tbuckley/cabot-search huggingface dataset:
The effect of procaine amide on components of excitability in long mammalian cardiac Purkinje fibers.
Authors: M F Arnsdorf, J T Bigger
Journal: Circulation Research (1976)

The microelectrode technique of intracellular constant current application and intracellular transmembrane voltage recording was used to study the effects of procaine amide (PA) on cardiac excitability. We measured the effect of PA in a concentration equivalent to clinically effective antiarrhythmic plasma levels (5 mug/ml), on nonnormalized and normalized strength-duration and charge-duration curves, membrane characteristics, and cable properties in long sheep Purkinje fibers in normal Tyrode's solution with [K+]0 = 4.0 mM. PA exerted a complex action and influenced passive resistance-capacitance (RC) and active generator properties by decreasing membrane conductance, primarily membrane sodium conductance. Whether PA increased or decreased excitability depended on the relative contribution of the drug-induced alterations in passive and active membrane properties. These findings may explain, in part, the conflicting results of studies on cardiac excitability in the whole animal, as well as the clinical observation that PA may exert both artiarrhythmic and arrhythmogenic effects. The primary mechanism by which PA modifies excitability would seem to differ considerably from that of the structurally similar local anesthetic agent lidocaine.
New Insights Into Fetal Atrioventricular Block Using Fetal Magnetocardiography⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Lisa K. Hornberger, Kathryn Collins
Journal: Journal of the American College of Cardiology (2008)
Abstract 19512: Right Ventricular Global Longitudinal Strain Improves Diagnostic and Prognostic Assessment in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Tetsuari Onishi, Kosuke Yoshii, Masato Tsuru, Akira Shimane, Katunori Okajima, Shinichiro Yamada, Yasuyo Taniguchi, Yoshinori Yasaka, Hiroya Kawai
Journal: Circulation (2014)

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable cardiomyopathy characterized by right ventricular (RV) myocardium dysfunction leading to RV failure and fatal arrhythmias. Hypothesis: RV global longitudinal strain (GLS) derived from two-dimensional speckle-tracking echocardiography (2DSTE) contributes to diagnostic and prognostic assessment in ARVC. Methods: We retrospectively evaluated the echocardiographic data of 67 patients referred with suspected ARVC and 27 age- and gender-matched healthy controls (Group C). Of 67 suspected ARVC patients, 34 patients (Group A) were diagnosed as ARVC, while remaining 33 patients (Group B) were not diagnosed due to not meeting criteria. Tricuspid annular plane systolic excursion (TAPSE), RV end-diastolic and end-systolic area (RVEDA, RVESA), RV fractional area change (RVFAC) and GLS were measured to assess the RV function. Outcome was assessed according to death and hospitalization with heart failure, fatal arrhythmia and appropriate defibrillator shock. Results: Patients in Group A had significantly reduced values of TAPSE, RVFAC and GLS, and significantly greater vales of RVEDA and RVESA in comparison among 3 groups. In Group A, 11 adverse cardiac events were observed during averaged 718 follow-up days. Multivariate Cox’s regression analysis showed that GLS was an independent prognostic factor. Kaplan-Meier survival analysis revealed there was a significant difference in outcome between patient groups divided by the median value (11%) of GLS in Group A. Conclusions: GLS in RV may be a tool to assist in diagnosis of ARVC, and be a superior prognostic factor in ARVC patients.
