tbuckley/cabot-search huggingface dataset:
Abstract 3644: C-Jun N-terminal kinases and autophagy promote adenoviral and ectopic tumor-associated antigen presentation
Authors: Sarah Renee Klein
Journal: Cancer Research (2014)

Abstract Adenoviruses are innately immunogenic; thus, targeted immunotherapy with recombinant, oncolytic adenoviruses is under investigation for the treatment of cancer. Evidence indicates adenoviruses induce autophagy that is required for cancer cell lysis. Importantly, autophagy is known to promote the presentation of self and foreign antigens for immune cell activation. The molecular regulation of autophagy and antigen presentation in adenovirus- infected cells remains undefined. Our data indicates adenovirus infection triggered phosphorylation of c-Jun N-terminal kinases (JNK) in vitro and in vivo, which was essential for autophagy. JNK-dependent B cell lymphoma-2 (Bcl-2) phosphorylation stimulated the dissociation of Bcl-2/beclin 1 heterodimers, enabling beclin 1 to initiate autophagy. Additionally, our data demonstrated for the first time that adenoviral epitopes were presented at the surface of infected cells through JNK- and autophagy-dependent mechanisms, as infected JNK- and autophagy-deficient cells were unable to activate splenocytes from adenovirus-immunized mice. Rapamycin, a chemical activator of autophagy, was able to enhance adenoviral antigen presentation. Contrary to starvation-induced autophagy, inhibiting adenovirus-mediated autophagy and antigen presentation required genetic knock-out of both JNK1 and JNK2 isoforms. We propose this unique mechanism for the processing of adenoviral antigens and consequent activation of immune cells can be leveraged in developing recombinant adenoviruses for the advancement of anti-tumor immunotherapy. Thus, we developed a novel adenovirus that expresses a chimeric fiber protein containing the cancer-specific, immunogenic epitope from the epidermal growth factor receptor variant III (EGFRvIII). We confirmed that the EGFRvIII epitope was presented at the surface of cells in an autophagy-dependent manner that could be enhanced by the pro-inflammatory cytokine, interferon gamma. Thus, we discovered molecular events regulating adenovirus-mediated autophagy and antigen presentation that differs from the conventional paradigm which could be employed for the advancement of adenovirus-based vaccines. Citation Format: Sarah Renee Klein. C-Jun N-terminal kinases and autophagy promote adenoviral and ectopic tumor-associated antigen presentation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2014-3644
A YAC-based physical map of the mouse genome
Authors: Chad Nusbaum, Donna K. Slonim, Katrina L. Harris, Bruce W. Birren, Robert G. Steen, Lincoln D. Stein, Joyce Miller, William F. Dietrich, Robert Nahf, Victoria Wang, Olga Merport, Andrew B. Castle, Zeeshan Husain, Gail Farino, Delphine Gray, Mechele O. Anderson, Richard Devine, Lloyd T. Horton, Wenjuan Ye, Xiaoyun Wu, Vardouhie Kouyoumjian, Irina S. Zemsteva, Yi Wu, Alville J. Collymore, Dorothy F. Courtney, James Tam, Matthew Cadman, Andrew R. Haynes, Christine Heuston, Tracy Marsland, Anne Southwell, Pamela Trickett, Mark A. Strivens, Mark T. Ross, Wojciech Makalowski, Yixun Xu, Mark S. Boguski, Nigel P. Carter, Paul Denny, Steve D.M. Brown, Thomas J. Hudson, Eric S. Lander
Journal: Nature Genetics (1999)
Abstract 12857: The Use of "Cell Sheet" Technique Enhances the Therapeutic Effects of Skeletal Myoblast Transplantation with Elimination of Arrhythmogenicity
Authors: Takuya Narita, Yasunori Shintani, Kunihiko Takahashi, Niall G Campbell, Steven R Coppen, Masahiro Kaneko, Narumi Harada, Scott Brouilette, Kenta Yashiro, Yoshiki Sawa, Ken Suzuki
Journal: Circulation (2010)

There is compelling experimental evidence to show that transplantation of skeletal myoblasts (SMBs) improves the function of failing hearts via paracrine effects. However, clinical application of t...
Riociguat for Pulmonary Hypertension
Authors: Jaewon Oh, Jong Chan Youn, Seok Min Kang
Journal: New England Journal of Medicine (2013)

