based regimen either in neoadjuvant or first-line metastatic disease were randomized to GD (G 1000 mg/m2 d1,8; D 75 mg/m2 d1) or CD (C 2500 mg/m2 d1–14; D 75 mg/m2 d1) q21 days; neoadjuvant pretreatment with taxanes was allowed if completed >6 months before entry. Results: Between October 2002 and March 2004, 305 pts were randomized; 295 pts were included in this analysis (150 GD, 145 CD). Arms were well balanced; median age was 55 years; 86% had visceral disease; 81% had ≥2 metastatic sites; 67% were ER/PR+; 17% were HER2 over-expressed; 17% received prior taxane; 34% received prior chemotherapy for metastatic disease. At time of analysis, 287 pts were evaluable for safety and 229 for response. PFS analysis will occur at 250 events (currently, 151 PD/60 death). On GD arm, pts received 754 cycles; 642 cycles were given on CD arm. ORR was 27% (95% CI, 18.4%–34.7%) for GD, and 31% (95% CI, 22.6%–39.5%) for CD (p=.4537). CTC grade 3/4 hematologic toxicity was similar in both arms, but febrile neutropenia was higher in CD arm (12% vs 7%). Nonhematologic toxicity was low in both arms, but diarrhea (17% vs 7%), mucositis (16% vs 4%), and hand-foot syndrome (24% vs 0%) were more pronounced in CD arm. More serious adverse events occurred in CD arm (36% vs 28%), causing discontinuation in 27% (CD arm) and 14% (GD arm) of pts. There were 2 toxic deaths, both in CD arm. Conclusions: GD demonstrated similar efficacy to CD in pts with MBC. Nonhematologic toxicity was higher in the CD arm. PFS, TtTF, QOL, updated ORR and toxicity data will be available at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly Eli Lilly Eli Lilly Eli Lilly Eli Lilly Eli Lilly
Prognostic significance of bcl-2 protein expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)
Authors: O Hermine, C Haioun, E Lepage, MF d'Agay, J Briere, C Lavignac, G Fillet, G Salles, JP Marolleau, J Diebold, F Reyas, P Gaulard
Journal: Blood (1996)
Novel IL-9-Producing Mucosal Mast Cells Promote IgE-Mediated Food Allergy
Authors: Yui-Hsi Wang
Journal: Journal of Allergy and Clinical Immunology (2016)

IgE-mediated food allergy is manifested by an overactive T-helper 2 immune response to dietary antigens in the gastrointestinal tract. Frequency of newly identified IL-9-producing mast cells (MMC9s) correlates positively with levels of intestinal mastocytosis. We hypothesize that induction of MMC9s is a pivotal step to acquire the susceptibility to IgE-mediated food allergy. Involvements of MMC9s in regulating susceptibility to food allergy were examined in mouse models of food allergy. Expression levels of MMC9-associated transcripts were analyzed in duodenal biopsies of atopic patients developed food allergy. MMC9s secrete prodigious amounts of IL-9 and mast cell protease-1 in response to IL-33 and antigen/IgE complex crosslinking, respectively. By producing significant amounts of IL-9, MMC9s cause pronounced intestinal mastocytosis and the production of mast cells. Repeated intragastric antigen challenge induces significant accumulations of both MMC9s and CD4+TH2 cells, which correlate positively with symptoms and susceptibility of murine strains to develop experimental food allergy. The development of MMC9s requires the presence of CD4+TH2 cells and the proteins of IL-4 and STAT6. Mice ablated or deficient of MMC9 induction fail to develop intestinal mastocytosis, which resulted in decreased food allergy symptoms that can be restored by adoptively transferred MMC9s. Finally, atopic patients that develop food allergy display increased intestinal expression of Il9 and MC-specific transcripts. MMC9s, the primary cellular source of IL-9, function to amplify intestinal allergic inflammation and perpetuates anaphylactic response to allergenic dietary proteins. The acquisition of MMC9s may be a key cellular checkpoint for the susceptibility to develop IgE-mediated food allergy.
Identification of Mithramycin Analogues with Improved Targeting of the EWS-FLI1 Transcription Factor
Authors: Christy L. Osgood, Nichole Maloney, Christopher G. Kidd, Susan Kitchen-Goosen, Laura Segars, Meti Gebregiorgis, Girma M. Woldemichael, Min He, Savita Sankar, Stephen L. Lessnick, Min Kang, Malcolm Smith, Lisa Turner, Zachary B. Madaj, Mary E. Winn, Luz-Elena Núñez, Javier González-Sabín, Lee J. Helman, Francisco Morís, Patrick J. Grohar
Journal: Clinical Cancer Research (2016)

