tbuckley/cabot-search huggingface dataset:
Abstract 4299: Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma <i>in vitro</i> and patient-derived xenografts <i>in vivo</i>
Authors: Mengqiu Song, Ran Zhao, Hua Xie, Hanyong Chen, Kangdong Liu, Ann M. Bode, Mee-Hyun Lee, Zigang Dong
Journal: Cancer Research (2019)

Abstract Esophageal cancer is the sixth leading cause of cancer death worldwide and has low survival rates with poor prognosis. Hyperactivation of AKT has been reported to modulate cell growth, survival, and gene expression in various solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens, has exhibited various pharmacologic and physiologic properties, including antitumor, antibacterial, and anti-inflammatory effects. In this study, we aimed to investigate the effects of oridonin on the proliferation and growth of ESCC and to elucidate its underlying mechanisms of action. We found that oridonin is an inhibitor of AKT and induces cell cycle arrest and apoptosis in ESCC cells and attenuates growth of patient derived xenograft (PDX) tumors in vivo by interfering with AKT signaling pathways through MTT assay, anchorage-independent cell growth assay and Cell cycle and apoptosis analyses. AKT was developed as a dierctly target of oridonin by in vitro kinase assay, ex vivo and in vitro pull-down assay and computational docking model. Mechanistically, oridonin diminished the phosphorylation and activation of AKT and supressed the downstream of p-GSK-3β, p-mTOR and NF-kB activity. Moreover, a combination of oridonin and 5-fluorouracil or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. Overall, our study suggests that oridonin can inhibit progression of ESCC tumors in vitro and in vivo by suppressing AKT signaling through its direct targeting of AKT. Thus, this study might provide useful information in the clinical application of oridonin for ESCC chemotherapy. Citation Format: Mengqiu Song, Ran Zhao, Hua Xie, Hanyong Chen, Kangdong Liu, Ann M. Bode, Mee-Hyun Lee, Zigang Dong. Targeting AKT with oridonin inhibits growth of esophageal squamous cell carcinoma in vitro and patient-derived xenografts in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4299.
POLARIX: A phase 3 study of polatuzumab vedotin (pola) plus R-CHP versus R-CHOP in patients (pts) with untreated DLBCL.
Authors: Herve Tilly, Christopher Flowers, Jonathan W. Friedberg, Charles Herbaux, Franck Morschhauser, Laurie Helen Sehn, Jeff Porter Sharman, Marek Trneny, Calvin Lee, Gilles A. Salles
Journal: Journal of Clinical Oncology (2019)

TPS7571 Background: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) remains the standard of care in pts with previously untreated diffuse large B-cell lymphoma (DLBCL) but outcomes remain poor in pts with high-risk disease. Pola is an antibody–drug conjugate targeting CD79b; it delivers the antimitotic agent monomethyl auristatin E. Addition of pola to bendamustine and R in pts with transplant-ineligible DLBCL resulted in improved OS (Sehn et al, 2018). In front-line treatment of DLBCL, pola is being evaluated as a replacement for vincristine within the R-CHOP regimen. In a phase Ib/II study in pts with higher risk DLBCL, pola + R-CHP demonstrated promising efficacy and a safety profile similar to that observed in the R-CHOP arm of the GOYA study (Tilly et al, 2017; Vitolo et al, 2017). The phase 3 POLARIX study investigates pola + R-CHP in untreated DLBCL. Methods: POLARIX is an ongoing, international, randomized, double-blind, active-placebo-controlled, phase 3 study in pts with previously untreated DLBCL. Pts aged 18–80 years with CD20-positive DLBCL (including DLBCL not otherwise specified, GCB, and ABC subtypes), ECOG performance status 0–2, and IPI score 2–5, are stratified by IPI score (2 vs 3–5), bulky disease and geographical region and randomized (1:1). Pts receive 6 cycles of either: pola 1.8 mg/kg on Day 1 plus R-CHP (standard dosing schedule) plus vincristine placebo; or pola placebo plus R-CHOP (standard dosing schedule). R monotherapy is administered in cycles 7 and 8 (both arms). PET-CT and CT scans are obtained at screening, after 4 cycles (planned interim assessment), and 6–8 weeks after end of study treatment. Follow-up will continue for 5 years after treatment. Primary endpoint: investigator-assessed progression-free survival (PFS; Lugano classification). Secondary endpoints: independent review committee-assessed PET-CT complete response rate at end of treatment, event-free survival, 2-year PFS rate, and OS. Enrolment began Nov 2017. This trial is currently recruiting, and plans to enrol 875 patients in 24 countries. Clinical trial information: NCT03274492.
Abstract 20713: Patient Perspectives on Cardiac Care Experiences Differ According to Gender
Authors: Cameron Taheri, Puru Panchal, Tanya Kakkar, Niveditha Pattathil, Catherine Kreatsoulas
Journal: Circulation (2016)