To the Editor: With regard to the articles on the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 (CHEST-1) and the Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1 (PATENT-1) by Ghofrani et al. (July 25 issue) 1,2 and the corresponding editorial by Archer, 3 we agree that pharmacotherapy should be available to patients with inoperable disease.However, the observed improvements in exercise capacity with riociguat for chronic thromboembolic pulmonary hypertension are inferior in magnitude, and their durability is unknown, as compared with reported outcomes after surgery, which is associated with an approximate 2% mortality and is curative in many patients. 4The importance of establishing operability in patients with chronic thromboembolic pulmonary hypertension is paramount before the initiation of medical therapy, and the definition of operability should be determined at experienced surgical centers.Our center has performed roughly 3000 operations, and many of our patients have had distal or segmental obstruction, high levels of pulmonary vascular resistance, or both and so have been deemed to have inoperable disease at some centers, but these patients have had excellent outcomes with interventions performed by experienced surgeons.Furthermore, medical therapy in chronic thromboembolic pulmonary hypertension may delay the operation unnecessarily and make removal of the organized thrombus more difficult. 5Accordingly, we emphasize caution with the use of temporizing therapies for a disease for which more definitive approaches are viable.
Attenuation of Ischemia/Reperfusion Injury by a Caspase Inhibitor
Authors: Pierre Weinmann, Alain Meulemans, Doumit Daou, Dominique Le Guludec
Journal: Circulation (2000)

To the Editor:Yaoita et al 1 present an interesting study of the attenuation of ischemia/reperfusion injury in rats by Z-Val-Ala-Asp (OMe)-CH 2 F (ZVAD-fmk), a caspase inhibitor.In a previous study, Gottlieb et al 2 reported that ZVAD-fmk was an apoptosis inhibitor in a preconditioning rabbit cardiomyocyte model.Because ZVAD-fmk seemed to exhibit interesting properties in the inhibition of the caspase cascade, we undertook a study to inhibit apoptosis in an animal model.ZVAD-fmk was directly purchased from the manufacturer (Enzyme Systems Products), and our first step was to check the purity of the compounds.High-performance liquid chromatography was performed on a C18 column (Hypersil, England) with a mobile phase (ammonium acetate pH 4.4, 0.1 mol ⅐ L Ϫ1 /acetonitrile: 40/60) pumping at 0.5 mL/min.Detection was performed with a photodiode array detector (Waters, France) for a 2-hour run.ZVAD-fmk was dissolved in dimethylsulfoxide and diluted with water at 2 mmol/L as recommended by the manufacturer.Three different peaks could be identified during the first 5 minutes, and no other peak in the remaining time.Since the manufacturer claims a 91% purity, we repeated the same experiment with a different lot.Unfortunately, we obtained similar results with a purity Ͻ50%.According to the chromatograms sent by the manufacturer from their quality-control record, it seems that their thin-layer chromatography does not have sufficient resolution and therefore is not capable of checking the purity of the compounds.ZVAD-fmk probably has the interesting biological properties that the 2 cited studies 1,2 have reported, but the exact identification of the involved compounds remains to be performed.We would advise checking the purity of the compounds as a first step when ZVAD-fmk is used.
Abstract 13771: Cardiopulmonary Exercise Testing is Predictive of Return to Work in Cardiac Patients After Rehabilitation
Authors: Heinz Voller, Annett Salzwedel, Rona Reibis, Stefan Kaminski, Hermann Buhlert, Sarah Eichler, Karl Wegscheider
Journal: Circulation (2014)

