tbuckley/cabot-search huggingface dataset:
Abstract 290: Concurrent Gout is Associated with Reduced In-hospital Mortality Among Postmenopausal Women with Acute Myocardial Infarction: Insights from a Nationwide Sample
Authors: Akintunde M Akinjero, Oluwole Adegbala, Eseosa Edo-Osagie, Nike E Akinjero, Tomi Akinyemiju
Journal: Circulation Research (2017)

Background: Gout has been shown to increase the risk of cardiovascular diseases among postmenopausal women. The mechanisms remain unclear. We sought to evaluate in-hospital outcomes among postmenopausal women hospitalized with coexisting gout and acute myocardial infarction (AMI). Methods: Data was retrieved from the Nationwide Inpatient Sample (NIS), using ICD-9-CM codes. We excluded women less than 55yrs old. Patients with acute myocardial infarction (AMI) and co-occurring gout were compared with those without gout. We then tested for associations with stroke, in-hospital mortality and length of stay using multivariate analysis to adjust for confounders. All analyses were performed using SAS. Results: There was a total of 335,403 hospital admissions for AMI. Out of these, 484 had co-occurring gout. Women with both co-occurring conditions were more likely to be white (64.1%). In adjusted models, co-occurring gout and AMI was significantly associated with a reduced likelihood of in-hospital mortality (aOR=0.50, 95% CI: 0.35-0.72, Table 1). However, co-occurring gout and AMI was not significantly associated with stroke rates (aOR=0.95, 95% CI: 0.59-1.55) or length of stay (aOR=1.46, 95% CI: 0.77-2.16). Conclusion: Results from this nationally representative sample suggests that co-occurring gout is associated with reduced in-hospital mortality among postmenopausal women admitted for AMI, while no significant associations were found for length of stay and stroke rates. Further prospective studies are needed to explore these associations.
Abstract 1343: SNPs in the NFKB alternative pathway genes <i>CD40, BAFFR</i> and <i>LTβR</i> in CRC
Authors: Anna Antonacopoulou, Anastasia Kottorou, Angelos Koutras, Foteinos-Ioannis Dimitrakopoulos, Thomas Makatsoris, Haralabos P. Kalofonos
Journal: Cancer Research (2019)

Abstract We sought to assess the role of single nucleotide polymorphisms (SNPs) in genes of the alternative NF-KB pathway, important in regulating different aspects of immune functions in colorectal cancer (CRC). The study comprised DNA samples from 418 patients with CRC and 299 age-matched healthy individuals. Genotyping was performed with real time PCR followed by high resolution melt curve analysis for the following SNPs: CD40 rs1883832 (C/T), BAFFR rs7290134 (A/G), LTβR rs10849448 (A/G). Genotypes of random samples were confirmed by sequencing. Genotype frequencies differed between CRC and healthy individuals for CD40 rs1883832 and LTβR rs10849448 (p = 0.001 and p = 0.016, respectively) but were similar for BAFFR rs7290134. The LTβR rs10849448 G allele was more frequent in CRC patients compared to healthy controls and increased risk for CRC by 61% (p = 0.024). Moreover, the G allele was found more frequently in stage D patients compared to stages A and C while the A allele was more prevalent in stage B patients (p = 0.007). Additionally, most patients with grade III tumors were G allele carriers whereas the majority of grade I tumors were AA homozygotes (p = 0.019). The CD40 rs1883832 T allele was less frequent in CRC patients and reduced risk for CRC by 71% (p = 0.027). The CD40 rs1883832 SNP proved to be a prognostic factor for PFS with the CC individuals displaying a longer PFS compared to T carriers (p = 0.045). The BAFFR rs7290134 SNP was independent of all clinical parameters evaluated. Primary site was independent of genotypes for all three SNPs. SNPs within genes of receptors of the NF-KB alternative pathway, CD40 rs1883832 and LTβR rs10849448, influence PFS and risk for CRC development. Additionally, particular genotypes correlated with stage and grade. Citation Format: Anna Antonacopoulou, Anastasia Kottorou, Angelos Koutras, Foteinos-Ioannis Dimitrakopoulos, Thomas Makatsoris, Haralabos P. Kalofonos. SNPs in the NFKB alternative pathway genes CD40, BAFFR and LTβR in CRC [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 1343.
Abstract 23094: Titin Truncating Variants Predict Life-threatening Arrhythmias in Patients With Dilated Cardiomyopathy
Authors: Ben Corden, Julian Jarman, Nicola Whiffin, Upasana Tayal, Rachel Buchan, Joban Sehmi, Andrew Harper, William Midwinter, Karen Lascelles, Vias Markides, Mark Mason, Dudley J Pennell, Paul J Barton, Sanjay K Prasad, Tom Wong, Stuart A Cook, James S Ware
Journal: Circulation (2017)