Introduction: Patients undergoing investigation for coronary artery disease (CAD) vary in their understanding of CAD prevalence, factors contributing to risk and symptomatic presentation. The role ...
Abstract 124: Simplified Dispatcher-Assisted Pediatric CPR Instructions Improves Bystander Chest Compression Quality
Authors: Silvana Arciniegas Rodriguez, Robert M Sutton, Marc D Berg, Akira Nishisaki, Jessica Leffelman, Matthew R Maltese, Dana E Niles, Peter A Meaney, Robert A Berg, Vinay M Nadkarni
Journal: Circulation (2013)

Background: Dispatcher-assisted bystander cardiopulmonary resuscitation (CPR) improves survival outcomes after out-of-hospital cardiac arrest. Our objective was to evaluate the effectiveness of sim...
Abstract 877: Novel role of truncated HMGA2 in regulating reactive oxygen species in prostate cancer cells
Authors: Ohuod Hawsawi, Veronica Henderson, Liza Burton, Jodi Dougan, Ana Cecillia Millena, Vanessa Adams, Elshaddai Z. White, Guang Di Wang, Qiang Zhang, Cimona Hinton, Shafiq Khan, Valerie Odero-Marah
Journal: Cancer Research (2019)

Abstract High mobility group A (HMGA2), a non-histone protein, is up-regulated in several cancers. Due to chromosomal rearrangement of HMGA2 gene, full-length or wild-type HMGA2 can be truncated leading to loss of the C-terminus and the 3’UTR. Both wild-type and truncated isoforms have been detected in uterine leiomyoma patients. However, the functional role of truncated HMGA2 has not been investigated. We hypothesize that truncated HMGA2 plays a role in prostate cancer progression. We analysed expression of wild-type vs truncated HMGA2 in a panel of prostate cancer cell lines using real-time PCR and western blot analyses. We utilized LNCaP cells stably overexpressing wild-type HMGA2 or truncated HMGA2 in LNCaP cells to detect the basal reactive oxygen species (ROS) levels using DCFDA dye. We analysed Jun-D expression, a putative downstream effector of HMGA2, by western blot analysis, and utilized siRNA to knockdown Jun-D. We performed migration and cell viability assays following Jun-D knockdown. Additionally, we performed proteomic analysis following immunoprecipitation with HMGA2 antibody in nuclear extracts from LNCaP cells overexpressing wild-type HMGA2 WT or cytoplasmic extracts from cells overexpressing truncated HMGA2. Finally, we utilized tissue microarray to analyse expression of HMGA2 by immunohistochemisty. Our results showed that prostate cancer cell lines expressed varying amounts of wild-type and truncated HMGA2. LNCaP cells overexpressing truncated HMGA2 exhibited increased nuclear expression of Jun-D, as well as increased ROS compared to LNCaP cells overexpressing wild-type HMGA2 or empty vector Neo control. Knockdown Jun-D in LNCaP cells overexpressing truncated HMGA2 abrogated ROS induction and cell migration with no effect on cell proliferation. Additionally, truncated HMGA2 interacted with a number of proteins, including Ras GTPase-activating protein-binding protein 1(G3BP1), a cytoplasmic stress granule protein that responds to oxidative stress. Truncated HMGA2 is mainly localized to the cytoplasm, and interestingly we also observed cytoplasmic HMGA expression in prostatic tissue with chronic inflammation. Therefore, truncated HMGA2 may promote prostate cancer progression via Jun-D-mediated ROS. GRANT SUPPORT: NIH 1P20MD002285 and NIH/NCRR/RCMI G12RR003062-22 Citation Format: Ohuod Hawsawi, Veronica Henderson, Liza Burton, Jodi Dougan, Ana Cecillia Millena, Vanessa Adams, Elshaddai Z. White, Guang Di Wang, Qiang Zhang, Cimona Hinton, Shafiq Khan, Valerie Odero-Marah. Novel role of truncated HMGA2 in regulating reactive oxygen species in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 877.
Evaluation of integrated interventions layered on mass drug administration for urogenital schistosomiasis elimination: a cluster-randomised trial
Authors: Stefanie Knopp, Bobbie Person, Shaali M Ame, Said M Ali, Jan Hattendorf, Saleh Juma, Juma Muhsin, Iddi S Khamis, Khalfan A Mohammed, Jürg Utzinger, Elizabeth Hollenberg, Fatma Kabole, David Rollinson
Journal: The Lancet Global Health (2019)

