tbuckley/cabot-search huggingface dataset:
Abstract 821: Discovery of catechol moiety-containing natural compounds as direct ERK2 inhibitors by in vitro kinase assay and co-crystallography
Authors: Seung Ho Shin, Margarita Malakhova, Igor Kurinov, Do Young Lim, Ann M. Bode, Zigang Dong
Journal: Cancer Research (2016)

Abstract Catechol (pyrocathechol, 1,2-dihydroxybenzene) is a chemical that is used by industry in the manufacture of certain products. Many natural compounds contain catechol as a functional group found in various fruits and vegetables such as apple, apricot, grape, bananas, soybean, peanut, pear, plum, mango, avocado, and mushroom. Extracellular signal-regulated kinase 2 (ERK2), a protein kinase that belongs to MAPK family, modulates many important functions such as cell growth, apoptosis and transcriptional regulation in cancer. The expression levels of ERK2 mRNA and protein are reportedly very high in many human cancers, including leukemia, colon, breast, lung and skin cancer. Previously, we reported that norathyriol and caffeic acid, which possess the catechol moiety, and catechol itself directly bind and inhibit ERK2 kinase activity. Those findings led us to test catechol moiety-containing natural compounds, luteolin, quercetin, fisetin, 7,3’,4’-trihydroxyisoflavone, and cyanidin, against ERK2 kinase activity. We found that all of these compounds directly bind to ERK2 and inhibit its activity. We further confirmed the results by resolving a co-crystal structure of ERK2 bound with luteolin in the ATP binding site. To apply this finding to cancer, the effect of the compounds was tested on the K562 human myelogenous leukemia cell line where ERK2 is highly expressed and knock-down of the protein reduced anchorage-independent growth. Five newly-found ERK2 inhibitors (luteolin, quercetin, fisetin, 7,3’,4’-trihydroxyisoflavone and cyanidin) and three known ERK2 inhibitors (norathyriol, caffeic acid and catechol) decreased cell viability of K562 at 40 ìM. When the eight compounds were used at the same dose in combination (5 ìM each and 40 ìM total), the mixture inhibited ERK2 and reduced cell viability of K562 cells. In summary, using in vitro kinase assays and co-crystallography, we identified new ERK2 inhibitors that contain the catechol functional group, and showed anti-cancer effects of the compounds by cell viability assay and soft agar assay. This work impacts the cancer prevention community by showing that many natural compounds can work together targeting ERK2, an important target in cancer. Citation Format: Seung Ho Shin, Margarita Malakhova, Igor Kurinov, Do Young Lim, Ann M. Bode, Zigang Dong. Discovery of catechol moiety-containing natural compounds as direct ERK2 inhibitors by in vitro kinase assay and co-crystallography. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 821.
Effect of rhenium Re188-P2045 on tumor growth in the AR42J rat pancreatic tumor xenograft nude mouse model.
Authors: Christopher Peter Adams, Carol Nelson, Michael Azure, Kurt Zinn
Journal: Journal of Clinical Oncology (2014)

e15224 Background: There is a significant medical need to treat pancreatic cancer. Many pancreatic cancers overexpress somatostatin receptors (SSTR). This study examined the effect of Rhenium (Re)188 P2045, a radiolabeled somatostatin analog that selectively targets SSTRs, on tumor growth in the AR42J rat pancreatic tumor xenograft mouse which over expresses somatostatin receptors. Methods: Fifty seven athymic nude mice bearing AR42J rat pancreatic tumors of approximately the same size were divided into 6 treatment groups of 7-1O animals/group. Five of the 6 groups received one of the following treatments by intravenous injection (100 µL) on study days 0, 3, 6, 9, 12 and 16: decayed W Re188 generator eluate (control); 530 ng of nonradiolabeled P2045 Peptide (control, equivalent to the amount of peptide in the high dose Re188 P2045 treatment); 50 µCi Re188 P2045 (low dose); 150 µCi Re188 P2045 (mid-dose); or 300 µCi Re188 P2045 (high dose). The amount of P2045 Peptide injected per dose in the low, mid, and high dose groups was 88, 265, and 530 ng per mouse, respectively with the sixth group receiving 600 µCi Y 90 DOTATOC as a comparator drug. Tumor length, width, and height were measured in a blinded fashion during the study. Results: The Rhenium Re188 P2045 treated mice showed a dose-related inhibition of tumor growth relative to the generator eluate control mice. On study day 16 the respective normalized tumor growth in the low, mid, and high dose Rhenium Re188 P2045 groups were 870%, 611%, and 135%, while the normalized tumor growth in the eluate control group was 9026%. Conclusions: Rhenium Re188 P2045 caused a dose-related inhibition of tumor growth, and a dose-related decrease in viable tumor size in the AR42J rat pancreatic tumor nude mouse model. These data indicate a potential efficacy of Rhenium Re188 P2045 in the treatment of pancreatic tumors having a high expression of SSTR.
Clinical Implications of Obesity With Specific Focus on Cardiovascular Disease
Authors: Samuel Klein, Lora E. Burke, George A. Bray, Steven Blair, David B. Allison, Xavier Pi-Sunyer, Yuling Hong, Robert H. Eckel
Journal: Circulation (2004)