<i>Hif1a</i> Deletion Reveals Pro-Neoplastic Function of B Cells in Pancreatic Neoplasia
Authors: Kyoung Eun Lee, Michelle Spata, Lauren J. Bayne, Elizabeth L. Buza, Amy C. Durham, David Allman, Robert H. Vonderheide, M. Celeste Simon
Journal: Cancer Discovery (2015)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths worldwide, with an exceedingly low 5-year survival rate. PDAC tumors are characterized by an extensive desmoplastic stromal response and hypovascularity, suggesting that tumor hypoxia could regulate PDAC initiation and/or progression. Using a well-defined, autochthonous KrasG12D-driven murine model, as well as human tumors, we demonstrate that hypoxia and stabilization of hypoxia-inducible factor 1α (HIF1α), a principal mediator of hypoxic adaptation, emerge early during preinvasive stages of PDAC. Surprisingly, pancreas-specific Hif1a deletion drastically accelerated KrasG12D-driven pancreatic neoplasia and was accompanied by significant increases in intrapancreatic B lymphocytes, featuring prominent influx of a rare “B1b” B-cell subtype. Finally, treatment of HIF1α-deficient mice with B cell–depleting αCD20 monoclonal antibodies inhibited progression of pancreatic intraepithelial neoplasia (PanIN). Our data reveal a previously unrecognized role for B cells in promoting pancreatic tumorigenesis and implicate HIF1α as a critical regulator of PDAC development. Significance: We show here that pancreas-specific Hif1a deletion promotes PDAC initiation, coincident with increased intrapancreatic accumulation of B cells, and that B-cell depletion suppresses pancreatic tumorigenesis. We therefore demonstrate a protective role for HIF1α in pancreatic cancer initiation and uncover a previously unrecognized function of B cells. Cancer Discov; 6(3); 256–69. ©2015 AACR. See related commentary by Roghanian et al., p. 230. See related article by Pylayeva-Gupta et al., p. 247. See related article by Gunderson et al., p. 270. This article is highlighted in the In This Issue feature, p. 217
Efficacy and safety of first-line bevacizumab (Bv) and cisplatin/gemcitabine (CG) in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC) in the BO17704 study (AVAiL)
Authors: N. B. Leighl, P. Zatloukal, J. Mezger, R. Ramlau, V. Archer, N. Moore, M. Reck
Journal: Journal of Clinical Oncology (2009)

8050 Background: AVAiL, an international, placebo-controlled, phase III trial, evaluated Bv plus CG in pts with previously untreated advanced, non-squamous NSCLC, with performance status 0/1. A retrospective analysis was performed to assess the efficacy and safety of Bv plus CG in the subpopulation of elderly pts (≥65 years [yrs]). Methods: 1,043 pts (age 20–83) were randomized to C 80mg/m 2 and G 1,250mg/m 2 q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (Bv 7.5; n=345), Bv 15mg/kg q3w (Bv 15; n=351) or placebo (Pl; n=347). Bv/Pl was administered until disease progression. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (RR) and safety. Efficacy and safety were compared between pts &lt;65 yrs vs ≥65 yrs. Results: Efficacy data were available for 304 pts ≥65 yrs (median age 68), and 739 pts &lt;65 yrs (median age 55). Baseline characteristics were similar between the groups. In the Bv arms, 179 pts (93%) received ≥1 cycle of treatment; 85 (47.5%) completed &gt;6 cycles. Bv-treated pts ≥65 yrs derived an improvement in PFS compared to Pl (Bv 7.5: HR 0.71, p 0.023; Bv 15: HR 0.84, p= 0.25). ORRs were 40%, 29% and 30% for pts ≥65 in the Bv 7.5, Bv 15 and Pl arms. Survival was similar in all treatment arms regardless of age, (pts ≥65 Bv 7.5 HR 0.84; Bv 15 HR 0.88, p=NS). Safety data were available for 284 pts ≥65 yrs and 702 pts &lt;65 yrs. There were no safety signals of concern in older