tbuckley/cabot-search huggingface dataset:
Abstract 11917: Midlife Cardiovascular Risk Factors and Late-Life Unrecognized and Recognized Myocardial Infarction Detected by Cardiac Magnetic Resonance (ICELAND-MI, the AGES-Reykjavik Study)
Authors: Dorothea McAreavey, Jean-Sébastien Vidal, Thor Aspelund, Gudny Eiriksdottir, Erik B Schelbert, Olafur Kjartansson, Jie J Cao, Gudmundur Thorgeirsson, Sigurdur Sigurdsson, Melissa Garcia, Tamara B Harris, Lenore J Launer, Vilmundur Gudnason, Andrew E Arai
Journal: Circulation (2015)

Introduction: The association of midlife atherosclerosis risk factors (RF) with later unrecognized myocardial infarction (UMI) is unclear. We investigated associations of midlife RF with UMI and recognized MI (RMI) detected 31 years later by cardiac magnetic resonance (CMR). Methods: The Reykjavik Study (1967-91) collected serial measures of RF in subjects born 1907-35, mean (SD) age 48 ± 7 years. In ICELAND-MI (2004-07), 936 randomly selected survivors (76 ± 5 years) were evaluated by CMR. Analysis included logistic regression and random effects modeling adjusted for age, sex, and covariates. All comparisons are relative to the no MI group. Results: At baseline midlife evaluation, atherosclerotic risk assessed by a modified Framingham risk score was significantly higher in RMI and UMI than in no MI (7.4 ± 6.3%; 7.1 ± 6.2% vs 5.4 ± 5.8% respectively, p&lt;0.001). RMI and UMI were more common in men (65%, 64% vs 43%; p&lt;0.0001). Compared with no MI, baseline systolic BP was significantly higher in UMI (138 ± 17 mm Hg vs 133 ± 17 mm Hg; p=0.006), and trended higher in RMI (p=0.06). Likewise, baseline diastolic BP was significantly elevated in both RMI and UMI (88 ± 10 mm Hg and 87 ± 10 mm Hg vs 84 ± 10 mm Hg; p&lt;0.02). Serum cholesterol was significantly higher in RMI (6.7 ± 1.1 mmol/L vs 6.2 ± 1.1 mmol/L; p=0.005), as were serum triglycerides (1.4 ± 0.7 mmol/L vs 1.3 ± 0.7 mmol/L; p&lt;0.03). Serum cholesterol trended higher in UMI (p=0.08). Compared to no MI, serial midlife systolic and diastolic BP were significantly higher in RMI [beta=4.03 ± 1.64 (SE) mm Hg, p=0.014 and 2.05 ± 0.94 mm Hg, p=0.025, respectively] as were cholesterol and triglycerides [0.43 ± 0.11 mmol/L, p=0.001 and 0.31 ± 0.07 mmol/L, p&lt;0.0001, respectively]. Systolic BP was significantly higher in UMI [beta=2.76 ±1.31 mm Hg, p=0.036, figure]. Conclusions: Midlife vascular risk factors are associated with UMI and RMI detected by CMR 31 years later. Systolic BP was the most important individual risk factor associated with later UMI.
Role of Endogenous Bradykinin in Human Coronary Vasomotor Control
Authors: PeterGroves, SabineKurz, HanjörgJust, HelmutDrexler
Journal: Circulation (1995)

Background Bradykinin is a potent vasodilator that acts through B2 kinin receptors to stimulate the release of endothelium-derived nitric oxide, prostacyclin, and hyperpolarizing factor. In this study, we investigated the contribution of endogenous bradykinin to vasomotor control in the human coronary circulation. Methods and Results The selective bradykinin B2 receptor antagonist HOE 140 was infused into the left main coronary artery (200 μg/min for 15 minutes) in 15 patients without significant coronary stenoses. Epicardial responses were evaluated by quantitative coronary blood flow with a Doppler flow-velocity wire. Flow-dependent dilation (n=10; intracoronary papaverine) and acetylcholine responses (n=5) were assessed before and after HOE 140. After HOE 140, there was a reduction in luminal area in the proximal (P<.001), mid (P<.001), and distal (P<.05) coronary arteries. HOE 140 led to an increase in coronary vascular resistance (P<.001) and a decrease in coronary blood flow (P<.001). After bradykin...
Abstract 14065: Asymptomatic Nonsustained Ventricular Tachycardia Detected on Pacemaker Interrogation Not Associated With Adverse Outcomes and Treatment Remains Unproven
Authors: Sajeel Mohammed, John Gierula, Haqeel A Jamil, Maria F Paton, Judith E Lowry, Richard M Cubbon, Mark T Kearney, Klaus K Witte
Journal: Circulation (2016)