Elimination of schistosomiasis as a public health problem and interruption of transmission in selected areas are targets set by WHO for 2025. Our aim was to assess biannual mass drug administration (MDA) applied alone or with complementary snail control or behaviour change interventions for the reduction of Schistosoma haematobium prevalence and infection intensity in children from Zanzibar and to compare the effect between the clusters.In a 5-year repeated cross-sectional cluster-randomised trial, 90 shehias (small administrative regions; clusters) in Zanzibar eligible owing to available natural open freshwater bodies and public primary schools were randomly allocated (ratio 1:1:1) to receive one of three interventions: biannual MDA with praziquantel alone (arm 1) or in combination with snail control (arm 2), or behaviour change activities (arm 3). Neither participants nor field or laboratory personnel were blinded to the intervention arms. From 2012 to 2017, annually, a single urine sample was collected from approximately 100 children aged 9-12 years in the main public primary school of each shehia. The primary outcome was S haematobium infection prevalence and intensity in 9-12-year-old children after 5 years of follow-up. This study is completed and was registered with the ISRCTN, number 48837681.The trial was done from Nov 1, 2011, through to Dec 31, 2017 and recruitment took place from Nov 2, 2011, until May 17, 2017. At baseline we enrolled 8278 participants, of whom 2899 (35%) were randomly allocated to arm 1, 2741 (33%) to arm 2, and 2638 (32%) to arm 3. 120 (4·2%) of 2853 in arm 1, 209 (7·8%) of 2688 in arm 2, and 167 (6·4%) of 2613 in arm 3 had S haematobium infections at baseline. Heavy infections (≥50 eggs per 10 mL of urine) were found in 126 (1·6%) of 8073 children at baseline. At the 5-year endline survey, 46 (1·4%) of 3184 in arm 1, 56 (1·7%) of 3217 (odds ratio [OR] 1·2 [95% CI 0·6-2·7] vs arm 1) in arm 2, and 58 (1·9%) of 3080 (1·3 [0·6-2·9]) in arm 3 had S haematobium infections. Heavy infections were detected in 33 (0·3%) of 9462 children.Biannual MDA substantially reduced the S haematobium prevalence and infection intensity but was insufficient to interrupt transmission. Although snail control or behaviour change activities did not significantly boost the effect of MDA in our study, they might enhance interruption of transmission when tailored to focal endemicity and applied for a longer period. It is now necessary to focus on reducing prevalence in remaining hotspot areas and to introduce new methods of surveillance and public health response so that the important gains can be maintained and advanced.University of Georgia Research Foundation Inc and Bill & Melinda Gates Foundation.
Abstract 15168: Early Repolarization is Associated With More Favorable Cardiac Structure and Function Over 25 Years of Follow-Up in a Young, Biracial Cohort: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Leonard Ilkhanoff, Hongyan Ning, Elsayed Z Soliman, Kiang Liu, Samuel Gidding, Joao Lima, Donald Lloyd-Jones
Journal: Circulation (2017)

Introduction: The longitudinal association of ECG early repolarization (ER) through young adulthood with left ventricular (LV) structure and function in middle age is unknown. Hypothesis: We sought...
Phase II study in progress to verify improved response with mFOLFOX6 after exposure to an immune checkpoint inhibitor in advanced gastric cancer
Authors: H. Ann, D. Manaka, S. Konishi, Y. Ikeda, T. Ota, R. Kudo, K. Kawaguchi, N. Sasaki, S. Hamasu, R. Nishitai
Journal: Annals of Oncology (2019)
Abstract LB-089: Direct BAX activation effectively induces apoptosis in anaplastic thyroid cancer cells
Authors: Xhesika Shanja-Grabarz, Francesca Di Cristofano, Evripidis Gavathiotis, Antonio Di Cristofano
Journal: Cancer Research (2019)