patients. Grade ≥3 toxicities occurred in 84%, 80% and 80% of older pts treated with Bv 7.5, Bv 15 and Pl. Pts ≥65 yrs had no episodes of severe hemoptysis, but in Bv 7.5 and Pl arms, were more likely to have other bleeding, compared to pts &lt;65. The incidence of hypertension and febrile neutropenia were similar in pts ≥65 and &lt;65 yrs. Treatment-related deaths were not increased in Bv-treated pts ≥65 yrs vs pts &lt;65 yrs or in Bv-arms vs Pl. Conclusions: The PFS benefit from Bv-based treatment in the elderly subpopulation is similar to that observed in the overall patient population. No particular safety signals were identified in this population, suggesting acceptable tolerability of Bv in elderly pts in AVAiL. [Table: see text]
Brief duration rituximab(R)/chemotherapy (CNOP or CVP) followed by maintenance rituximab in elderly/poor performance status patients (pts) with diffuse large B-cell lymphoma (DLBCL): A phase II trial of the Minnie Pearl Cancer Research Network
Authors: E. L. Raefsky, F. A. Greco, D. R. Spigel, H. H. Doss, C. Farley, R. Saez, M. Kommor, J. D. Hainsworth
Journal: Journal of Clinical Oncology (2006)

7577 Background: R-CHOP is the standard first-line treatment for pts with DLBCL; however, some pts are poor candidates due to general debility, cardiac disease, or other medical problems. Maintenance R is not effective after full course R-CHOP chemotherapy for DLBCL (ECOG 4494), but improves outcome following CHOP alone. In this phase II trial, we evaluated short course R/chemotherapy, followed by maintenance R, in pts who were not candidates for full-course R-CHOP. Methods: Eligibility: previously untreated DLBCL; stage II-IV; ECOG PS 0–2; age ≥ 70 years or poor CHOP candidate; adequate kidney, liver, bone marrow function; no HIV infection; informed consent. Pts received 3 courses of R-CNOP (cyclophosphamide 500mg/m 2 , mitoxantrone 10mg/m 2 , vincristine 1.0mg/m 2 , prednisone 80mg PO days 1–5, rituximab 375mg/m 2 ) followed by pegfilgrastim 6mg sq day 2, at 21-day intervals. Mitoxantrone was omitted for pts with EF &lt; 40%. Pts with response/stable disease after chemotherapy began maintenance R (375mg/m 2 weekly × 4 doses, administered at 6-month intervals × 4 courses). Results: 31 pts entered this trial between 5/03 and 11/05. Clinical characteristics: median age, 78 years; ECOG PS 2, 45%; IPI 3–5, 79%. 27 pts (87%) have completed short course R-chemotherapy; 20 pts (65%) are currently receiving maintenance R. After completion of R-chemotherapy, 17 pts (63%) had responses (9 CR/CR u , 8 PR); 10 pts had stable disease/minor response. After median 16 month follow-up, 29 of 31 pts (94%) are progression-free; actuarial 2-year PFS is 90%. The 2-year overall survival is 74%. 4 pts have died (progressive lymphoma 2, intercurrent illnesses 2). Grade 3/4 toxicities: neutropenia 38%, other toxicities &lt; 10%, no treatment-related deaths. Conclusions: Short-course R-chemotherapy followed by maintenance R was active and well tolerated in a group of elderly, poor prognosis pts with DLBCL. In spite of modest CR/CR u rate; the 90% 2-year PFS suggests a role for maintenance R. If these findings persist with further followup, this approach is worthy of further study in this patient group. [Table: see text]
Profiling Non–Small Cell Lung Cancer: From Tumor to Blood
Authors: Dana W.Y. Tsui, Michael F. Berger
Journal: Clinical Cancer Research (2015)

Circulating cell-free tumor DNA has shown great promise for noninvasive genomic profiling to guide the administration of targeted therapies in non-small cell lung cancer. With advancements in molecular technology, it is now possible to interrogate multiple clinically actionable genetic drivers in the blood with a single assay.