Introduction: Nonsustained ventricular tachycardia (NSVT) is frequently identified in patients with permanent pacemakers (PPMs), but its associated features, prognostic relevance and benefit of tre...
Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high‐risk MDS: Phase 2 study results
Authors: Jorge E. Cortes, B. Douglas Smith, Eunice S. Wang, Akil Merchant, Vivian G. Oehler, Martha Arellano, Daniel J. DeAngelo, Daniel A. Pollyea, Mikkael A. Sekeres, Tadeusz Robak, Weidong Wendy Ma, Mirjana Zeremski, M. Naveed Shaik, A. Douglas Laird, Ashleigh O'Connell, Geoffrey Chan, Mark A. Schroeder
Journal: American Journal of Hematology (2018)

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m2 on days 1-7 and daunorubicin 60 mg/m2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9-48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4-19.3) months, with 12-month survival probability 66.6% (80% CI 58.5-73.4). The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing.
Abstract 1271: Restricted feeding of a high-fat diet to the dark phase of the day attenuates mammary tumorigenesis in MMTV-PyMT mice
Authors: Sneha Sundaram, Lin Yan
Journal: Cancer Research (2018)

Abstract Obesity is a risk factor for breast cancer. Chronic overeating during the rest phase of the day leads to metabolic dysfunction and obesity. Lifestyle changes including restriction of meal times may be successful weight loss strategies. In the present study, we tested the hypothesis that restricted feeding of a high-fat diet to the dark phase (the active phase) of the day reduces diet-enhanced mammary tumorigenesis in an MMTV-PyMT transgenic mouse model. Mice (female) were fed the AIN93G diet (16% of energy from soybean oil) or the high-fat diet (45% of energy from soybean oil) with or without restricted feeding to the dark phase (12 hours) over eight weeks of the study. The body fat mass of the restricted feeding group was lower than the high-fat group but similar to the AIN93G control group. The mammary tumor latency was 5.8, 7.0, and 6.4 weeks for the control, high-fat and high-fat restricted groups, respectively. Restricted feeding reduced mammary tumor progression by 58% compared to the unrestricted feeding of the high-fat diet. Compared to the AIN93 diet, the high-fat diet significantly increased plasma concentrations of plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, resistin, leptin, insulin, angiopoietin-2, hepatocyte growth factor and vascular endothelial growth factor. The restricted feeding reduced concentrations of the aforementioned variables in plasma, except resistin, leptin, and insulin. In summary, restricted feeding of the high-fat diet to the dark phase reduces diet-enhanced mammary tumorigenesis. This protection of the restricted feeding against breast tumorigenesis may be associated with its actions in attenuating adipogenesis and production of related inflammatory cytokines and angiogenic factors. Citation Format: Sneha Sundaram, Lin Yan. Restricted feeding of a high-fat diet to the dark phase of the day attenuates mammary tumorigenesis in MMTV-PyMT mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1271.
Hadiza Bawa-Garba wins right to practise again
Authors: Clare Dyer
Journal: BMJ (2018)

Hadiza Bawa-Garba, the trainee paediatrician whose erasure from the UK medical register provoked a storm of protest from doctors around the world, has won her appeal to be allowed to practise again.1

She was found guilty of gross negligence manslaughter in November 2015 for contributing to the death of 6 year old Jack Adcock from septic shock at Leicester Royal Infirmary.2 A medical practitioners tribunal, which took account of systemic failings at the hospital and the extreme pressure under which she was working, decided to suspend her for 12 months rather than strike her off.3 But the General Medical Council (GMC) appealed to the High Court, which erased her from the register in January 2018.4