Abstract Despite recent advancements in chemotherapy and radiation, anaplastic thyroid cancer (ATC) remains an almost invariably lethal disease with an average life expectancy of 2-6 months. Current interventions, including surgery are palliative, underlining the urgent need for novel, effective approaches. Targeting the apoptosis pathway using BH3 mimetics is effective in hematologic malignancies. However, in solid tumors, the response to these compounds is usually limited and short-lived. In addition, most ATCs have lost p53, resulting in a significant dampening of the pro-apoptotic signals deriving from chemotherapy or radiation. We hypothesized that a small molecule that directly binds to and activates BAX, bypassing the need for upstream activating signals, might effectively induce apoptosis in ATC cells. We used a novel activator, EGAV1, that is derived from the previously described BTSA1 molecule, and a panel of 10 ATC cell lines, representing the entire mutation spectrum observed in patients. We generated dose-response profiles of these cell lines both in traditional 2D cell cultures and in 3D spheroid cultures, and found that EGAV1 induces prompt apoptosis in all cell lines. However, co-immunoprecipitation assays showed that EGAV1-activated BAX can still be sequestered by BCL-XL, which may reduce its efficacy. Thus, we tested the ability of the BH3 mimetic Navitoclax (ABT-263) to increase EGAV1 efficacy by inhibiting BCL-XL and BCL2. In fact, we found a dramatic decrease in the EGAV1 IC50 in the presence of a low dose of Navitoclax that has no effect as single agent. Also, we found that the efficacy of Navitoclax was equally amplified by a low dose of EGAV1. Time-course analysis of caspase 3/7 activity confirmed that these compounds induce prompt apoptosis, peaking between four and eight hours after treatment. Taken together these data suggest that there is an important therapeutic opportunity in targeting the apoptosis pathway in ATC with a BAX activator accompanied by a BH3 mimetic. Citation Format: Xhesika Shanja-Grabarz, Francesca Di Cristofano, Evripidis Gavathiotis, Antonio Di Cristofano. Direct BAX activation effectively induces apoptosis in anaplastic thyroid cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-089.
Abstract 790: STAT3 control of mitochondrial RNA stability and translation is a vulnerability in tumors
Authors: Chamira D. Fernando, Daniel J. Garama, Daniel J. Gough
Journal: Cancer Research (2019)

Abstract Signal Transducer and Activator of Transcription (STAT)3 is a critical signalling molecule and transcription factor activated downstream of cytokines and growth factors to regulate immune responses, metabolism, proliferation and cell death. Whilst the activity of STAT3 is crucial for sustenance of life, aberrant activity is observed in around 50% of all human cancers. However, recent evidence has shown non-transcriptional activities of STAT3 that are critical for tumor growth. Mitochondria are the central powerhouse of the cell and provide the biomolecules required for rapid cell proliferation. Recently we showed that a pool of STAT3 resides in mitochondria and enhances the activity of complex I, II and V of the electron transport chain (ETC) driving Ras-dependent malignant transformation. Whilst STAT3 can physically interact with complex I, its low abundance compared to complex I suggests that a direct protein-protein interaction is unlikely to dictate metabolic activity of the ETC.To elucidate mitochondrial activity of STAT3, we isolated STAT3 from mitochondrial fractions of Ras-driven lung adenocarcinoma (A549 cell line) and identified its interactome using mass spectrometry. We show that STAT3 forms a stable 400 kDa complex with the LRPPRC/SLIRP proteins which are key regulators of mitochondrial mRNA stability and translation. STAT3 loss significantly reduced steady state levels of polyadenylated mitochondrial RNA which is due to instability of the polyadenylated transcripts but not due to changes in mitochondrial DNA copy number, differences in mitochondrial transcription kinetics or mitochondrial RNA processing. Furthermore, in the absence of STAT3 there is defective delivery of these transcripts to the mitochondrial ribosomes resulting in delayed mitochondrial translational kinetics. We propose that the ability of STAT3 to regulate mitochondrial transcription and translation is the fundamental mechanism by which a small pool of STAT3 can regulate highly abundant key component proteins of the ETC. Importantly, this activity is required for tumor formation, but is dispensable in normal tissues which makes this activity of STAT3 an attractive therapeutic target that will diminish tumor growth whilst preserving the critical nuclear functions of STAT3. Citation Format: Chamira D. Fernando, Daniel J. Garama, Daniel J. Gough. STAT3 control of mitochondrial RNA stability and translation is a vulnerability in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 790.
Top 10 Research Priorities in Spatial Lifecourse Epidemiology
Authors: Peng Jia, Jeroen Lakerveld, Jianguo Wu, Alfred Stein, Elisabeth D. Root, Clive E. Sabel, Roel Vermeulen, Justin V. Remais, Xi Chen, Ross C. Brownson, Sherif Amer, Qian Xiao, Limin Wang, W. M. Monique Verschuren, Tong Wu, Youfa Wang, Peter James
Journal: Environmental Health Perspectives (2019)

