tbuckley/cabot-search huggingface dataset:
Abstract 4915: Preclinical pharmacology and toxicology of intravenous BPM31510, a coenzyme Q10-containing lipid nanodispersion
Authors: David Linsenmayer, Shiva Kazerounian, Khampaseuth Thapa, Carrie Spencer, Aishwarya Sarma, John McCook, Stephane Gesta, Vivek Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan
Journal: Cancer Research (2018)

Abstract Coenzyme Q10 (CoQ10) plays an important role in cellular metabolism with redox capabilities beyond the mitochondria. Although, the role of CoQ10 in providing benefit in diseases such as cardiovascular, neurodegeneration, and cancer is well established, it has been limited by the absence of delivery methods to achieve physiologically relevant bio-availability. BPM31510 is a CoQ10 (ubidecarenone) containing lipid nanodispersion that delivers supraphysiological concentrations of CoQ10 to tissues, cells and mitochondria. BPM31510 is currently in clinical trials for the treatment of solid tumors including pancreatic cancer and glioblastoma multiforme. This study describes the preclinical pharmacokinetic (PK) and toxicokinetic assessment of BPM31510 (62.5, 125, and 250 mg/kg) after acute (single) intravenous (IV) administration and chronic (3 times a week for 4 weeks), and after a two week recovery from the last exposure in rats. Here, it was demonstrated that the formulation enables an effective delivery of CoQ10 with a robust increase in plasma level and dose-dependent accumulation in several tissues. PK analysis of mean plasma concentration of CoQ10 after a single and repeat dose administration revealed a dose proportion effect on peak (Cmax) and total exposure (AUC0-t). Tissue analysis of CoQ10 levels demonstrates a dose-dependent increase in liver, lung and pancreas 72 hours post-last dose. A dose dependent elimination was observed in both male and females. No difference in pharmacokinetic of CoQ10 using this formulation was observed between males and females. Notably, chronic exposure to BPM31510 does not lead to toxicities as assessed by hematology and coagulation, clinical chemistry, histopathology and gross necropsy. These results indicate that the effective delivery and bioavailability of supraphysiological levels of CoQ10 after IV administration of BPM31510 is well tolerated. Citation Format: David Linsenmayer, Shiva Kazerounian, Khampaseuth Thapa, Carrie Spencer, Aishwarya Sarma, John McCook, Stephane Gesta, Vivek Vishnudas, Niven R. Narain, Rangaprasad Sarangarajan. Preclinical pharmacology and toxicology of intravenous BPM31510, a coenzyme Q10-containing lipid nanodispersion [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 4915.
Adrenomedullin Infusion Attenuates Myocardial Ischemia/Reperfusion Injury Through the Phosphatidylinositol 3-Kinase/Akt-Dependent Pathway
Authors: HiroyukiOkumura, NoritoshiNagaya, TakefumiItoh, IchiroOkano, JunHino, KenjiMori, YoshitaneTsukamoto, HatsueIshibashi-Ueda, SenriMiwa, KeiichiTambara, ShinyaToyokuni, ChikaoYutani, KenjiKangawa
Journal: Circulation (2004)