Obesity adversely affects cardiac function, increases the risk factors for coronary heart disease, and is an independent risk factor for cardiovascular disease. The risk of developing coronary heart disease is directly related to the concomitant burden of obesity-related risk factors. Modest weight loss can improve diastolic function and affect the entire cluster of coronary heart disease risk factors simultaneously. This statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism reviews the relationship between obesity and the cardiovascular system, evaluates the effect of weight loss on coronary heart disease risk factors and coronary heart disease, and provides practical weight management treatment guidelines for cardiovascular healthcare professionals. The data demonstrate that weight loss and physical activity can prevent and treat obesity-related coronary heart disease risk factors and should be considered a primary therapy for obese patients with cardiovascular disease.
Abstract 527: Myeloid PTEN deficiency impairs tumor immune surveillance via immune checkpoint inhibition
Authors: Mario Kuttke, Emine Sahin, Julia Pisoni, Sophie Percig, Andrea Vogel, Daniel Kraemmer, Leslie Hanzl, Julia Stefanie Brunner, Hannah Paar, Klara Soukup, Angela Halfmann, Alexander Dohnal, Carl-Walter Steiner, Stephan Blüml, Jose Basilio, Bernhard Hochreiter, Manuel Salzmann, Bastian Hoesel, Günther Lametschwandtner, Robert Eferl, Johannes Schmid, Gernot Schabbauer
Journal: Cancer Research (2016)

Abstract In the current study we are investigating the effects of PTEN-deficient myeloid cells on tumor immune surveillance. We could previously show that hyper-activation of the PI3K signaling cascade by genetic knock-out of the counteracting phosphatase PTEN induced an anti-inflammatory phenotype in myeloid cells. This resulted in protection of conditional knock-out mice in models of acute infection and inflammation. A reduction in pro-inflammatory responses could however increase tumor burden. To address this question we induced colitis associated colon cancer in conditional PTEN-KO mice and found an increase in tumor burden and a reduction in survival in male KO mice. This was accompanied by increased numbers of splenic antigen-presenting cells (APC) expressing the immune checkpoint regulators PD-L1 and PD-L2. Furthermore, transcriptome analysis in these cells revealed a shift towards gene expression profiles found in professional APCs capable of cross-presentation. As expected, ex-vivo stimulated T-cells from KO-mice showed a reduction in proliferative capacity. These findings were further substantiated by findings in a second tumor model using implanted B16 melanoma cells. In this model myeloid PTEN-deficient mice showed a decrease in T-cell activation and a reduction in melanoma cell killing capacity. Taken together, our findings show that genetic deletion of PTEN in cells of myeloid origin increases splenic APCs expressing immune checkpoint regulators resulting in a decrease in tumor immune surveillance. Our study shows that PI3K-inhibitors which are currently tested as anti-cancer drugs might have additional beneficial effects on immune cells by shifting their inflammatory phenotype. Citation Format: Mario Kuttke, Emine Sahin, Julia Pisoni, Sophie Percig, Andrea Vogel, Daniel Kraemmer, Leslie Hanzl, Julia Stefanie Brunner, Hannah Paar, Klara Soukup, Angela Halfmann, Alexander Dohnal, Carl-Walter Steiner, Stephan Blüml, Jose Basilio, Bernhard Hochreiter, Manuel Salzmann, Bastian Hoesel, Günther Lametschwandtner, Robert Eferl, Johannes Schmid, Gernot Schabbauer. Myeloid PTEN deficiency impairs tumor immune surveillance via immune checkpoint inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 527.
Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis
Authors: William Leung, Giorgi Kvizhinadze, Nisha Nair, Tony Blakely
Journal: PLoS Medicine (2016)