Summary: The International Initiative on Spatial Lifecourse Epidemiology (ISLE) convened its first International Symposium on Lifecourse Epidemiology and Spatial Science at the Lorentz Center in Leiden, Netherlands, 16–20 July 2018. Its aim was to further an emerging transdisciplinary field: Spatial Lifecourse Epidemiology. This field draws from a broad perspective of scientific disciplines including lifecourse epidemiology, environmental epidemiology, community health, spatial science, health geography, biostatistics, spatial statistics, environmental science, climate change, exposure science, health economics, evidence-based public health, and landscape ecology. The participants, spanning 30 institutions in 10 countries, sought to identify the key issues and research priorities in spatial lifecourse epidemiology. The results published here are a synthesis of the top 10 list that emerged out of the discussion by a panel of leading experts, reflecting a set of grand challenges for spatial lifecourse epidemiology in the coming years. https://doi.org/10.1289/EHP4868
Abstract 12233: Low Cardiovascular Risk in Midlife Predicts Active and Healthy Aging
Authors: Timo Strandberg, Kirsi Rantanen
Journal: Circulation (2015)

Introduction and hypothesis: Low cardiovascular disease (CVD) risk in midlife predicts survival and fewer CVD events up to old age. But do they also predict a broad concept of “active and healthy aging” (“successful aging”)? We studied this in our long-term cohort. Methods: The Helsinki Businessmen Study is a follow-up study of socioeconomically homogenous cohort of men born 1919-1934 (n=3293). Midlife (average age 42 years) risk factors included BMI, smoking, cholesterol, blood pressure, and one-hour glucose. Total CVD risk was also assessed with Keys’ risk score including age, BMI, smoking, cholesterol, and systolic blood pressure. Mortality follow-up was through 2010 whereupon mailed questionnaire data, including lifestyle, diseases, and quality of life was obtained from survivors. As there is no consensus criteria on active and healthy aging, our definition included the following 6 criteria which in general could be considered important: survival to an average age of 82 years, and 5 dimensions related to health, wellbeing, and physical, cognitive, and social functioning. In the analyses we divided the cohort into 3 age groups: men born 1919-1924 (n=969), 1925-1929 (n=1481), and 1930-1934 (n=843). Results: By 2010, 1788 of the midlife cohort had died and 894 (59% of survivors) responded to mailed questionnaire survey. According to our definition, only 154 men (4.8%) of the whole cohort experienced active and healthy aging fulfilling all 6 criteria. Of the individual midlife CVD risk factors only higher systolic blood pressure reduced odds of active and healthy aging (OR per SD 0.65. 95% CI 0.52 to 0.82, P&lt;0.001) in adjusted analyses. Keys’ score was a powerful predictor of active and healthy aging overall (OR per SD of log value: 0.49, 95% CI 0.41-0.60, P&lt;0.001), and in all age groups. ORs were: 0.52, 95% CI 0.29-0.95 (P=0.03); 0.52, 95% CI 0.38-0.72 (P&lt;0.001), and 0.65, 95% CI 0.46-0.92 (P=0.01) in the oldest, middle and youngest age group, respectively. Conclusions: From a life-course viewpoint, active and healthy aging was relatively infrequent among men of higher social class. Lower systolic blood pressure and CVD risk overall in early midlife strongly predicted active and healthy aging giving impetus to controlling CVD risk in time in aging societies.