Background— Infusion of adrenomedullin (AM) has beneficial hemodynamic effects in patients with heart failure. However, the effect of AM on myocardial ischemia/reperfusion remains unknown. Methods and Results— Male Sprague-Dawley rats were exposed to a 30-minute period of ischemia induced by ligation of the left coronary artery. They were randomized to receive AM, AM plus wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), or saline for 60 minutes after coronary ligation. Hemodynamics and infarct size were examined 24 hours after reperfusion. Myocardial apoptosis was also examined 6 hours after reperfusion. The effect of AM on Akt phosphorylation in cardiac tissues was examined by Western blotting. Intravenous administration of AM significantly reduced myocardial infarct size (28±4% to 16±1%, P<0.01), left ventricular end-diastolic pressure (19±2 to 8±2 mm Hg, P<0.05), and myocardial apoptotic death (19±2% to 9±4%, P<0.05). Western blot analysis showed that AM infusion accelerated Akt phosphory...
Abstract 3329: A newly developed Septin9 gene methylation assay dectecting double DNA strands for screening of colorectal cancer
Authors: Qiuju Liang, Zhengbin Huang, Qingwen Xu, Feipeng Xu, Wenwei Huang, Wenfang Xie, Lei Zeng, Jiasu Liu, De-Hua Yu
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is one of the most common malignant tumors and places an enormous burden on society. The US FDA approved the application of Epi proColon on 12 April 2016, and permitted the application of the Septin9 gene methylation assay as a CRC screening test for average-risk population over 50 years old. The effectiveness of methylated Septin9 for CRC detection has been reviewed in the newly published recommendation statement by US Preventive Services Task Force (USPSTF). The Septin9 gene methylation assay is more cost efficient with higher compliance than the stool DNA test, and has been proven to be an accurate, reliable, fast, and convenient molecular test. However, the currently FDA approved Epi proColon assay needs to perform triplicated PCR reactions for each sample which leads to high cost. In order to improve the sensitivity and specificity, simplify the operational procesure, and reduce cost, we have developed an new Septin9 gene methylation assay in which the specific sequences of both methylated DNA strands and control gene could be amplificated and detected in one reaction. We evaluated sensitivity, specificity, and clinical performance using plasma samples from colonoscopy negative individuals and CRC patients. The preliminary data showed that the sensitivity and specificity for CRC detection was 77.4%(41/53) ,97.8%(90/92) respectively. A large scale clinical study with more than 1000 subjects is currently in progress. In conclusion, we have developed a new Septin9 gene methylation assay detecting double DNA strands, which demonstrated improved performance for early detection of CRC in clinical setting. Citation Format: Qiuju Liang, Zhengbin Huang, Qingwen Xu, Feipeng Xu, Wenwei Huang, Wenfang Xie, Lei Zeng, Jiasu Liu, De-Hua Yu. A newly developed Septin9 gene methylation assay dectecting double DNA strands for screening of colorectal 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 3329.
Abstract 612: Nivolumab-induced changes associated with patient outcomes are disparate in metastatic melanoma patient Tregs versus conventional T cells
Authors: David M. Woods
Journal: Cancer Research (2018)

Abstract The PD1 blocking antibody nivolumab induces durable responses in metastatic melanoma patients. However, many patients do not respond and biomarkers differentiating patient response remain unidentified. To address this need, we investigated the effects of nivolumab on peripheral blood conventional CD4+ (Tcons) and regulatory T-cells (Tregs) of metastatic melanoma patients receiving nivolumab as adjuvant therapy or for metastatic disease. An increased ratio of PD1 expression on Tregs compared with Tcons was found at baseline patients with no evidence of disease (NED), while relapsing patients had a lower ratio (p&amp;lt;0.05). Intriguingly, NED patients had an increase in circulating Treg percentages post-nivolumab (p&amp;lt;0.05), which was not observed in relapsing patients. In vitro treatment of isolated T-cells with αPD1 resulted in increased proliferation (p&amp;lt;0.001). RNA-seq analysis of Tcons and Tregs showed distinct gene expression changes based on cell type and patient outcome. Pathway analysis demonstrated: upregulation of proliferation associated genes in NED Tregs, but not in relapse Tregs; downregulation of oxidative phosphorylation associated genes in NED patient Tregs and upregulation in NED Tcons; upregulation of heme metabolism associated genes in NED Tcons and downregulated in relapsing patient Tcons; and similar differences in MTORC1, heme metabolism and hypoxia pathways (all pathways q&amp;lt;0.01). Both Tcons and Tregs from non-relapsing patients had induction of phosphoSTAT3 (pSTAT3) expression post-nivolumab (p=0.012), which was absent in relapsing patients. This was also observed in a cohort of active disease patients (p=0.022), and the magnitude of change in pSTAT3 was positively correlated with patient survival (R2=0.49, p&amp;lt;0.05). Enhanced pSTAT3 expression was recapitulated in vitro in isolated T-cells (p&amp;lt;0.05). Post-nivolumab Tregs from patients with positive outcomes also had reduced suppressive function in mixed lymphocyte reactions (p&amp;lt;0.05), while patients with negative outcomes had no changes. In vitro treatment of Tregs with PD1 blocking antibodies resulted in a reduction in suppressive function (p&amp;lt;0.0001), while addition of a STAT3 inhibitor enhanced suppressive function (p&amp;lt;0.0001). These results suggest that nivolumab alters Treg signaling and metabolism pathways, hindering immune suppressive function. Collectively, our data demonstrate distinct effects of nivolumab on Tcons vs. Tregs, and highlight several potential biomarkers of patient benefit, warranting further exploration. Citation Format: David M. Woods. Nivolumab-induced changes associated with patient outcomes are disparate in metastatic melanoma patient Tregs versus conventional T cells [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 612.
Abstract 3166: The HU177 cryptic collagen epitope selectively regulates melanoma cell behavior by a CDK5 and PTPN12 associated mechanism
Authors: Xianghua Han, Jennifer M. Caron, Peter C. Brooks
Journal: Cancer Research (2018)