Abstract Purpose: The goal of this study was to identify second-generation mithramycin analogues that better target the EWS-FLI1 transcription factor for Ewing sarcoma. We previously established mithramycin as an EWS-FLI1 inhibitor, but the compound's toxicity prevented its use at effective concentrations in patients. Experimental Design: We screened a panel of mithralogs to establish their ability to inhibit EWS-FLI1 in Ewing sarcoma. We compared the IC50 with the MTD established in mice to determine the relationship between efficacy and toxicity. We confirmed the suppression of EWS-FLI1 at the promoter, mRNA, gene signature, and protein levels. We established an improved therapeutic window by using time-lapse microscopy to model the effects on cellular proliferation in Ewing sarcoma cells relative to HepG2 control cells. Finally, we established an improved therapeutic window using a xenograft model of Ewing sarcoma. Results: EC-8105 was found to be the most potent analogue and was able to suppress EWS-FLI1 activity at concentrations nontoxic to other cell types. EC-8042 was substantially less toxic than mithramycin in multiple species but maintained suppression of EWS-FLI1 at similar concentrations. Both compounds markedly suppressed Ewing sarcoma xenograft growth and inhibited EWS-FLI1 in vivo. Conclusions: These results provide a basis for the continued development of EC-8042 and EC-8105 as EWS-FLI1 inhibitors for the clinic. Clin Cancer Res; 22(16); 4105–18. ©2016 AACR.
Austerity and old-age mortality in England: a longitudinal cross-local area analysis, 2007–2013
Authors: Rachel Loopstra, Martin McKee, Srinivasa Vittal Katikireddi, David Taylor-Robinson, Ben Barr, David Stuckler
Journal: Journal of the Royal Society of Medicine (2016)

Objective There has been significant concern that austerity measures have negatively impacted health in the UK. We examined whether budgetary reductions in Pension Credit and social care have been associated with recent rises in mortality rates among pensioners aged 85 years and over. Design Cross-local authority longitudinal study. Setting Three hundred and twenty-four lower tier local authorities in England. Main outcome measure Annual percentage changes in mortality rates among pensioners aged 85 years or over. Results Between 2007 and 2013, each 1% decline in Pension Credit spending (support for low income pensioners) per beneficiary was associated with an increase in 0.68% in old-age mortality (95% CI: 0.41 to 0.95). Each reduction in the number of beneficiaries per 1000 pensioners was associated with an increase in 0.20% (95% CI: 0.15 to 0.24). Each 1% decline in social care spending was associated with a significant rise in old-age mortality (0.08%, 95% CI: 0.0006–0.12) but not after adjusting for Pension Credit spending. Similar patterns were seen in both men and women. Weaker associations observed for those aged 75 to 84 years, and none among those 65 to 74 years. Categories of service expenditure not expected to affect old-age mortality, such as transportation, showed no association. Conclusions Rising mortality rates among pensioners aged 85 years and over were linked to reductions in spending on income support for poor pensioners and social care. Findings suggest austerity measures in England have affected vulnerable old-age adults.
Abstract 9761: Survival Benefit of Orally Administered Telmisartan in Hypertensive Rats is NOT a Class Effect of Angiotensin II type 1 Receptor Blockers
Authors: Takuya Kishi, Yoshitaka Hirooka, Kenji Sunagawa
Journal: Circulation (2012)

