tbuckley/cabot-search huggingface dataset:
Abstract A100: Role of HER3 ligand-independent activation in EGFR resistance in pancreatic cancer
Authors: Donald J. Buchsbaum, Tong Zhou
Journal: Cancer Research (2015)

Abstract The purpose of this study was to investigate the role of HER3 ligand-independent activation in EGFR resistance in pancreatic cancer. The expression and activation status of EGFR and HER3 were determined in a panel of 13 human pancreatic cancer cell lines by immunoprecipitation and Western blot analysis. To determine whether HER3 plays a central role in EGFR resistance, the effect of combination treatment with erlotinib and anti-HER3 on signaling pathways was examined in 2 pancreatic cancer cell lines. This was done using a novel anti-HER3 antibody (1A5) capable of inhibiting HER3 activation in a ligand-independent fashion, and a classic anti-HER3 antibody (3D4) primarily blocking ligand-induced HER3 activation. The MEK inhibitor trametinib was used to investigate EGFR and HER3 activation. Combination treatment studies in athymic nude mice bearing BxPC-3 xenografts involved anti-HER3, lapatinib, trametinib, and gemcitabine treatment. The majority of pancreatic cancer cell lines expressed high levels of total EGFR and HER3, and had variable levels of phospho-EGFR (Tyr1068) and phospho-HER3. Erlotinib treatment did not reduce the levels of phospho-EGFR. Although ligand-independent and ligand-dependent anti-HER3 antibodies did not alter the levels of phospho-EGFR, they did reduce the levels of phospho-AKT. Combination treatment with anti-HER3 antibodies and erlotinib or trametinib reduced the levels of phospho-EGFR and phospho-AKT. When MEK/ERK was inhibited by trametinib, both EGFR and HER3 were activated. Treatment of BxPC-3 xenografts with lapatinib, trametinib, anti-HER3, and gemcitabine produced the greatest inhibition of tumor growth as compared to any single agent or combinations of two or three agents. These results show that EGFR is expressed and highly activated in pancreatic cancer cell lines, but the cell lines are resistant to an EGFR inhibitor. They also suggest that ligand-independent activation of HER3 may lead to erlotinib resistance via the AKT pathway. These results reveal a novel mechanism by which HER3 is activated in a ligand-independent fashion via inhibition of the MEK/ERK pathway. This is an important observation as it indicates that HER3 ligand-independent activation must be inhibited when the MEK/ERK pathway is targeted. Overall, these results indicate that HER3 ligand-independent activation is a key target for overcoming EGFR resistance in pancreatic cancer cells, and suggest a combination strategy of anti-HER3 antibodies with either erlotinib or trametinib for the treatment of pancreatic cancer. Citation Format: Donald J. Buchsbaum, Tong Zhou. Role of HER3 ligand-independent activation in EGFR resistance in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A100.
Abstract 857: Notch Regulates Cardiac Progenitor Cell Commitment and Myocyte Formation in the Embryonic Mouse Heart
Authors: Francesca Delucchi, Konrad Urbanek, Alessandro Boni, Robert Siggins, Katsuya Amano, Grazia Iaffaldano, Saori Yasuzawa-Amano, Nicole LeCapitaine, Serena Vitale, Arantxa Gonzalez, Andrea Di Marco, Irina Trofimova, Roberto Rizzi, Yu Misao, Piero Anversa, Jan Kajstura, Annarosa Leri
Journal: Circulation (2007)
Expression pattern of MAP3K8 and MMP9 in lung cancer cell lines
Authors: Jyotsna Pandey, Jamie Dempsey, Adam Clark, John Brooks, Jonathan Wiest
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