Abstract Previous studies indicate that selectively inhibiting cellular interactions with the HU177 cryptic collagen epitope, which can be generated in vivo during structural remodeling of the extracellular matrix (ECM), inhibits tumor growth and metastasis. However, a detailed understanding of the mechanisms by which antagonists of the HU177 collagen epitope inhibit these pathological processes is not fully understood. Uncovering the molecular mechanisms by which cellular interactions with this collagen epitope regulate tumor cell behavior may allow the development of more effective clinical strategies targeting tumor cell-ECM interactions. Here we provide evidence for the first time, that specific targeting of the HU177 cryptic collagen epitope reduces phosphorylation of cyclin-dependent kinase (CDK5) and in addition, reduces the expression of the phosphatase PTPN12 in melanoma cells attached to denatured collagen. Importantly, both CDK5 &amp;lt; PTPN12 play a functional role in the ability of the HU177 collagen epitope to regulate migration of melanoma cells as reducing expression of these molecules inhibited the anti-migratory activity of the anti-HU177 antibody. Surprisingly, reduction in either CDK5 or PTPN12 also inhibited nuclear accumulation of YAP. These novel findings help define a previously unknown signaling mechanism by which both CDK5 &amp;lt; PTPN12 may play a selective role in controlling nuclear accumulations of the transcriptional co-activator YAP following melanoma cell interactions with the HU177 cryptic collagen epitope. Taken together, these studies provide new molecular insight into the role of the HU177 collagen epitope in controlling melanoma cell behavior. Given that direct targeting of integrin receptors that mediate tumor cellular interactions with the ECM have demonstrated only limited anti-tumor activity in human clinical trials, a more detailed molecular understanding of how generation of biologically relevant cryptic elements of the ECM control melanoma cell behavior will likely facilitate the development of more effective new clinical strategies to control tumor progression. Citation Format: Xianghua Han, Jennifer M. Caron, Peter C. Brooks. The HU177 cryptic collagen epitope selectively regulates melanoma cell behavior by a CDK5 and PTPN12 associated mechanism [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 3166.
Elevated Serum Triglyceride Levels and Long-Term Mortality in Patients With Coronary Heart Disease
Authors: MotiHaim, MichalBenderly, DanielBrunner, SolomonBehar, EranGraff, HenriettaReicher-Reiss, UriGoldbourt
Journal: Circulation (1999)

Background—The association between elevated blood triglyceride levels and subsequent mortality risk in patients with established coronary heart disease (CHD) has been investigated rarely. The aim of the present study was to investigate this association. Methods and Results—We evaluated mortality over a mean follow-up time of 5.1 years among 9033 male and 2499 female CHD patients who were screened for participation in the Bezafibrate Infarction Prevention (BIP) Study. A stepwise increase in mortality with increasing serum triglyceride levels was observed in patients with desirable or elevated serum total cholesterol levels and in patients with either desirable or abnormally low HDL cholesterol levels. Multivariate adjustment for factors other than HDL cholesterol yielded a slightly increased adjusted mortality risk with a 1-natural-log-unit elevation of triglyceride levels in men (hazard ratio [HR] 1.14, 95% CI 1.00 to 1.30) and women (HR 1.37, 95% CI 1.04 to 1.88). Excess covariate-adjusted risk was noted...
Abstract 17140: Altered Epigenetic Signaling in the Coronary Arteries of Patients With Pulmonary Arterial Hypertension: the Role for BRD4 in the Development of Comorbidities
Authors: ValerieNadeau, JolyaneMeloche, EveTremblay, Marie-ClaudeLampron, FrancoisPotus, OlivierBoucherat, RoxanePaulin, EricCharbonneau, SteeveProvencher, SebastienBonnet
Journal: Circulation (2016)