[Backgrounds] Previous studies have suggested that abnormal sympathoexcitation worsen the prognosis of hypertensive heart disease. We have demonstrated, in animal models of hypertension, that brain angiotensin II type 1 receptor (AT1R) induces reactive oxygen species (ROS) and ROS causes sympathoexcitation. We also have demonstrated that orally administered AT1R blocker (ARB) telmisartan, not candesartan, reduces the brain ROS and causes sympathoinhibition via blockade of brain AT1R, despite their similar depressor effects. Previous clinical trials have demonstrated that ARBs have beneficial effects in patients with hypertensive. However, it is not clarified whether the benefits are class-effects or not. The aim of the present study was to determine whether orally administered telmisartan improves survival rate of severely hypertensive rats and whether the benefits were class effects of ARBs or not. [Methods and Results] Angiotensin II-infused (100 ng/kg/day) and salt-loaded (8% NaCl diet) stroke-prone spontaneously hypertensive rats (SHRSP) were divided into telmisartan-treated (TLM), candesartan-treated (CND), and control groups. At 5 weeks after the treatment, both telmisartan and candesartan comparably lowered systolic blood pressure (122±14 mmHg vs. 124±9 mmHg, p=ns) and increased survival rate relative to the control (100%, 100%, and 70%, respectively, n=20 for each). However, brain ROS and urinary norepinephrine excretion (uNE: a marker of sympathoexcitation) were significantly lower in TLM than in CND (brain ROS: 0.8±0.1 μmol/g vs. 1.1±0.1 μmol/g, p&lt;0.01 and uNE: 1.1±0.2 μg/day vs. 1.5±0.2 μg/day, n=20 for each, p&lt;0.05). At 7 weeks, the survival rate was higher in TLM than CND (85% vs. 60%). At 9 weeks no rats survived in CND, whereas 40% survived in TLM. Heart/body weight, left ventricular (LV) end-systolic dimension, and LV wall thickness were significantly lower in TLM than in CND (Heart/body weight; 2.8±0.2 mg/g vs. 3.5±0.1 mg/g, n= 12 and 20, p&lt;0.05). [Conclusion] Orally administered telmisartan prevents LV hypertrophy, preserves LV function and markedly improves survival rate of severely hypertensive rats associated with sympathoinhibition via antioxidant in the brain. These benefits of TLM are not class effects of ARBs.
Effects of Tocopherol and Deprenyl on the Progression of Disability in Early Parkinson's Disease
Journal: New England Journal of Medicine (1993)

In 1987 we began a multicenter controlled clinical trial of deprenyl (a monoamine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levodopa. An interim analysis showed that deprenyl was beneficial (N Engl J Med 1989;321:1364-71). We report the results of tocopherol treatment after a mean (+/- SD) follow-up of 14 +/- 6 months, as well as the follow-up results for deprenyl.There was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. The beneficial effects of deprenyl, which occurred largely during the first 12 months of treatment, remained strong and significantly delayed the onset of disability requiring levodopa therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.41 to 0.62; P < 0.001). The difference in the estimated median time to the end point was about nine months. The ratings for Parkinson's disease improved during the first three months of deprenyl treatment; the motor performance of deprenyl-treated patients worsened after the treatments were withdrawn.Deprenyl (10 mg per day) but not tocopherol (2000 IU per day) delays the onset of disability associated with early, otherwise untreated Parkinson's disease. The action of deprenyl that accounts for its beneficial effects remains unclear.
Abstract 297: Modulation of Ischemia-Resuscitation Injury by TAT-Mediated PTEN Inhibitors
Authors: Xiangdong Zhu, Zuo-Hui Shao, Changqing Li, Jing Li, Qiang Zhong, Angelo Meliton, Lucille Meliton, Alan R Leff, Terry L Vanden Hoek
Journal: Circulation (2012)