Background The anti–human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. Methods and Findings A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50–54 y; 95% CI 2.29–2.37) for the worst prognosis (ER−/PR−) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25–29 to 90–94 y (0.44 times for the age group 50–54 y; 95% CI 0.43–0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]–adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER−/PR− subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR− cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of treatment-effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. Conclusions This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine.
Sequence-Specific Talens-Induced DLEU1 Gene Disruption Significantly Suppresses Apoptosis and Increases Phosphorylation Of AKT and Ikba In Pediatric Burkitt Lymphoma (PBL): DLEU1 May Act As a Tumor Suppressor Gene In PBL
Authors: Sanghoon Lee, Changhong Yin, Timmy O'Connell, Janet Ayello, Carmella van de Ven, Mitchell S. Cairo
Journal: Blood (2013)
Abstract 18160: Predictors of Survival to Orthotopic Heart Transplant in Patients with Immunoglobulin Light Chain Amyloid Cardiomyopathy
Authors: Khue Ton, James Watts, Rajeev Malhotra, Vaishali Sanchorawala, David Seldin, Megan Borase, Marc Semigran
Journal: Circulation (2011)

Introduction: Heart failure from immunoglobulin AL amyloidosis is rapidly fatal. Serial orthotopic heart transplant (OHT) followed by high dose melphalan / autologous stem cell transplant (ASCT) improves outcomes in selected patients. Debates still focus on the appropriate selection criteria for this approach. Methods: We performed a retrospective analysis of all patients with AL amyloidosis evaluated at Massachusetts General Hospital (2000 - 2011). Demographic and clinical data were obtained at the time of evaluation for OHT and ASCT. Kaplan-Meier and Cox regression analyses were performed to identify predictors of survival to OHT. Results: Of 41 patients (age 56 ±9 years), 18 (44%) underwent OHT, of which 14 subsequently underwent ASCT. One patient died before ASCT of sepsis, and 3 are awaiting ASCT. Three-year survival is 75%. Of the 14 patients, 3 (21%) died from sepsis (n=1), progressive amyloidosis (n=1), or cardiac arrest (n=1). Of the 23 untransplanted patients, 21 (91%) died with a median time to death from initial evaluation of 55 days. Thirteen were listed for OHT but 12 died before transplant from cardiac arrest (n=5), progressive systemic amyloidosis (n=4), sepsis (n=2), and heart failure (n=1). Ten were not listed for OHT due to contra-indicating factors (severe systemic amyloidosis (n=3), cardiac arrest (n=2), coagulopathy (n=1), sepsis (n=1), heart failure (n=1), stroke (n=1), severe depression (n=1)). Of those listed for OHT (n=31), higher weight and BMI were associated with a lower likelihood of survival to transplant (189 ± 46 vs. 162 ± 20 lbs, P=0.03; Cox hazard ratio (HR) of death before OHT of 1.22 for every 10-lb increase in weight, 95% CI 1.03-1.44). For patients undergoing OHT, wait time from evaluation correlated with BMI (r=0.48, P=0.04). Of the hemodynamic variables studied, greater systemic arterial pulse pressure predicted survival to OHT (HR for death before transplant 0.43 for every 10 mmHg increase, 95% CI 0.19-0.98, P=0.045). Conclusion: Long-term survival is excellent in cardiac amyloid patients receiving serial OHT and ASCT. Mortality remains high while patients await cardiac donors. Predictors of survival to OHT include increased systemic pulse pressure and lower weight and BMI due to shorter wait time for suitable organs.
Somatodendritic Expression of JAM2 Inhibits Oligodendrocyte Myelination
Authors: Stephanie A. Redmond, Feng Mei, Yael Eshed-Eisenbach, Lindsay A. Osso, Dena Leshkowitz, Yun-An A. Shen, Jeremy N. Kay, Michel Aurrand-Lions, David A. Lyons, Elior Peles, Jonah R. Chan
Journal: Neuron (2016)
Abstract 4648: Uncover novel drug combinations for triple negative breast cancer
Authors: Carlotta Costa, Anahita Dastur, Rachel Peterson, Damon Leah, Regina Egan, Ryan March, Cyril Benes, Jeffrey Engelman
Journal: Cancer Research (2016)

Abstract Therapeutic options for triple negative breast cancers (TNBC) are limited to multiple lines of chemotherapy with no FDA-approved targeted therapies. In the absence of a clear driver oncogene, the most common molecular alterations, including EGF receptor and genes involved in cell cycle, DNA repair and the PI3K pathway, may represent new therapeutic opportunities in TNBC. Indeed clinical benefits from PARP, EGFR and PI3K inhibitors have been reported in some TNBC patient. However, none of these studies have demonstrated durable responses, indicating that inhibition of additional pathways might be necessary to successfully improve the clinical efficacy of targeted therapies in TNBC. To develop novel, combinatorial therapeutic approaches for TNBC we performed a pharmacological screen testing 672 unique drug combinations in multiple TNBC models. The screen identified previously known and efficacious synergies, such as between EGFR and PI3K inhibitors, supporting the validity of our data and analysis. Importantly, we also identified novel promising drug combinations that we are currently exploring. Citation Format: Carlotta Costa, Anahita Dastur, Rachel Peterson, Damon Leah, Regina Egan, Ryan March, Cyril Benes, Jeffrey Engelman. Uncover novel drug combinations for triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4648.
Abstract 5043: Molecular mechanism of resveratrol induced cell death in multidrug resistance prostate cancer
Authors: Santosh K. Singh, Saswati Banerjee, James W. Lillard, Rajesh Singh
Journal: Cancer Research (2016)