Introduction: There is an urgent need for better arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy (DCM), where the benefit of ICD implantation is unclear. Titin truncating variants (TTNtv) are the commonest genetic cause of DCM and are associated with early onset non-sustained ventricular tachycardia (NSVT) and atrial fibrillation (AF) in these patients. Hypothesis: We hypothesize that TTNtv status can predict potentially life threatening ventricular tachycardia (VT) or fibrillation (VF) and development of new persistent AF in DCM patients with CRT-D or ICD devices. Methods: We studied 117 DCM patients with an ICD or CRT-D and documented device-recorded arrhythmia over a median period of 4.2 years. Patients were stratified by TTN genotype (28 positive for a TTNtv, 89 negative). The primary outcome was time to first device-treated VT &gt;200bpm or VF. Secondary outcome measures included time to first development of persistent AF. Results: TTNtv predicted the risk of receiving an appropriate ICD therapy for VT/VF (hazard ratio [HR] = 4.9, 95% confidence interval [CI]=2.3-10.7, P&lt;0.0001). This association was independent of all covariates, including replacement fibrosis measured by late-gadolinium enhancement (LGE), (adjusted HR = 8.2, 95% CI 1.9-36.5, P=0.005). Individuals with both a TTNtv and fibrosis had a markedly greater risk for appropriate device therapy than those with neither (HR = 16.6, CI 3.5-79.3, P&lt;0.0001). TTNtv were also a risk factor for developing new persistent AF (HR = 4.4, 95% CI = 1.45-13.1, P=0.006). Conclusion: TTNtv status is an important risk factor for clinically significant arrhythmia in patients with DCM and CRT-D or ICD devices. TTNtv status alone, or more powerfully in combination with fibrosis imaging by MRI, may provide an effective approach for risk stratifying the need for ICD therapy in DCM patients.
Abstract 3796: Selonsertib, an ASK1 inhibitor, antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance
Authors: Ning Ji, Yuqi Yang, Chao-Yun Cai, Zi-Ning Lei, Jing-Quan Wang, Pranav Gupta, Suneet Shukla, Suresh V. Ambudkar, Dexin Kong, Zhe-Sheng Chen
Journal: Cancer Research (2019)

Abstract The overexpression of ATP-binding cassette (ABC) transporters has known to be one of the most important mechanisms responsible for the development of multidrug resistance (MDR). Selonsertib, an apoptosis signal-regulating kinase 1 (ASK1) inhibitor, is in phase III clinical trial for the treatment of non-alcoholic steatohepatitis (NASH). In this study, we investigated whether selonsertib could antagonize MDR mediated by ABC transporters, involving in ABCB1, ABCG2, ABCC1 and ABCC10. The results showed that selonsertib significantly reversed ABCB1- and ABCG2-mediated MDR, but not MDR-mediated by ABCC1 or ABCC10. Mechanistically, our studies indicated that the reversal effect of selonsertib was related to the attenuation of the efflux function of ABCB1 and ABCG2 transporters, consequently enhancing intracellular accumulation of substrate drugs. Meanwhile, selonsertib, at reversal concentration, affected neither the expression level of ABCB1 and ABCG2 nor the localization of corresponding proteins in subcellular level. Selonsertib stimulated the ATPase activity of both ABCB1 and ABCG2 in a concentration-dependent manner. Our in silico docking study showed that selonsertib could interact with the substrate-binding sites of both ABCB1 and ABCG2. This study provides a clue into a novel treatment strategy, which includes a combination of selonsertib with antineoplastic drugs to circumvent ABCB1- or ABCG2- mediated MDR. Citation Format: Ning Ji, Yuqi Yang, Chao-Yun Cai, Zi-Ning Lei, Jing-Quan Wang, Pranav Gupta, Suneet Shukla, Suresh V. Ambudkar, Dexin Kong, Zhe-Sheng Chen. Selonsertib, an ASK1 inhibitor, antagonizes ABCB1- and ABCG2-mediated chemotherapeutic drug resistance [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 3796.
The optimisation of noninvasive ventilation in amyotrophic lateral sclerosis: a systematic review
Authors: David O'Brien, Theocharis Stavroulakis, Susan Baxter, Paul Norman, Stephen Bianchi, Mark Elliott, Maxine Johnson, Mark Clowes, Aldara Garcia-Sánchez, Esther Hobson, Christopher McDermott
Journal: European Respiratory Journal (2019)