Introduction: Recent work shows that mouse cardiac arrest and heart cell ischemia cause PI3K-Akt deactivation, while cardioprotective cooling appears mediated by Akt. To further test the role of PI3K-Akt during ischemic arrest/resuscitation, we developed novel TAT-p85 fusion proteins designed to enter cells rapidly to modulate Akt activation. p85 can both activate Akt via p110 binding, and via feedback deactivate Akt by PTEN binding. We hypothesized that TAT fused p85 lacking the PTEN binding site (TAT-Delta PTEN p85) would enhance p-Akt cardioprotection. Conversely, TAT fused p85 lacking the p110 binding site (TAT-delta p110p85) would decrease p-Akt and abrogate protection. Methods: A TAT-delta p110 p85 plasmid was constructed by deletion of nucleotides encoding amino acids 478-513. The TAT-delta PTEN p85 plasmid deleted amino acids 1-313. A TAT-GFP plasmid produced fluorescence-tagged TAT protein for measuring cell penetration kinetics. TAT proteins were expressed in E. Coli and purified. Cardiomyocytes were isolated from C57BL6/J mice and exposed to up to 90 min ischemic arrest with 3 h reperfusion (I/R). Cell viability was evaluated by propidium iodide uptake and p-Akt was measured by Western blot. PTEN activity was measured by Malachite green assay using PIP3 as substrate. Results: Western blot analysis demonstrated that TAT-delta p110 p85 could be transduced into cardiomyocytes within 5 min and levels maintained for more than 2h. TAT-delta p110 p85 blocked H2O2 induced p-Akt at both S473 and T308 sites in a dose-dependent fashion, while PTEN inhibition using TAT-delta PTEN p85 increased p-Akt. During cardiac cell ischemic arrest, p-Akt decreased within 30 min of arrest time. PTEN activity during ischemia increased 2-fold from baseline and was inversely correlated with Akt phosphorylation during I/R. TAT-delta p110 p85 increased cell death from 44.6 +/- 2.7% to 92.5 +/- 3.4%, while TAT-delta PTEN p85 decreased cell death caused by I/R in a concentration-dependent manner from 47.8 +/- 1.4% to 11.9 +/- 5.3%. Conclusions: We conclude that TAT-delta PTEN p85 with resulting PTEN inhibition may be a promising strategy to mimic and enhance protective cooling by more rapidly reactivating cellular Akt during heart ischemic arrest and resuscitation.
Predictive Value of Left Atrial Deformation on Prognosis in Severe Primary Mitral Regurgitation
Authors: Li-Tan Yang, Jhih-Yuan Shih, Yen-Wen Liu, Yi-Heng Li, Liang-Miin Tsai, Chwan-Yau Luo, Wei-Chuan Tsai
Journal: Circulation (2013)
University of McGill massive open online course: pioneering sport and exercise medicine education
Authors: Steffan Griffin, Ian Shrier
Journal: British Journal of Sports Medicine (2016)

<h3>Abstract</h3> <h3>Background</h3> Animal-assisted intervention (AAI) programs, used widely for patient benefit, have increasingly been used for healthcare workers (HCW) to reduce occupational stress. However, there are barriers to these programs which limit their utilization, for both patients and HCW, specifically infectious disease concerns. The aim of the research project is to identify barriers and facilitators to AAI program use for healthcare worker benefit, and determine knowledge, beliefs, and practices regarding infectious disease risk and control policies, in order to understand the contextual parameters of program implementation. <h3>Methods</h3> We collected perceptions of key stakeholders involved with hospital AAI programs (HCW and AAI workers) through semi-structured in-depth interviews. We used framework analysis to guide thematic coding, completed independently by three researchers. <h3>Results</h3> We interviewed 37 participants. We divided our themes into two topic areas: program use for HCW and perceived infectious disease risk. Use for healthcare workers included perspectives on the benefits for HCW and program barriers and facilitators (specifically collaboration and leadership). Perceived risk included opinions on infection concerns with AAI, thoughts on control measures to reduce this risk, and responsibility for safety during these programs. <h3>Conclusions</h3> While significant benefits were reported for HCW, they were limited by administrative barriers and hazard concerns. Facilitators to surmount these barriers are best implemented with collaboration across the hospital and appropriate leadership roles to direct safe program implementation. By addressing these barriers through targeted facilitators in the form of evidence-backed guidelines, AAI programs can be used to benefit both patients and HCW.
Accuracy of endobronchial ultrasound-directed transbronchial needle aspiration (EBUS-TBNA) for mediastinal staging in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: M. G. Tupayachi, P. J. Hosein, D. M. Nguyen, R. T. Thurer, M. T. Garcia, L. E. Raez, E. Donna
Journal: Journal of Clinical Oncology (2010)