2480 

MAP3K8 has been identified as a transforming proto-oncogene. Increased expression of MAP3K8 is seen in many solid tumors. However forced over-expression of MAP3K8 in normal fibroblasts leads to slowed proliferation and activation of apoptotic pathways. This suggests that MAP3K8 may be important in late stages of tumorigenesis. Matrix metalloproteinase 9 (MMP9) is rate limiting extracellular protease involved in cell migration across basement membranes and facilitates tumor cell invasion. We have previously shown that MAP3K8 is over-expressed in several lung cancer cell lines. We have also demonstrated that the MAP3K8 promoter is a GC rich, TATA-less promoter with transcription factor binding site motifs like AP-1, Sp-1, and NF-κB. We now report that MAP3K8 levels are elevated in lung cancer cell lines derived from pleural metastatsis but not in the cell lines derived from metastatic lung cancer cells from lymph nodes and bone marrow. Using a Zymogram assay we studied the expression pattern of MMP9 and found a direct correlation with the elevated MAP3K8 levels. We further investigated the direct effect of MAP3K8 using a dominant negative construct and also forced over-expression of the gene. Searching for the transcription factor binding site motifs in the 5’ flanking region of the MMP9 gene we found a number of common factors like AP-1, Sp-1 and NF-κB, in addition to MAP kinase pathway mediated sites like PEA3/Ets. The findings suggest a role for MAP3K8 upstream of MMP9 mediated cell migration and invasion.
Abstract 18: Coronary Perfusion Pressure in VF and in PEA/A Cardiac Arrest Animals
Authors: Gregory Walcott, Sharon Melnick, Cheryl Killingsworth
Journal: Circulation (2011)

We hypothesized that equivalent chest compressions are less effective at perfusing the heart in pulseless electrical activity/asystole (PEA/A) cardiac arrest than in ventricular fibrillation (VF) cardiac arrest. We tested this hypothesis in two swine models of cardiac arrest. Two groups of pigs (33+4 kg) were anesthetized and instrumented to measure coronary perfusion pressure (CPP). CPP was calculated as aortic minus right atrial pressure measured just before the initiation of a chest compression. Group 1 underwent 5 minutes of unsupported electrically induced ventricular fibrillation. Group 2 animals were ventilated with a 12% oxygen and balance nitrogen mixture until aortic pulsations were less than 2 mmHg. Animals remained unsupported for an additional 6 minutes. Both groups were resuscitated with chest compressions (100/min) and ventilations (100% O2, 10/min). After 7 minutes, Group 1 animals were defibrillated. Resuscitation continued until either return of spontaneous circulation occurred or 20 minutes elapsed. Return of spontaneous circulation occurred in 6 of 7 Group 1 and 2 of 6 Group 2 pigs. CPP during resuscitation started at ~5 mmHg for both groups. Group 1 CPP increased to 13 mmHg in the first 3 minutes of chest compressions while the CPP in Group 2 remained at 5 mmHg. Decompression central venous pressure was the same for both groups (7 mmHg). CPP correlated with decompression aortic pressure in both groups. CPP was lower in Group 2 animals than in Group 1 animals and this difference was reflected in the number of animals who had return of spontaneous circulation. This data would suggest that one reason why PEA/A patients survive cardiac arrest less frequently than VF patients is that chest compressions perfuse the heart less effectively in PEA/A patients than in VF patients.
Integration
Authors: Lindsay A. Mazotti
Journal: JAMA (2010)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Influenza A(H1N1)2009 antibody seroprevalence in Scotland following the 2010/11 influenza season
Authors: W E Adamson, E C McGregor, K Kavanagh, J McMenamin, S McDonagh, P J Molyneaux, K E Templeton, W F Carman
Journal: Eurosurveillance (2011)

Following the 2010/11 influenza season, we determined the age- and location-specific seroprevalence of antibodies against the influenza A(H1N1)2009 virus in Scotland. Samples were analysed by microneutralisation assay. Age/seropositivity profiles varied significantly between cities. The increases in seroprevalence relative to the previous influenza season (2009/10) were similar across age groups and geographic locations. However, the increased seropositivity in older adults appeared to be driven by exposure to vaccination, indicating significantly lower levels of infection than in younger age groups.
Abstract 865: Gata-4 Is An Angiogenic Survival Factor Of The Infarcted Heart
Authors: Olli Tenhunen, Hanna Leskinen, Raisa Serpi, Jaana Rysä, Harri Pennanen, Ylermi Soini, Mona Nemer, Heikki Ruskoaho
Journal: Circulation (2007)