Noninvasive ventilation (NIV) prolongs survival and quality of life in amyotrophic lateral sclerosis (ALS); however, its benefits depend upon the optimisation of both ventilation and adherence. We aimed to identify factors associated with effective initiation and ongoing use of NIV in ALS to develop evidence-based guidance and identify areas for further research.We searched 11 electronic databases (January 1998 to May 2018) for all types of quantitative and qualitative studies. Supplementary grey literature searches were conducted. Records were screened against eligibility criteria, data were extracted from included studies and risk of bias was assessed. We present findings using a narrative synthesis.We screened 2430 unique records and included 52 quantitative and six qualitative papers. Factors reported to be associated with NIV optimisation included coordinated multidisciplinary care, place of initiation, selection of interfaces, ventilator modes and settings appropriate for the individual patient, and adequate secretion management. The literature indicated that patients with significant bulbar dysfunction can still derive considerable benefit from NIV if their needs are met. Research emphasises that obstructive airway events, mask leak and uncontrolled secretions should be addressed by adjustments to the interface and machine settings, and the concomitant use of cough augmentation.This review highlights that NIV optimisation requires an individualised approach to respiratory management tailored to the differing needs of each patient. Ultimately, this should lead to improved survival and quality of life. This review expands on recommendations in current international guidelines for NIV use in ALS and identifies areas for future research.
Abstract 2764: Small activating RNA induced expression of VHL gene in renal cell carcinoma
Authors: Jong Soon Kang, Moo RIm Kang, Ki Hwan Park
Journal: Cancer Research (2019)

Abstract Recent studies have reported that chemically synthesized double-stranded RNAs (dsRNAs), also known as small activating RNA (saRNAs), can specifically induce gene expression by targeting promoter sequences in a mechanism termed RNA activation (RNAa). In the present study, we designed four candidate dsRNAs targeting the Von Hippel-Lindau (VHL) gene promoter. Among these dsRNAs, dsVHL-821 significantly inhibited cell growth by up-regulating VHL at both the mRNA and protein levels in renal cell carcinoma 769-P cells. Functional analysis showed that dsVHL-821 induced apoptosis by increasing p53, decreasing Bcl-xL, activating caspase 3/7 and poly-ADP-ribose polymerase in a dose-dependent manner. Chromatin immunoprecipitation analysis revealed that dsVHL-821 increased the enrichment of Ago2 and RNA polymerase II at the dsVHL-821 target site. In addition, Ago2 depletion significantly suppressed dsVHL-821-induced up-regulation of VHL gene expression and related effects. Consistent with previous studies on RNAa of other genes, single transfection of dsVHL-821 caused long-lasting (14 days) VHL up-regulation. Furthermore, the activation of VHL by dsVHL-821 was accompanied by an increase in dimethylation of histone 3 at lysine 4 (H3K4me2) and acetylation of histone 4 (H4ac) and a decrease in dimethylation of histone 3 at lysine 9 (H3K9me2) and lysine 27 (H3K27me2) in the dsVHL-821 target region. Taken together, these results demonstrate that dsVHL-821, a novel saRNA for VHL, induces the expression of the VHL gene by epigenetic changes, resulting in inhibition of cell growth and induction of apoptosis. Targeted activation of VHL by dsVHL-821 may be explored as a novel treatment of renal cell carcinoma. Citation Format: Jong Soon Kang, Moo RIm Kang, Ki Hwan Park. Small activating RNA induced expression of VHL gene in renal cell carcinoma [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 2764.
Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT).
Authors: Stephen R. D. Johnston, Mark Basik, Roberto Hegg, Wirote Lausoontornsiri, Lukasz Grzeda, Mark Clemons, Lydia Mary Dreosti, Serban Ghiorghiu, Helen Mann, Donal Landers, Mary Stuart, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2013)