Rationale: Pulmonary arterial hypertension (PAH) is a devastating vasculopathy. Recent progress in understanding its pathogenesis led to an increase in patient’s quality of life but also to the occurrence of comorbidities including coronary artery diseases (CAD), which has a prevalence 4 times higher in PAH compared to the global population. Both CAD and PAH, are associated with a pro-proliferative/anti-apoptotic phenotype of smooth muscle cells (SMCs), attributable to inflammation-induced DNA damage signaling pathways including the Bromodomain-containing protein 4 (BRD4). We thus hypothesized that the increase in circulating cytokines like IL-6- and TNF secreted by peripheral blood mononuclear cell (PBMC) seen in PAH patients promote DNA damage/BRD4 axis activation in the coronary circulation of PAH patients triggering CAD. Methods/Results: We demonstrated in both human and experimental models of PAH (monocrotaline & sugen rats) that PAH was associated with a significant remodeling of the coronary arteri...
Abstract 11685: Early Myocardial Gene Expression Profiling After Deep Hypothermic Circulatory Arrest Reveals Ontogenetic Adaptive Mechanisms Underlying Ischemia-Reperfusion Tolerance in the Swine
Authors: MikiYamada, AmirSheikh, KevinCollins, JamesFrederiksen, GeorgeQuick, AndrewLodge, MihaiPodgoreanu
Journal: Circulation (2014)

Previous studies suggest that immature hearts are more tolerant to ischemia than adult myocardium; whether differences exist during ontogenic development in severity of global myocardial ischemia/reperfusion (I/R) injury associated with cardiac surgery remains unknown. We employed swine models of deep hypothermic circulatory arrest (DHCA) to test the hypothesis that early differential regulation of cardioprotective genes is associated with increased tolerance of neonatal myocardium to surgical I/R. Male neonatal and adult pigs were randomized to DHCA or sham (N=5-14/group). DHCA animals underwent cardiopulmonary bypass (18°C), DHCA 60 min, and were recovered for 3h. Severity of perioperative myocardial injury was determined biochemically (Troponin I) and echocardiographically. Transcript levels were quantified in left ventricular myocardium using Affymetrix Porcine Genome arrays, followed by differential expression and pathway analysis. A 2-fold increase in severity of perioperative myocardial injury was ...
Reciprocal Control of hERG Stability by Hsp70 and Hsc70 With Implication for Restoration of LQT2 Mutant Stability
Authors: PeiliLi, HaruakiNinomiya, YasutakaKurata, MasaruKato, JunichiroMiake, YasutakaYamamoto, OsamuIgawa, AkiraNakai, KatsumiHigaki, FutoshiToyoda, JieWu, MinoruHorie, HiroshiMatsuura, AkioYoshida, YasuakiShirayoshi, MasayasuHiraoka, IchiroHisatome
Journal: Circulation Research (2011)

Rationale:The human ether-a-go-go–related gene (hERG) encodes the α subunit of the potassium current IKr. It is highly expressed in cardiomyocytes and its mutations cause long QT syndrome type 2. Heat shock protein (Hsp)70 is known to promote maturation of hERG. Hsp70 and heat shock cognate (Hsc70) 70 has been suggested to play a similar function. However, Hsc70 has recently been reported to counteract Hsp70. Objective:We investigated whether Hsc70 counteracts Hsp70 in the control of wild-type and mutant hERG stability. Methods and Results:Coexpression of Hsp70 with hERG in HEK293 cells suppressed hERG ubiquitination and increased the levels of both immature and mature forms of hERG. Immunocytochemistry revealed increased levels of hERG in the endoplasmic reticulum and on the cell surface. Electrophysiological studies showed increased IKr. All these effects of Hsp70 were abolished by Hsc70 coexpression. Heat shock treatment of HL-1 mouse cardiomyocytes induced endogenous Hsp70, switched mouse ERG associat...
Abstract 5470: IKK-epsilon supports anchorage independent growth via alternative NF-kB signaling in triple-negative breast cancer
Authors: Carrie D. House, Valentina Grajales, Michelle Ozaki, Elizabeth Jordan, Helmae Wubneh, Danielle Kimble, Marianne Kim, Christina M. Annunziata
Journal: Cancer Research (2018)