Introduction: Cardiopulmonary exercise testing (CPX) has an independent prognostic value, especially in cardiovascular patients. We aimed to evaluate parameters of CPX as predictors for return to work (RTW) at discharge of cardiac rehabilitation (CR). Hypothesis: Besides psychosocial as well as clinical parameters CPX variables are independent predictors of return to work in patients with cardiovascular diseases. Methods: We analysed sociodemographic and clinical data from a prospective registry of 489 patients (mean age 51.5±6.9 years, 87.9% men), who were referred to shortterm (3 weeks) inpatient CR between 06/2009 to 12/2011, predominantly after PCI (62.6%), CABG (17.2%) and heart valve replacement (9.0%). At admission, patients underwent noninvasive cardiac diagnostic (2D echo, exercise ECG, 6MWT) and a psychodiagnostic screening (HADS). CPX was performed at discharge for defining fitness. Results: During a mean follow up of 26.5±11.9 months 373 (76.3%) patients returned to work, 116 (23.7%) did not and 60 (12.3%) were retired. A higher number of comorbidities (p=0.011) and heavy work (p&lt;0.001) were negatively associated with RTW whereas a higher exercise capacity at entry of CR (p&lt;0.001) and elective PCI (p=0.02) increased the probability of RTW. After adjustment for covariates, max. work load (Watt) at CPX termination and the VE/VCO2-slope had an independent prognostic significance for RTW. A higher work load increased (p=0.009) while a higher VE/VCO2-slope decreased (p=0.027) the probability of RTW. Even for retirement, CPX had a prognostic value: the likelihood of retirement was smaller with increasing VO2AT (p=0.016). Conclusion: CPX is a meaningful tool to assess patients’ ability for return to work. Therefore it should be an essential part of functional assessment in CR for predicting participation in employment during two years after CR.
Abstract P352: Racial/Ethnic Differences in Cardiovascular Disease Outcomes among Patients with Hypertension or Type 2 Diabetes
Authors: Jia Pu, Sukyung Chung, Beinan Zhao, Vani Nimbal, Elsie J Wang, Stephen P Fortmann, Latha P Palaniappan
Journal: Circulation (2015)

Background: This study assesses racial/ethnic differences in CVD outcomes among patients with hypertension (HTN) or type 2 diabetes (T2DM) across Asian American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese), Mexican, non-Hispanic black (NHB), and non-Hispanic White (NHW) in a large, mixed payer ambulatory care setting in northern California. Study Design: We estimated the rate of CVD incidence among adult patients with HTN (N=171,864) or T2DM (N=10,570), or both (N=36,589) using electronic health records between 2000-2013. Average follow-up was 4.5 years. CVD, including CHD (410-414), PVD (415, 440.2, 440.3, 443.9, 451, 453), and stroke (430-434), was defined by ICD-9 codes; HTN and T2DM were defined by ICD-9 codes, medication history, or two or more elevated blood pressure measures/abnormal glucose lab test results. Cox proportional hazard models were used to estimate hazard ratios for CHD, PVD, and stroke across race/ethnicity. Results: Among these patients, 10.5% developed CVD by the end of year 2013 (5.4% CHD, 3.4%PVD, 3.6% stroke). There was a gender difference in the risk of incident CHD. Among males, the age-adjusted hazard ratios for CHD were significantly higher for Asian Indians (HR: 1.3, 95% CI: 1.2-1.5) and significantly lower for Chinese (HR: 0.6, CI: 0.5-0.7) and Japanese (HR: 0.8, CI: 0.6-0.9) compared to NHWs. Among females, the age-adjusted hazard ratios for CHD were significantly higher for Mexican (HR: 1.3, CI: 1.1-1.5) and NHBs (HR: 1.7, CI: 1.4-2.0) and significantly lower for Chinese (HR: 0.6, CI: 0.5-0.7) and Japanese (HR: 0.5, CI: 0.4-0.7). NHB men and women also had significantly higher age-adjusted hazard ratios for PVD (men: HR: 1.5, CI: 1.2-1.9; women: HR: 1.6, CI: 1.3-1.9) and stroke (men: HR: 1.3, CI: 1.1-1.7; women: HR: 1.3, CI: 1.1-1.6) compared to NHWs. The age-adjusted hazard ratios for PVD and stroke were lower or equivalent to NHWs for all Asian subgroups and Mexican men and women. Patients with both HTN and T2DM were at elevated risk to develop CVD compared to patients with only one of the two conditions, regardless of their race/ethnicity. Conclusions: Compared to previous studies, we found less racial/ethnic variation in CVD outcomes, in particular stroke, among patients with HTN or T2DM. Our finding suggests the higher stroke incidence rates in several races/ethnicities are likely to be explained by the higher prevalence of HTN and T2DM among these groups. However, Asian Indian men and NHB and Mexican women with HTN or T2DM were at elevated risk for CHD compared to NHWs. Since the majority of patients in the study cohort had health insurance, further studies are needed to better understand the reasons for the observed racial/ethnic differences beyond disparities in access to health care. Special attention needs to be paid to patients with multiple conditions.
Reducing antibiotic use for acute bronchitis in primary care: blinded, randomised controlled trial of patient information leaflet * Commentary: More self reliance in patients and fewer antibiotics: still room for improvement
Authors: J. Macfarlane, W. Holmes, P. Gard, D. Thornhill, R. Macfarlane, R. Hubbard, C. van Weel
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objective:</b> To assess whether sharing the uncertainty of the value of antibiotics for acute bronchitis in the form of written and verbal advice affects the likelihood of patients taking antibiotics. <b>Design:</b> Nested, single blind, randomised controlled trial. <b>Setting:</b> Three suburban general practices in Nottingham. <b>Participants:</b> 259 previously well adults presenting with acute bronchitis. <b>Intervention:</b> In group A, 212 patients were judged by their general practitioner not to need antibiotics that day but were given a prescription to use if they got worse and standard verbal reassurance. Half of them (106) were also given an information leaflet. All patients in group B (47) were judged to need antibiotics and were given a prescription and encouraged to use it. <b>Main outcome measures:</b> Antibiotic use in the next two weeks. Reconsultation for the same symptoms in the next month. <b>Results:</b> In group A fewer patients who received the information leaflet took antibiotics compared with those who did not receive the leaflet (49 <i>v</i> 63, risk ratio 0.76, 95% confidence interval 0.59 to 0.97, P=0.04). Numbers reconsulting were similar (11 <i>v</i> 14). In group B, 44 patients took the antibiotics. <b>Conclusion:</b> Most previously well adults with acute bronchitis were judged not to need antibiotics. Reassuring these patients and sharing the uncertainty about prescribing in a information leaflet supported by verbal advice is a safe strategy and reduces antibiotic use. <h3>What is already known on this topic</h3> Most adults with acute bronchitis who consult their general practitioner will receive antibiotics For most patients antibiotics do not modify the natural course of the symptoms The widespread belief among patients that infection is the problem and antibiotics the solution has considerable influence on prescribing by general practitioners, even when they judge that antibiotics are not definitely indicated <h3>What this study adds</h3> General practitioners judged that about four in five adults with acute bronchitis did not definitely need antibiotics on the day they consulted Antibiotic use was reduced by a quarter in such patients, who received verbal and written information and reassurance in addition to a prescription for antibiotics Sharing with the patient the uncertainty about the decision to prescribe seems safe and effective
Expression of specific voltage dependent anion channel (VDAC) isoforms confers differential sensitivity to cisplatin
Authors: Kevin Cullen, Zejia Yang, Lisa Schumaker, Zhongmin Guo, Tatiana Sheiko, William Craigen
Journal: Cancer Research (2007)