Recent data suggest that the cardiac-restricted transcription factor GATA-4 is an anti-apoptotic factor required for adaptive responses as well as a key regulator of hypertrophy and hypertrophy-associated genes in the heart. As a leading cause of chronic heart failure, reversal of post-infarction left ventricular remodeling represents an important target for therapeutic interventions. Here we studied the role of GATA-4 as a mediator of post-infarction remodeling. Rats were subjected to experimental myocardial infarction (MI) by ligating the left anterior descending coronary artery (LAD). Ligation of the LAD decreased the DNA binding activity of GATA-4 by 69 % at day 1 after MI (P&lt;0.001, n=7– 8) as assessed by gel mobility shift assays. At 2 weeks the GATA-4 DNA binding was significantly upregulated (2.4-fold, P&lt;0.05, n=7), and returned to baseline at 4 weeks. To determine the functional role of GATA-4, rats underwent LAD ligation followed by peri-infarct intramyocardial delivery of adenoviral vector expressing GATA-4. Hearts treated with the GATA-4 gene transfer exhibited significantly increased ejection fraction (58±5% vs. 38±3% in LacZ-treated control animals with MI, P&lt;0.001, n=8 –9) and fractional shortening (28±3% vs. 16±1%, P&lt;0.001, n=8 –9) 2 weeks after MI. Accordingly, the infarct size was significantly reduced (26±4% vs. 45±4%, P&lt;0.01, n=8 –9). To determine the cardioprotective mechanisms of GATA-4, the number of cardiac stem cells, apoptotic cardiomyocytes and capillaries were assessed. The number of capillaries (59±4/field vs. 48±3/field, P&lt;0.051, n=7– 8) and c-kit positive stem cells (13±5 cells vs. 4±2 cells, P&lt;0.05, n=7– 8) were increased in GATA-4 treated hearts, and a tendency to decreased apoptosis was observed in TUNEL-stained histological sections. These results indicate that the reversal of reduced GATA-4 activity prevents adverse post-infarction remodeling through increased angiogenesis, recruitment of cardiac stem cells and anti-apoptosis. GATA-4-based gene transfer may represent a novel, efficient therapeutic approach for heart failure.
Influence of micrometastasis on N stage in gastric cancer and clinical application.
Authors: H Y Yun, E Bandou, T Kawamura, N Kojima, I Itoh, T Kameya, Y Yonemura
Journal: Journal of experimental & clinical cancer research (2005)

In order to evaluate the real extent of lymph node metastasis (LNM) in gastric cancer, an immunohistochemical (IHC) analysis was performed. We examined 11173 lymph nodes removed from 355 patients with all stages of gastric carcinoma. Tissue preparations were stained with cytokeratin 18, monoclonal antibody against cytokeratin. Micrometastases were found in 2.5% of the lymph nodes and in 31.3% of patients. The incidence of the patients with LNM increased to 9.1% in T(1m) (n = 99), 31.6% in T(1sm) (n = 95, 23.1% in sm1, 34.8% in sm2), 66.7% in T2 (n = 108, 48.8% in mp, 76.5% in ss), 88.1% in T3 (n = 42), and 90.9% in T4 (n = 11) lesions. Upstage was identified in 8.5% of patients: 6.7% in T1 (4.0% in m, 7.7% in sm1, 10.1% in sm2), 14.8% in T2 (20% in mp, 11.8% in ss), 2.4% in T3, and 0% in T4. Factors related to LNM were: tumor size and lymphatic invasion in mucosal lesions; only lymphatic invasion in submucosal lesions; size and depth of tumor, and lymphatic invasion in T2 lesions. In conclusion, the incidence of micrometastasis in regional lymph nodes was higher than we imagined in T1 lesions, more than D1 lymphadenectomy for sm1 and selected cases of mucosal cancer, and D2 lymphadenectomy for sm2 are necessary.
Abstract 12987: A Combined Analysis of the Transcriptional Response of iPS-cell Derived Human Cardiomyocytes and GWAS for Left Ventricular Hypertrophy Reveals Common Biology in Both African American and Caucasians
Authors: Alexander J Stoddard, Andrea Matter, Donna K Arnett, Hemant Tiwari, Charles Gu, DC Rao, Steven C Hunt, Emile Nuwaysir, Thomas Burke, Blake D Anson, Ulrich Broeckel
Journal: Circulation (2011)