7071 Background: Accurate staging is critical in defining which pts are surgical candidates in NSCLC. CT and 18FDG-PET can identify mediastinal lymphadenopathy (LAD) but lack specificity. Thoracotomy/thoracoscopy (T) or mediastinoscopy (M) are the gold standards for staging. EBUS-TBNA is a minimally invasive method for sampling mediastinal and hilar LAD and may avoid the need for T or M. Methods: We reviewed all pts who underwent EBUS-TBNA procedures from 2006 to 2009 at the University of Miami/Sylvester Comprehensive Cancer Center. Pts were selected for inclusion if the procedure was done for diagnosis and/or staging of NSCLC. All positive EBUS-TBNA's for NSCLC were considered true positives (TP). A false negative (FN) was defined as a negative EBUS-TBNA when T or M was positive for NSCLC. A true negative (TN) was defined as a negative EBUS-TBNA confirmed by a negative T or M for NSCLC. A TN was also recorded in pts who did not have T or M but were followed up for > 1 year and did not have NSCLC diagnosed in the location of the EBUS-TBNA. If NSCLC was diagnosed within 1 year in a location of a negative EBUS-TBNA, this was considered a FN. All other cases were labeled as non-diagnostic (ND). The accuracy of preprocedure CT and PET for nodal staging was compared to EBUS- TBNA using McNemar's test for paired data. Results: 151 pts underwent EBUS-TBNA, 69 of whom had the procedure for nodal staging of NSCLC. There were 43 TP's, 4 FN's, 17 TN's and 5 ND procedures. The sensitivity, specificity, positive predictive value negative predictive value (NPV) and accuracy of EBUS-TBNA for nodal staging were 91%, 100%, 100%, 81% and 94% respectively. The accuracy of EBUS-TBNA was superior to CT (94% vs 77%, p=0.004). Among the 52 pts who had PET, the accuracy of EBUS-TBNA was superior to PET (96% vs 73%, p=0.019). Among the 23 pts who had T or M after EBUS-TBNA, the results were concordant in 21 (91%). Conclusions: EBUS-TBNA was more accurate than CT and PET for mediastinal staging of NSCLC. T and M can be avoided in up to 62% of cases, but the relatively low NPV of EBUS-TBNA suggests that the more invasive staging modalities should be pursued in negative or non-diagnostic cases. No significant financial relationships to disclose.
Heterogeneity of Karyotype and Growth Potential in Simian Virus 40-Transformed Chinese Hamster Cell Clones23
Authors: Rosemary E. Zuna, John M. Lehman
Journal: JNCI Journal of the National Cancer Institute (1977)

Journal Article Heterogeneity of Karyotype and Growth Potential in Simian Virus 40-Transformed Chinese Hamster Cell Clones Get access Rosemary E. Zuna, Rosemary E. Zuna Search for other works by this author on: Oxford Academic PubMed Google Scholar John M. Lehman John M. Lehman 5 5Address reprint requests to Dr. Lehman. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 58, Issue 5, May 1977, Pages 1463–1472, https://doi.org/10.1093/jnci/58.5.1463 Published: 01 May 1977 Article history Received: 16 September 1976 Accepted: 27 October 1976 Published: 01 May 1977
A randomized, placebo-controlled trial of parenteral hydration in terminally ill cancer patients
Authors: E. Bruera, R. Sala, M. A. Rico, J. R. Moyano, C. Centeno, J. Willey, J. L. Palmer
Journal: Journal of Clinical Oncology (2004)

8004 Background: Most cancer patients develop decreased oral intake and dehydration before death. Parenteral hydration is provided to almost no patients in hospices and almost all patients in acute care facilities. Methods: 51 Patients with clinical evidence of mild to moderate dehydration and oral intake of less than 1000 ml per day were randomized to receive parenteral hydration with 1000 ml normal saline (SC or IV) versus placebo (100 ml normal saline SC or IV) over 4 hours on days 1 and 2. Patients were evaluated for target symptoms (hallucinations, myoclonus, fatigue and sedation), and global well being at baseline and on day 2 of the study using 0 to 10 numerical scales. Overall benefit of the treatment was assessed by the patient and the investigator using 1 to 7 scales. Results: 49 patients were evaluable (96%): 27 patients randomized to parenteral hydration had improvement in 53/73 (73%) evaluable target symptoms versus 33/67 (49%) in 22 patients who received placebo (p=0.005). 15/18 (83%) and 15/18 (83%) patients had improved myoclonus and sedation after hydration versus 8/17 (47%) and 5/15 (33%) after placebo (p=0.03 and p=0.005, respectively). There were no significant differences of improvement in hallucinations and fatigue. Patients assessed hydration as effective in 17/27 (63%) cases and placebo effective in 9/22 (41%) cases (p=0.78). Investigators found hydration was effective in 20/27 (74%) cases and placebo in 12/22 (54%) cases (p=0.15). The mean of pain and swelling at the injection site in subcutaneous hydration (n=20) and subcutaneous placebo (n=17) were 2.1 (+/-2.95) versus 1.75 (+/-2.55) (p=0.1), and 0.82 (+/-1.13) versus 1.41 (=/-1.66) (p=0.64), respectively. Conclusions: Parenteral hydration improved symptoms in terminally ill cancer patients with decreased fluid intake. Hydration was well tolerated and placebo effect were observed. Studies with longer follow-up are required. No significant financial relationships to disclose.