Supporters raised over £350 000 (€393 000; $448 000) to crowdfund her appeal against the High Court ruling, and yesterday (13 August) three senior judges, headed by the Lord Chief …
Abstract 5821: Atorvastatin antagonizes carboplatin, synergizes with the glycolytic inhibitor PFK-158, and induces lipid laden multilamellar bodies in ovarian cancer
Authors: Eleftheria Kalogera, Debarshi Roy, Jamie N. Bakkum-Gamez, William A. Cliby, Sean C. Dowdy, Viji Shridhar
Journal: Cancer Research (2018)

Abstract Objectives: To investigate the antitumor potential of the widely used anticholesterol drug Atorvastatin (ATV) alone, in combination with Carboplatin (CBPT) and with the glycolytic inhibitor PFK158 (PFKi) in ovarian cancer (OC). Methods: MTT assay and the Chou-Talalay methodology were used to test anticancer activity in vitro; half maximal inhibitory concentration (IC50) and combination index (CI) were calculated. Cellular changes were studied with transmission electron microscopy (TEM). ATV was combined with PFKi as we previously showed that PFKi, in addition to glycolysis, inhibits lipid metabolism by targeting PLA2G3. PLA2G3 expression was studied by western blot given that downregulation in OVCAR8 using two shRNAs (sh33, sh35) induced autophagy, a prodeath condition in OC, and was associated with chemosensitization compared to nontargeted controls (NTC) (unpublished data). A random sample of 10 patient-derived OC xenografts (PDX) was studied by TEM. Results: OVCAR8 exhibited a dose dependent proliferation inhibition when treated with ATV (IC50 8μM). PFKi and CBPT IC50 were 4μM and 78μM. PFKi treatment combined with 4μM and 8μM of ATV resulted in ATV sensitizing cells to PFKi by shifting PFKi IC50 down to 2.7μM and 0.4μM, respectively. When ATV was combined in constant ratio with CBPT, CIs were &amp;gt;1.1 indicating antagonism. Combination of ATV 4μM with PFKi 2μM resulted in greater decrease in PLA2G3 and p62 and greater increase in cleaved PARP compared to PFKi alone suggesting higher levels of autophagy and apoptosis. ATV and combination treatment resulted in increased caveolin-1 levels, previously shown to be associated with apoptotic cell death. TEM analysis of ATV and PFKi treated cells showed greater number of lipid rich multilamellar bodies (MLB) compared to controls. PLA2G3 knockdowns exhibited higher MBL formation, lower p62, and when treated with statin and with PFKi, cleaved PARP was significantly higher compared to NTCs. TEM showed that PDXs clustered in low and high MLB groups suggesting a distinct novel phenotype. Conclusions: ATV could enhance PFKi antitumor activity by jointly targeting PLA2G3 leading to metabolic reprogramming of OC. Importantly, ATV antagonized CBPT. Additional studies are in progress to explore the mechanistic pathway of ATV and characterize the significance of MLB in OC as a prodeath phenotype and biomarker of response. Citation Format: Eleftheria Kalogera, Debarshi Roy, Jamie N. Bakkum-Gamez, William A. Cliby, Sean C. Dowdy, Viji Shridhar. Atorvastatin antagonizes carboplatin, synergizes with the glycolytic inhibitor PFK-158, and induces lipid laden multilamellar bodies in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5821.
Loss-of-function zinc finger mutation in the EGLN1 gene associated with erythrocytosis
Authors: Margje Sinnema, Daisheng Song, Wei Guan, Johanna W. H. Janssen, Richard van Wijk, Bradleigh E. Navalsky, Kai Peng, Albertine E. Donker, Alexander P. A. Stegmann, Frank S. Lee
Journal: Blood (2018)
Finding useful biomarkers for Parkinson’s disease
Authors: Alice S. Chen-Plotkin, Roger Albin, Roy Alcalay, Debra Babcock, Vikram Bajaj, Dubois Bowman, Alex Buko, Jesse Cedarbaum, Daniel Chelsky, Mark R. Cookson, Ted M. Dawson, Richard Dewey, Tatiana Foroud, Mark Frasier, Dwight German, Katrina Gwinn, Xuemei Huang, Catherine Kopil, Thomas Kremer, Shirley Lasch, Ken Marek, Jarrod A. Marto, Kalpana Merchant, Brit Mollenhauer, Anna Naito, Judith Potashkin, Alyssa Reimer, Liana S. Rosenthal, Rachel Saunders-Pullman, Clemens R. Scherzer, Todd Sherer, Andrew Singleton, Margaret Sutherland, Ines Thiele, Marcel van der Brug, Kendall Van Keuren-Jensen, David Vaillancourt, David Walt, Andrew West, Jing Zhang
Journal: Science Translational Medicine (2018)