Left ventricular hypertrophy (LVH) is a significant and independent risk factor for cardiovascular disease. Previously we have conducted a family-based GWAS in the HyperGEN cohort (Caucasians, Cau, 1304 individuals; African Americans, AA, 1256 individuals) and identified a number of SNPs associated with LVH. However, understanding how individually identified, and often functionally unannotated, SNPs contribute to the disease mechanism has remained a major challenge. Moreover, with little overlap in AA and Cau association signals it is unknown if common pathways underlie the LVH phenotype in these groups. Human cardiomyocytes derived from induced pluripotent stem-cells (iPSC) provide a new model to study cardiovascular biology. We established a novel iPSC derived human cardiomyocyte model of hypertrophy, using transcriptional profiling to identify candidate functional modules in the LVH GWAS results to test the hypothesis that common biological mechanisms are perturbed in both Cau and AA. Global expression profiling was performed to find differentially expressed genes in human iPSC cardiomyocytes stimulated for 3 days with each of three hypertrophy inducing agents ( angiotensin II (10-5 M), endothelin 1 (10-6 M) and isoproterenol (10-5 M). We applied gene set enrichment analysis using these functionally derived sets to the GWAS results of both AA and Cau cohorts. All three stimulation sets provided significantly enriched gene groups in both ethnicities (FDR
Abstract 17819: Predicting the Proportional Risk of Sudden Cardiac Death in a Multicenter Heart Failure Cohort
Authors: Ramin Shadman, Jeanne E Poole, Dariush Mozaffarian, John G Cleland, Karl Swedberg, Aldo P Maggioni, Inder S Anand, Peter Carson, Wayne Levy
Journal: Circulation (2011)

Introduction: Many patients with heart failure die suddenly. Implantable cardiac defibrillators (ICDs) can reduce the rate of sudden death. Strategies that help identify patients who have most to gain from an ICD could reduce morbidity and maximize cost-effectiveness of ICDs. Methods: We used data from 9,885 heart failure patients, of whom 2,549 died during an average follow-up of 2.3 years. Using commonly available baseline clinical and demographic information, we developed a mode-specific multinomial logistic regression model to identify variables associated with a disproportionate fraction of total mortality due to sudden death. Results: In multivariable-adjusted models, we confirmed that commonly utilized variables for ICD implantation decisions, such as lower ejection fraction (OR for sudden death vs. other deaths: 1.15 per 10% decrease, p=0.005) and better New York Heart Association functional class (OR 1.30 for class 2 versus 3/4, p=0.004) were associated with greater proportion of deaths due to sudden death. We also demonstrated that younger age (OR 1.25 per decade younger, p&lt;0.001), male sex (OR 1.40, p=0.002), and higher body mass index (BMI) (OR 1.24 per 5 kg/m 2 , p&lt;0.001) independently increased the chance that if a patient died, it would be due to sudden death. Patients with diabetes (OR 0.75, p=0.001), systolic BP deviating above or below 140mmHg (OR 0.92 per 10mmHg, p=0.005), higher creatinine (OR 0.65 per mg/dL, p&lt;0.001), or lower serum sodium (OR 0.96 per mEq below 138, p=0.029) had a lower proportional risk of sudden death. The use of several heart failure medications, left ventricular end-diastolic dimension, or plasma NT-proBNP levels was not independently associated with risk of sudden versus non-sudden death. Conclusions: Several demographic and clinical variables beyond ejection fraction and functional class are independently associated with higher or lower proportional risk for sudden death. Our findings support the need for further investigation whether this novel predictive model, in the context of absolute mortality rates, can be used to target the use of ICDs and other life-saving therapies to populations who will derive greatest benefit from their application.
Efficacy and safety profile of GS-9219, a novel guanine nucleotide analog prodrug, for the treatment of lymphoid malignancies using pet dogs with spontaneous non-Hodgkin's lymphoma as a model
Authors: David Vail, Douglas Thamm, Daniel Tumas, H Reiser, A Ray, W Watkins, Ilene Kurzman, Robert Jeraj, Susan Plaza, Christine Anderson, MacKenzie Wessel
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5730 