531 Background: Preclinical data suggest a key role for EGFR inhibition in delaying acquired resistance to ET in ER+ breast cancer (BC). Retrospective analyses of 2 Phase II studies suggested adding gefitinib to ET delayed PFS in ET naive (ETN) BC. This randomized, double-blind, placebo-controlled multi-center study (NCT01151215) was conducted to prospectively test the hypothesis that adding AZD8931, an inhibitor of EGFR, HER2 and HER3 signaling, to A would be beneficial in delaying endocrine resistance in an advanced ETN BC population. Methods: Post-menopausal women with ER+ and/or PR+, ETN, HER2-negative, advanced BC were randomized (1:1:1) to receive A (1 mg od) plus AZD8931 20 or 40 mg bd or placebo (P). The primary endpoint was PFS (ITT population). Data presented are from an interim analysis (data cutoff 31 Aug 2012; 39% pts had a progression event). Results: Between Jun 2010 and Jun 2012, 359 pts (median age 61 years) were randomized to A combined with AZD8931 20 mg (n=118), 40 mg (n=120) or P (n=121). At the interim analysis, median PFS in the AZD8931 20 mg, 40 mg and P arms was 10.9, 13.8 and 14.0 months, respectively; PFS HR (95% CI) for AZD8931 20 mg:P was 1.37 (0.91–2.06, P=0.135) and for AZD8931 40 mg:P was 1.16 (0.77–1.75, P=0.485). Deaths were reported for 20 (17%), 16 (13%) and 12 pts (10%) in the AZD8931 20 mg, 40 mg and P arms, respectively. Grade ≥3 AEs were reported for 22 (19%), 44 (37%) and 18 (15%) pts in the AZD8931 20 mg, 40 mg, and P arms, respectively, the most frequent being rash (0% vs 8% vs 2%), acneiform dermatitis (0% vs 7% vs 0%) and hypertension (3% vs 3% vs 2%). Serious AEs were reported for 12%, 14% and 9% pts in the AZD8931 20 mg, 40 mg and P arms, respectively, and discontinuation (of AZD8931 or P) due to an AE in 5%, 8% and 2% pts, respectively. Conclusions: Co-blockade of EGFR, HER2, HER3 in combination with aromatase inhibition does not appear to delay endocrine resistance to ETN BC. Based on the low probability of demonstrating superior efficacy with addition of AZD8931 to A and the overall risk/benefit, the study was closed at the recommendation of the IDMC and pts discontinued AZD8931. Clinical trial information: NCT01151215.
Expression and prognostic relevance of calcium calmodulin-dependent protein kinase kinase 2 (CaMKK2) in chronic lymphocytic leukemia (CLL).
Authors: Shekeab Jauhari, Alicia D. Volkheimer, Ian Barak, Eross Guadalupe, J. Brice Weinberg, Nelson Jen An Chao, Zhiguo Li, Luigi Racioppi
Journal: Journal of Clinical Oncology (2019)