5734  CDDP (cis-diamminedichloroplatinum II) has been in widespread clinical use for more than 30 years. Despite the importance of this agent in the treatment of head and neck cancer (HNSCC) and other malignancies, there are many uncertainties about its molecular pharmacology and ultimate mechanism of action. Cisplatin adducts to nuclear DNA are felt to be the molecular lesion that triggers apoptosis, but the mechanism linking nuclear DNA adduct formation and cell death is unclear. We recently demonstrated that cisplatin binds preferentially to mitochondrial DNA compared to nuclear DNA and isolated mitochondria from head and neck squamous cell cancers rapidly release cytochrome-c after exposure to pharmacologic concentrations of cisplatin. Cisplatin also binds preferentially to mitochondrial membrane proteins including VDAC. Following exposure of intact tumor cells to cisplatin, the concentration of CDDP binding to VDAC was more than 200 fold higher than binding to total cell proteins. (Clin Cancer Res 12:5817, 2006). This raised the possibility that VDAC could be a molecular target of cisplatin action.  In the present study, we evaluated a series of VDAC knockout mouse embryo fibroblasts. Homozygous knockouts for VDAC isoforms 1, 2 and 3 were evaluated for sensitivity to cisplatin in standard XTT assays. IC50 for the wild type mouse embryo fibroblasts was 7μM. IC50 for VDAC 1, 2 and 3 homozygous knockouts were 22μM, 6μM and 0.6μM respectively. In other words, the VDAC 1 homozygous knockout cells were 3 times more resistant to cisplatin than the parental cells while the VDAC 3 knockout cells were 12 times more sensitive to cisplatin than the parental cell line. VDAC 3 knockout cells were nearly 40 times more sensitive to cisplatin than the VDAC I knockout cells. This effect was specific for cisplatin as a control drug, the topoisomerase inhibitor irinotecan, showed no difference in sensitivity for VDAC 2 or VDAC 3 knockouts while VDAC I knockouts were minimally more resistant to irinotecan than the parental cell line.These data suggest that expression of specific VDAC isoforms may be important in determining cell sensitivity to the chemotherapy agent cisplatin. Specifically, loss of expression of VDAC 1 is associated with resistance to cisplatin while loss of expression of VDAC 3 is associated with significant increased sensitivity to the drug. These data support the concept that the cytotoxic effects of cisplatin may be mediated in significant part through direct action on mitochondria and that sensitivity to apoptosis may reflect expression of specific VDAC isoforms.
Increase in malaria cases imported from Pakistan to Germany in 2012
Authors: K Stark, I Schöneberg
Journal: Eurosurveillance (2012)