Abstract Metastatic breast cancer carries a poor prognosis despite the success of newly targeted therapies and treatment options remain especially limited for the subtype of triple negative breast cancer (TNBC). Several signaling pathways, including NF-κB, are altered in TNBC. Given that ΙΚΚε behaves as an oncogene in breast cancer we hypothesized that IKKε regulates classical or alternative NF-κB signaling to control diverse oncogenic functions in TNBC. Vector expression and RNA interference were used to investigate the functional role of IKKε in triple-negative breast cancer cells. Viability, protein expression, NF-κB binding activity, invasion, anoikis, and spheroid formation were examined in cells expressing high or low levels of IKKε in conjunction with alternative NF-κB p52 RNA interference or MEK inhibition. Our data show that p52 protein levels and binding activity are inversely proportional to ΙΚΚε. Moreover, knockdown of IKKε leads to increased expression of p52 and the p52-regulated gene CXCL1. This interaction was confirmed by CHiP-PCR experiments showing increased binding of p52 in the CXCL1 promoter of cells with IKKε knockdown relative to control. We further found that IKKε and MEK were required for growth in anchorage supportive conditions whereas p52 was required in anchorage resistant conditions. Western blots confirm diminished IKKε expression and enhanced p52 processing in anchorage resistant conditions relative to anchorage supportive conditions. In this model, IKKε and MEK cooperate to support growth of cancer cells in the attached, anchored environment, whereas p52 is required for growth in unattached 3-D environment. These studies reveal novel information about the role of IKKε in TNBC and highlight the adaptability of NF-κB signaling in maintaining cancer cell survival under different growth conditions. Current studies are underway to clarify the mechanism of IKKε regulation of p52. A better understanding of the diversity of NF-κB signaling may ultimately improve the development of novel therapeutic regimens for TNBC. Citation Format: Carrie D. House, Valentina Grajales, Michelle Ozaki, Elizabeth Jordan, Helmae Wubneh, Danielle Kimble, Marianne Kim, Christina M. Annunziata. IKK-epsilon supports anchorage independent growth via alternative NF-kB signaling in triple-negative breast 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 5470.
Abstract 3867: Activating <i>ESR1</i> mutations detection by single ddPCR assay
Authors: Francois-Clement Bidard, Emmanuelle Jeannot, Luc Cabel, Nicolas Epaillard, Radouane El Ayachy, Aurelien Noret, Anne Vincent-Salomon, Jean-Yves Pierga, Ivan Bieche, Charlotte Proudhon, Marc-Henri Stern
Journal: Cancer Research (2018)

Abstract Background: In metastatic breast cancer, most mutations of ESR1 (which encodes the estrogen receptor alpha ERα) occur in exon 5 (E380Q) and/or 8 (L536, Y537, D538). These mutations are responsible for acquired resistance to hormone deprivation but can be targeted by selective estrogen receptor degraders (SERD) such as fulvestrant. Circulating tumor DNA (ctDNA) allows a non-invasive assessment of ESR1 mutations, but implementing its routine use requires a sensitive, specific and fast technique, at a moderate cost. Methods: We designed a ddPCR assay scanning for all mutations targeting the 536-538 amino acid residues of ERα with a unique pair of probes and multiplexed it with other probes targeting E380Q. Sensitivity and specificity were assessed in vitro; this multiple hotspot scanning (MHS) ddPCR was used to detect ESR1 mutants in cohorts of patients with hormone deprivation-resistant metastatic breast cancer. Results: All the above-mentioned mutations were detected in a single MHS ddPCR assay with a high specificity and with a limit of detection of ~0.1% in mutant allele frequency, allowing ESR1 mutant detection in circulating tumor DNA. A perfect concordance with targeted next generation sequencing was observed in the first 31 clinical plasma samples tested. This technique also detected ESR1 polyclonal mutations. Conclusion: This technique allows for a sensitive, large scale and repeated screening of ESR1 mutants with a single ddPCR assay. The clinical utility of ESR1 mutation detection by this technique is now investigated in the randomized phase 3 PADA-1 trial (sponsors: Unicancer/Gineco), in which patients with rising levels of circulating ESR1 mutants during aromatase inhibitor / palbociclib therapy are eventually switched to fulvestrant / palbociclib (NCT03079011). ESR1 mutants detectable in a single ddPCR assayAA changesMutant frequency (as per Toy et al, Cancer Discov 2017).E380Q19%L536H4%L536P2%L536R1%Y537S11%Y537C6%Y537N5%Y537D1%D538G32%D538-L539ins1%total % of mutations covered~82% (Many of the 18% remaining mutations occur outside exon 5 &amp; 8 and have no proven functional impact) Citation Format: Francois-Clement Bidard, Emmanuelle Jeannot, Luc Cabel, Nicolas Epaillard, Radouane El Ayachy, Aurelien Noret, Anne Vincent-Salomon, Jean-Yves Pierga, Ivan Bieche, Charlotte Proudhon, Marc-Henri Stern. Activating ESR1 mutations detection by single ddPCR assay [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 3867.