The diversity of Bet v 1–specific IgG 4 antibodies remains mostly constant during the course of birch pollen immunotherapy
Authors: Brinda Subbarayal, Dirk Schiller, Christian Möbs, Wolfgang Pfützner, Beatrice Jahn-Schmid, Barbara Gepp, Heimo Breiteneder, Stefan Vieths, Barbara Bohle
Journal: Journal of Allergy and Clinical Immunology (2015)
Sensitivity to halichondrin analog E7389 and hemiasterlin analog E7974 correlates with βIII tubulin isotype expression in human breast cancer cell lines
Authors: S. Agoulnik, G. Kuznetsov, K. Tendyke, L. A. Parent, J. P. Marsh, N. Twine, F. G. Renshaw, S. Silberman, B. A. Littlefield
Journal: Journal of Clinical Oncology (2005)

2012 Background: Resistance to tubulin-targeted agents has been associated with differential tubulin isotype expression in cancer cells. In this study we investigated whether β-tubulin isotype composition of tumor cells affects their sensitivity to 2 natural product-based antitubulin agents: halichondrin analog E7389 and hemiasterlin analog E7974. Methods: Antiproliferative effects of E7389, E7974, paclitaxel and vinblastine against a panel of human breast cancer cell lines were determined by methylene blue-based or MTT-based cell growth inhibition assays. Cell lines were tested for evidence of PgP expression by monitoring effects of the PgP blocker verapamil on paclitaxel sensitivity. Using quantitative PCR with specific primers, expression levels of the seven human β-tubulin isotypes were determined (I, II, III, IVa, IVb, V, and VI). Results: No evidence for PgP expression was found in any of the cell lines tested. In growth inhibition studies, interdrug correlations were seen between sensitivities to the 3 microtubule polymerization inhibitors E7974, E7389 and vinblastine, but not between the microtubule stabilizer paclitaxel and the other agents. All 7 β-tubulin isotypes were detected at different levels in each cell line, with isotypes I and IVb showing the least variation while isotypes II, III, and IVa showed the greatest variability between the cell lines. A significant correlation was demonstrated between β III tubulin expression levels and sensitivity to both E7389 and E7974. Conclusions: These findings in cancer cell lines suggest that tumors expressing higher levels of βIII tubulin isotype may be more responsive to treatment with E7389 and E7974. If confirmed clinically, such preclinical insights may lay the foundation for selection of patient populations with enhanced sensitivities to these 2 natural product-based antitubulin agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai Medical Research Institute
Increasing the Therapeutic Ratio of Stereotactic Ablative Radiotherapy by Individualized Isotoxic Dose Prescription
Authors: Jaap D. Zindler, Charles R. Thomas, Stephen M. Hahn, Aswin L. Hoffmann, Esther G.C. Troost, Philippe Lambin
Journal: JNCI Journal of the National Cancer Institute (2015)

To obtain a favorable tradeoff between treatment benefits and morbidity ("therapeutic ratio"), radiotherapy (RT) dose is prescribed according to the tumor volume, with the goal of controlling the disease while respecting normal tissue tolerance levels. We propose a new paradigm for tumor dose prescription in stereotactic ablative radiotherapy (SABR) based on organ-at-risk (OAR) tolerance levels called isotoxic dose prescription (IDP), which is derived from experiences and limitations of conventionally fractionated radiotherapy. With IDP, the radiation dose is prescribed based on the predefined level of normal tissue complication probability of a nearby dose-limiting OAR at a prespecified dose-volume constraint. Simultaneously, the prescribed total tumor dose (TTD) is maximized to the technically highest achievable level in order to increase the local tumor control probability (TCP). IDP is especially relevant for tumors located at eloquent locations or for large tumors in which severe toxicity has been described. IDP will result in a lower RT dose or a treatment scheduled with more fractions if the OAR tolerance level is exceeded, and potential dose escalation occurs when the OAR tolerance level allows it and when it is expected to be beneficial (if TCP < 90%). For patients with small tumors at noneloquent sites, the current SABR dose prescription already results in high rates of local control at low toxicity rates. In this review, the concept of IDP is described in the context of SABR.