A significant increase of malaria cases imported to Germany from Pakistan was observed in 2012. As of 14 November, Pakistan was the country of infection in 32 out of 434 malaria cases in 2012, compared to zero to eight annual malaria cases (out of over 500 cases) in previous years. Physicians and public health authorities should consider malaria in febrile patients returning or migrating from Pakistan.
Financial Consequences of Drug Benefit Plans
Authors: Bartholomew E. Clark, Robert I. Garis
Journal: JAMA (2003)

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Abstract 4010: The Effect of Bivalirudin on Bleeding Risk in Patients with Chronic Renal Failure Undergoing Contemporary Percutaneous Coronary Intervention (PCI): an Analysis From a Large Multicenter PCI Registry
Authors: Mauro Moscucci, Dean E Smith, Chris D'Haem, Kirit Patel, Thomas LaLonde, Sanjaya Khanal, Herbert D Aronow, Arthur Riba, Robert Safian, David Share
Journal: Circulation (2006)

Background: Prior studies have shown the non-inferiority of bivalirudin compared with heparin and GP IIbIIIa inhibition in patients undergoing PCI, and have suggested a reduction in bleeding risk p...
Abstract 3519: The c-Myc oncogene over-activates dormant replication origins and sensitizes cancer cells to chemotherapy drugs
Authors: Victoria Bryant, Mark G. Alexandrow
Journal: Cancer Research (2014)

Abstract Several clinical studies have shown a correlation between elevated c-Myc levels and a better response to chemotherapy. Although elevated c-Myc might indirectly cause such chemosensitivity, it is possible that a direct effect is occurring due to underlying molecular mechanisms. The purpose of the current study was to determine whether c-Myc overexpression could acutely cause chemosensitivity. The c-Myc protein is known to activate DNA replication origins, but the mechanism for this is unknown. Origins are regulated by the loading of MCM2-7 hexamers, which form the core of the helicase that starts the initiation of replication. Mammalian cells load more MCM complexes than are necessary to complete one round of replication. The excess MCM complexes function as backups to allow recovery of replication when forks stall during drug treatment. Consistent with this, we found that loss of Mcm4 or Mcm7 sensitizes PDAC cell lines to 5-FU and Gemcitabine, two S phase stress drugs that are used to treat PDAC patients but are not highly effective on their own. Similar to depletion of backup MCM complexes via loss of Mcm4 or Mcm7, elevated c-Myc expression over-activates backup MCMs, leaving fewer available to recover from drug treatment. Cells containing overexpressed c-Myc display increased chemosensitivity to Gemcitabine that is not seen in cells containing normal c-Myc levels or a non-functional c-Myc mutant. These results demonstrate that reduction in backup MCM complexes, either by direct downregulation or by oncogene driven over-activation (via c-Myc), render cells sensitive to chemotherapy drugs. These results suggest that development of drugs that target MCM functionality may be useful in combination with S-phase stress drugs currently used in the clinic. These results also demonstrate that c-Myc has the ability to acutely cause chemosensitivity and c-Myc elevated tumors may respond better to chemotherapy due to the c-Myc effects on MCM complexes. Citation Format: Victoria Bryant, Mark G. Alexandrow. The c-Myc oncogene over-activates dormant replication origins and sensitizes cancer cells to chemotherapy drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3519. doi:10.1158/1538-7445.AM2014-3519