The recent advent of an “ecosystem” of shared biosample biorepositories and data sets will aid efforts to define biomarkers for Parkinson’s disease.
Abstract 1009: Reciprocal roles of cancer associated fibroblasts and CD4+ T cells in ovarian cancer progression
Authors: Ye Hu, Sandra Orsulic
Journal: Cancer Research (2018)

Abstract Recent evidence suggests that the efficacy of tumor immunotherapy is reliant on the signals received from the tumor microenvironment. The two prevalent cell types in the tumor microenvironment are immune cells and cancer-associated fibroblasts (CAFs). The presence of CAFs has been associated with poor survival in multiple cancer types and CAF-targeting in several experimental mouse cancer models has been shown to improve tumoral immune response and therapeutic efficacy. By conducting immunohistochemistry in 42 patient-matched primary, metastatic, and recurrent ovarian tumors, We have shown that both CAF activation and CD4+ T cell infiltration increase during cancer progression. Upon co-culturing human CAFs with CD4+ T cells, We found that CAFs physically attract CD4+ T cells. In turn, CD4+ T cells activate CAFs, as indicated by the increased ability of CAFs to contract extracellular matrix. Further experiments showed more immune suppressive T cell subtypes (Th2 and Treg cells), when co-culture activated human CAFs with CD4+ Naive T cells. A recent analysis of chemokines has shown that their expression is highly variable in primary ovarian tumors. Differential expression of chemokines in different areas of the tumor may result in a skewed distribution of immune cell types. We searched for genes that belong to the KEEG pathway ‘cytokine-cytokine receptor interaction' that are differentially expressed in the mesenchymal and mesenchymal subtype-equivalent C1 subtypes compared to all other subtypes in the TGCA and GEO datasets. Our comparison of the top 50 differentially expressed cytokine-cytokine receptor interaction genes in the mesenchymal and C1 subtypes revealed high gene signature conservation, with 32 of 50 genes being shared, including CXCL12, CXCL14, CCL11, CCL26 and KDR. Flow cytometry results showed over-expression of some cytokines in CAFs could foster CAFs into more active state, which created an immune suppressive environment by turning more T cells to Th2 and Treg subtypes. In summary, ovarian CAFs may have great impact on immune cells proliferation and differentiation, thus influence tumor progression. Citation Format: Ye Hu, Sandra Orsulic. Reciprocal roles of cancer associated fibroblasts and CD4+ T cells in ovarian cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1009.
Brigatinib Activity in Patients with ALK plus NSCLC and Intracranial CNS Metastases in Two Clinical Trials
Authors: Scott Gettinger, Dong-Wan Kim, Marcello Tiseo, Corey Langer, Myung-Ju Ahn, Alice Shaw, Rudolf Huber, Maximilian Hochmair, Sang-We Kim, Lyudmila Bazhenova, Kathryn Gold, Sai-Hong Ou, Howard West, William Reichmann, Jeff Haney, Tim Clackson, Frank Haluska, David Kerstein, D. Ross Camidge
Journal: Journal of Thoracic Oncology (2017)
Abstract 2436: Anti-cancer effect by combination treatment of CDK and HSP90 inhibitors through HIF1α inhibition
Authors: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry
Journal: Cancer Research (2018)