Abstract In order to understanding the molecular mechanisms of drug resistance as well as enhancing the efficacy of docetaxel we established docetaxel-resistant prostate cancer (PCa) cells. The IC50 for docetaxel in PCa resistant cells was about 50-fold higher than parental PCa cells. In the current study we used resveratrol (RES), a natural compound with chemo preventive potential to test its ability to enhance the effectiveness of docetaxel on PCa as well as to explore the mechanism of acquired docetaxel resistance. PCa (PC3, C4-2B and DU145) cell lines treated with different dose of RES or DTX alone or in combination followed by analyzed cell proliferation (MTT assay), apoptosis (flow-cytometric analysis of annexin V/propidium iodide-stained cells and western blot methods).The expression of ABC transporter markers in the development of docetaxel resistance was examined using RT-PCR. Our result shows that the expression of 18 ABC transporter genes were down regulated in PCa cells at 48 and 72 hrs in RES treatment group. The up regulations of pro-apoptotic proteins (Bax, Bad, Bim) and down regulation of anti-apoptotic protein (Bcl2, Mcl1) further confirmed the effectiveness of RES or DTX alone or in combination with DTX. In conclusion these studies suggest that RES inhibits ABC gene expression and resensitizes docetaxel resistant PCa cells to DTX treatment with enhancing apoptotic cell death. Citation Format: Santosh K. Singh, Saswati Banerjee, James W. Lillard, Rajesh Singh. Molecular mechanism of resveratrol induced cell death in multidrug resistance prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5043.
Is Amifostine Effective on the Protection of Mitoxantrone-Induced Acute Cardiotoxicity? A Biochemical and Histopathological Experimental Study.
Authors: Gurhan Kadikoylu, Ibrahim Meteoglu, Hulya Aybek, Mete Kalak, Suleyman Demir, Muharrem Balkaya, Cigdem Yenisey, Zahit Bolaman, Mutlu Arat
Journal: Blood (2006)
CHAPTER IX: Hemodynamic Results of Therapy
Journal: Circulation (1973)

The hemodynamic status of patients with pulmonary embolism was essentially unaltered 24 hours after initiation of heparin therapy. However, 24 hours after initiation of urokinase therapy a significant lowering of right ventricular systolic and diastolic pressures, as well as of pulmonary arterial and right atrial mean pressures, was observed. Total pulmonary resistance also fell significantly after urokinase. These changes indicate that the resolution of pulmonary embolic obstruction was accelerated by urokinase therapy. Massiveness of embolism appeared to be a determinant of the efficacy of urokinase therapy, inasmuch as the hemodynamic treatment effect was more pronounced in patients with massive embolism than in those with submassive embolism. Patients also appeared to have a more favorable response to urokinase if their preinfusion chest roentgenogram was free of infiltrate. Previous history of cardiopulmonary disease did not appear to influence response to urokinase therapy. Therapeutic interventions other than urokinase did not influence hemodynamic responses, nor did acute bleeding complications (which were more frequent in patients treated with urokinase).
The Importance of Fostering Ownership During Medical Training
Authors: Alex Dubov, Liana Fraenkel, Elizabeth Seng
Journal: The American Journal of Bioethics (2016)

There is a need to consider the impact of the new resident-hours regulations on the variety of aspects of medical education and patient care. Most existing literature about this subject has focused on the role of fatigue in resident performance, education, and health care delivery. However, there are other possible consequences of these new regulations, including a negative impact on decision ownership. Our main assumption of is that increased shift work in medicine can decrease ownership of treatment decisions and impact negatively on quality of care. We review some potential components of decision ownership in treatment context and suggest possible ways in which the absence of decision ownership may decrease the quality of medical decision making. The article opens with the definition of decision ownership and the overview of some contextual factors that may contribute to the development of ownership in medical residency. The following section discusses decision ownership in medical care from the perspective of "diffusion of responsibility." We question the quality of choices made within narrow decisional frames. We also compare isolated and interrelated choices, assuming that residents make more isolated decisions during their shifts. Lastly, we discuss the consequences of decreased decision ownership impacting the delivery of health care.