Non-Hodgkin's lymphoma (NHL) is a common hematopoietic cancer in humans and pet dogs. While clinical remission can be induced using currently available chemotherapeutic agents, drug resistant relapse is common. Canine NHL has proven to be a relevant model for preclinical testing of novel therapeutics prior to human trials. GS-9219, a novel double prodrug of the anti-proliferative nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine (PMEG), has been shown to have potent cytotoxic activity in lymphoblasts and leukemia cell lines. The relatively higher levels of the requisite enzymes to produce the active metabolite, PMEG-diphosphate, in lymphoid cells and relatively high proliferation index of lymphoblasts creates the potential to functionally target lymphoid malignancies with GS-9219. To generate proof-of-concept, activity and safety data in lymphoid malignancies, a dose-finding (phase I) trial with GS-9219 monotherapy was initiated in pet dogs with naturally occurring chemotherapy naive or refractory NHL. Three to 6-dog dose cohorts were treated using several schedules including daily treatments for 5 consecutive days out of every 21 days, once weekly, once biweekly and once every 3 weeks. Pre- and post-treatment tumor tissues and peripheral blood mononuclear cells were collected from dogs for further analysis including evaluation of intracellular levels of active metabolite. Major antitumor responses (complete and partial remissions) have been noted in the large majority of dogs treated to date (n >30 dogs) in all doses and schedules investigated with GS-9219 monotherapy, as measured by tumor size, cytopathology, and clinical imaging. A subset of dogs was evaluated with 18F-fluorothymidine PET/CT imaging; in all dogs evaluated profound antiproliferative activity was documented in the lymphoid tumors following GS-9219 treatment. Importantly, responses were noted in both previously untreated dogs and dogs with chemotherapy-refractory NHL, implying a role both in induction therapy and in the rescue of drug resistant disease. Adverse events, when observed, were manageable and were dose- and regimen-dependent. Activity was also documented in additional subsets of pet dogs with multiple myeloma, acute lymphoblastic leukemia and acute myelogenous leukemia. This relevant preclinical model provides valuable translational data that should accelerate and guide the development of human clinical trials to follow.
Abstract 290: Cardiac Myocyte Gq Signaling Decreases Cardiac Function During Chronic High Blood Pressure Through Cardiac Remodeling
Authors: David M Harris, Xiongwen Chen, Stephanie Pesant, Heather I Cohn, Scott M MacDonnell, Mattieu Boucher, Korin Faulkner, Maggie Shapiro, Patrick Most, Steven R Houser, Walter J Koch, Andrea D Eckhart
Journal: Circulation (2007)

Chronic pressure overload and elevated levels of neurohormones initiate cardiac hypertrophy(HYP) and dysfunction. These neurohormones bind to Gq protein-coupled receptors which are an integral part...
Animal Studies Show Stem Cells’ Promise
Authors: Tracy Hampton
Journal: JAMA (2004)

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 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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
Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles
Authors: M E Thase, D J Buysse, E Frank, C R Cherry, C L Cornes, A G Mallinger, D J Kupfer
Journal: American Journal of Psychiatry (1997)

The authors tested the hypothesis that patients whose episodes of major depression evidenced more neurobiological disturbance would be less responsive to psychotherapy.The study subjects were outpatients who were given a diagnosis of recurrent major depressive disorder (unipolar or bipolar II), according to the Research Diagnostic Criteria, following an interview with the Schedule for Affective Disorders and Schizophrenia. They were classified into a group with normal sleep profiles (N = 50) and a group with abnormal sleep profiles (N = 41) on the basis of a validated index score derived from three EEG sleep variables monitored for 2 nights: sleep efficiency, REM latency, and REM density. The groups' responses to short-term interpersonal psychotherapy were compared by means of chi-square tests and life table and random effects model analyses. Responses to the addition of pharmacotherapy for subjects who did not respond to interpersonal psychotherapy were also compared.The patients with abnormal sleep profiles had significantly poorer clinical outcomes with respect to symptom ratings, attrition rates, and remission rates than the patients with more normal sleep profiles. Seventy-five percent of the patients who did not respond to interpersonal psychotherapy had remissions during subsequent pharmacotherapy.These findings help to define further a neurobiological "boundary" that may limit response to psychotherapy in depression. An abnormal sleep profile may reflect a more marked disturbance of CNS arousal that warrants pharmacotherapy.