Abstract Hypoxia-inducible factor 1α (HIF1α) is the main mediator of the adaptive response to intra-tumoral hypoxia. HIF1α overexpression contributes to tumor angiogenesis, cancer cell survival and metastasis. Thus, targeting HIF1α provides new opportunities for cancer therapy. We have previously shown that cyclin-dependent kinase 1 (CDK1) stabilizes HIF1α through direct phosphorylation of its Ser668 residue in a Von Hippel-Lindau (VHL)-independent or p53-independent manner both under hypoxia and at G2/M under normoxia (Warfel et al., Cell Cycle, 2013). Because heat shock protein 90 (HSP90) is a VHL-independent HIF1α stabilizer, we hypothesized CDK and CDK inhibitor effects in the stabilization/destabilization mechanism. We found that CDK1 inhibition disrupts the interaction between HSP90 and HIF1α. Moreover, administration of the CDK1 inhibitor, Ro-3306, partially reversed a heat shock (40°C) response dependent increase in the level of HIF1α, which suggests that CDK1 activity may contribute to HSP90-mediated HIF1α stabilization. Combination treatment with both HSP90 inhibitor and CDK1 inhibition/knockdown decreased HIF1α level more robustly than either single treatment. Dual inhibition of CDK1 and HSP90 not only synergistically decreased cell viability but also remarkably reduced colony formation of HCT116 colon cancer cells. Previously we have also shown that similar to CDK1, CDK4 plays a role in HIF1α stabilization as well. This led us to investigate the effect of CDK4/HSP90 dual inhibition on colorectal cancer cells. The combination treatment of CDK4 knockdown/inhibition and HSP90 inhibition reduced the level of HIF1α in various cancer cell lines (e.g., colorectal, glioblastoma, prostate cancers). The FDA-approved CDK4 inhibitor palbociclib along with ganetespib synergistically inhibited cell viability in SW480 colon cancer cells under hypoxia or normoxia. No reduction in cell viability was noted in WI38 normal cells under normoxia at similar concentrations. In addition, we tested the therapeutic potential of the dual CDKi/HSP90i therapy in vivo. The combination treatment of palbociclib and ganetespib inhibited tumor growth in the HT29 colon cancer cell xenograft mouse model at relatively low doses. Immunohistochemistry staining of the tumor samples revealed higher levels of apoptosis, lower levels of VEGF expression and reduced microvessel formation in the combination treatment group. Our findings provide a compelling rationale for a therapeutic strategy to target HIF1α through the combination of CDK and HSP90 inhibitors in cancer therapy. Citation Format: Shuai Zhao, Lanlan Zhou, David T. Dicker, Wafik S. El-Deiry. Anti-cancer effect by combination treatment of CDK and HSP90 inhibitors through HIF1α inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2436.
Abstract 16651: Development of a Novel Cardiac Arrest Model in Aged Mice
Authors: Huaxin Sheng, Huaqin Liu, Bin Xu, Zhui Yu, Wulf Paschen, David S Warner, Wei Yang
Journal: Circulation (2015)

Introduction: Cardiac arrest (CA) occurs commonly in daily life, especially for elderly patients. However, most studies in CA and cardiopulmonary resuscitation (CPR) were performed in young animals. A relevant CA/CPR experimental model in aged animals is needed for better understanding the mechanisms of this disease and seeking advanced therapeutic approaches. In this study, we aimed to develop a novel mouse model that can be used to investigate CA/CPR in aged mice. Hypothesis: The aged mice subjected to CA/CPR would be resuscitated. Methods: Male C57Bl6 mice were subject to 8 min of KCl induced cardiac arrest and then resuscitated by epinephrine infusion and chest compression. The use of KCl was minimized by withdrawal of blood from jugular vein for better resuscitation and recovery. 22 months old mice were performed and 8-10 weeks old mice served as reference (n=10 per group). All mice had withdrawal of 0.5 ml of blood followed by infusing 30μl 0.5 M KCl to induce flat EKG. Blood was infused back at 3 min after onset of cardiac arrest. Epinephrine (32μL/mL) was slowly infused 30 seconds before resuscitation until regular EKG appeared. Resuscitation time and survival rate were recorded. Spontaneous activity was measured in smart cage at pre-injury and days 1, 2, and 3 post-injury. Neurological score (9 points ) was measured at day 3 after CA/CPR. Results: All mice were successfully resuscitated and survived for 24 hours. Young mice restored spontaneous heart activity within 1 min and however, most of aged mice took more than 1 min (p=0.014). Aged mice had a significantly decline of spontaneous activity including travel time and travel distance (travel time p=0.02 compared to young mice group, Fig 1). 3 days of survival rate was 40% in aged mice and 90% in young mice (p=0.03, Fig 2). Aged mice also had a worse neurological score at day 3 post-injury (p=0.026). Conclusions: This modified procedure ensured all mice resuscitated and survived for 24 hours. Declined spontaneous activity and neurological function represent the success of this disease model. Our on-going experiment is to define the age related stress responses and SUMO conjugation using this novel mouse model and seek new targets for treatment of this injury.