Abstract #4410: Rescue of extracellular matrix detachment induced metabolic defects by ErbB2 and antioxidants
Authors: Alexandra Grassian, Zachary Schafer, Joan Brugge
Journal: Cancer Research (2009)

%9One hallmark of tumor cells is their ability to survive without attachment to the extracellular matrix (ECM). Previous studies have shown that inhibition of apoptosis is not sufficient for survival when cells are detached from ECM. Our laboratory has recently found that matrix detachment of immortalized breast epithelial cells (MCF10A) causes a metabolic impairment independent of apoptosis. This impairment is characterized by decreased levels of glucose uptake, ATP and reduced glutathione, and increased levels of reactive oxygen species (ROS). Overexpression of ErbB2 rescues the decrease in glucose uptake and leads to a decrease in ROS levels; this decrease is dependent on the pentose phosphate pathway (PPP). %9Our lab has demonstrated that EGFR signaling is critical for ErbB2 rescue of ATP levels and that ErbB2 overexpression prevents the loss of EGFR in ECM-deprived cells. EGFR stimulation of PI3K activity is essential for ErbB2 rescue of glucose transport and ATP levels in suspended cells. Consistent with these findings, the defects due to loss of matrix attachment are rescued by ectopic expression of activated variants of PIK3CA and Akt. Inhibition of Erk signaling has little effect on ErbB2 rescue of ATP. We are now further investigating the mechanism by which ErbB2 rescues glucose uptake and EGFR levels. %9As stated above, the ErbB2 rescue of ATP production is dependent on PPP flux for reduction of ROS levels induced by matrix detachment. Interestingly, we have also found that reduction of ROS levels with antioxidant treatment rescues ATP independently of glucose uptake by relieving an ROS-mediated inhibition of ATP generation by fatty acid oxidation. Several enzymatic antioxidant enzymes are upregulated in breast cancer. This raises the question as to whether antioxidants can rescue metabolic defects that result from displacement or migration of tumors cells from their natural niches, particularly in cells with anti-apoptotic oncogenic insults. Therefore, we are examining how overexpression of the enzymatic antioxidants catalase and superoxide dismutase effects ATP levels. These studies will provide insights into potential mechanisms that could contribute to the previously reported activities of antioxidants as tumor promoters.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4410.
Poem for David
Authors: Jack Coulehan
Journal: JAMA (2015)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract #5672: The role of IKK\#946;/TSC1 regulation in tumorigenesis and insulin resistance
Authors: Hsu-Ping Kuo, Dung-Fang Lee, Mien-Chie Hung
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Breast cancer is the most common cancer in women. Many factors have been suggested to contribute to the development of this disease and inflammation is one of them. Among the inflammatory cytokines, TNF-\#945; is considered one of the most important factors involved in the inflammation-mediated tumorigenesis. In the present study, we showed that in response to TNF\#945; stimulation, IKK\#946;, a major downstream kinase in the TNF\#945; signaling pathway, is able to induce the activation of mTOR activity. While investigating which molecule in the mTOR pathway involved in IKK\#946;-mediated mTOR regulation, we found that IKK\#946; physically associates with TSC1. Kinase assays and mass spectrometry analyses revealed that IKK\#946; phosphorylates TSC1 at Ser487 and Ser511 in vitro and in vivo. Elucidating the underlying mechanisms which cause the mTOR activation by TSC1 phosphorylation, our results showed that phosphorylation of TSC1 by IKK\#946; alters its membrane localization, inhibits its association with TSC2, decreases its protein stability, thereby activating the mTOR pathway. In vitro angiogenesis assays and orthotopic breast cancer model further revealed that phosphorylation of TSC1 by IKK\#946; enhances VEGF expression, angiogenesis and tumorigenesis. Moreover, the immunohistochemical study suggested that phosphorylation of TSC1 by IKK\#946; promotes mTOR activation and VEGF production and is associated with poor clinical outcome of breast cancer patients. Recently, activation of mTOR signaling pathway has been found to suppress insulin sensitivity through serine phosphorylation of IRS1. Here we further showed the role of TSC1 phosphorylation by IKK\#946; in TNF\#945;-induced insulin resistance. Collectively, dysregulation of the TSC1/mTOR signaling pathway by IKK\#946; is a common molecular switch for both cancer pathogenesis and insulin resistance.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5672.