e19002 Background: CaMKK2 has restricted tissue expression in humans, regulates diverse cell functions, and is overexpressed in several human malignancies. Blocking its function reduces cancer cell migration and survival in vitro and in vivo. The relevance of CaMKK2 signaling in lymphoma is uncertain, however. Here, we sought to characterize CaMKK2 expression in CLL, as well as its predictive variables and prognostic relevance. Methods: B cell samples from 39 CLL patients and 4 healthy donors were obtained from a biorepository at our institution through an active protocol. Commercially available kits were used for RNA isolation, cDNA generation, and RT-PCR. The Kolmogorov-Smirnov test was used to compare CaMKK2 expression between patients and donors. Regression analysis was used to identify independent predictors of CaMKK2 expression. Treatment-free survival was estimated using the Kaplan-Meier method. Results: CaMKK2 mRNA was standardized to actin and overexpressed in CLL cells v. healthy donor B cells (2.27 - 11.83 x 10 -2 v. 0.93 - 1.67 x 10 -2 , p = 0.0014). Nine variables were evaluated for possible association, including age, gender, race, WBC and monocyte count, IGVH mutation status, FISH panel, Zap70 and CD38 status. By univariate analysis, unmutated IGVH and African-American race were associated with higher CaMKK2 expression (p = 0.0023 and 0.0238). Race was identified as a potential confounder for IGVH mutation status and vice versa. In a multivariate model, only IGVH mutation status predicted for CaMKK2 expression. Patients in the highest quartile of CaMKK2 expression had lower 2 year treatment-free survival compared with all others (10.7% v. 59.2%, p = 0.0054). Conclusions: CaMKK2 mRNA is over-expressed in CLL cells relative to normal B cells. Higher CaMKK2 expression in CLL may be associated with unmutated IGVH and African-American race and predict shorter time to treatment. Our analyses are limited by all unmutated IGVH patients receiving early treatment in our cohort. [Table: see text]
Abstract 5284: Hypoxia promote self-renewal in pancreatic cancer by modulating L-2-Hydroxyglutarate level
Authors: Vineet K. Gupta, Nikita Sharma, Kousik Kesh, Roey Hadad, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee
Journal: Cancer Research (2019)

Abstract Pancreatic cancer cells undergo extensive metabolic reprogramming to fulfil the demands of metabolic nutrients to fuel their rapid proliferation. This results in abnormal accumulation of various metabolites which causes both metabolic and nonmetabolic dysregulation and potential transformation to malignancy and therefore termed as “oncometabolites”. Hypoxia is a major hallmark of pancreatic tumors which associated with increase in self-renewal. The present study investigates the role of Hypoxia mediated altered oncometabolite in regulating self-renewal in pancreatic cancer. GC-mass spectrometric analysis of pancreatic cancer cells under hypoxia showed significant accumulation of 2-hydroxyglutarate (2-HG) both in cells and culture supernatant. Further analysis of hypoxic cells showed selective accumulation L- enantiomer form. Self-renewal requires critical balance between stemness and differentiation. Present study showed for the first time that L-2-HG regulates self-renewal by increasing expression of genes associated with stemness (Sox-2, CD133) and by decreasing expression of differentiation genes (PdX-1, HB9, NKX6.1). Further analysis showed that L-2-HG mediated epigenetic changes regulates these self-renewal gens in pancreatic cancer. Our results indicated that hypoxia mediated metabolic changes results in accumulation of L-2-HG which upregulate self-renewal by shifting critical balance of gene expression towards stemness in pancreatic cancer which contribute to chemoresistance and metastasis in Pancreatic cancer. Citation Format: Vineet K. Gupta, Nikita Sharma, Kousik Kesh, Roey Hadad, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Hypoxia promote self-renewal in pancreatic cancer by modulating L-2-Hydroxyglutarate level [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 5284.
PARADIGM study: A multicenter, randomized, phase III study of mFOLFOX6 plus panitumumab or bevacizumab as first-line treatment in patients with RAS (KRAS/NRAS) wild-type metastatic colorectal cancer
Authors: K. Muro, H. Uetake, K. Tsuchihara, K. Shitara, K. Yamazaki, M. Ota, E. Oki, T. Sato, T. Naitoh, Y. Komatsu, T. Kato, K. Yamanaka, I. Mori, J. Soeda, M. Hihara, T. Yamanaka, K. Akagi, A. Ochiai, T. Yoshino
Journal: Annals of Oncology (2019)
Abstract 49: ET-1 receptor blockade in engineered 3D high-grade serous ovarian cancer tumoroids
Authors: Laura Rosanò, Judith Pape, Umber Cheema, Marilena Loizidou, Anna Bagnato
Journal: Cancer Research (2019)

Abstract High-grade serous ovarian cancer (HG-SOC), accounting for 70-80% of ovarian cancer deaths, is characterized by widespred and rapid metastatic nature, suggesting that unraveling determinants of metastasis may implement new therapeutic strategies on clinical care. In this tumor, autocrine or paracrine activation of the endothelin-1 receptors (ET-1R) are recognized drivers of tumor progression, promoting epithelial-mesenchymal transition (EMT), invasion, and metastasis, as well as tumor angiogenesis and lymphangiogenesis. However, since the metastatic spread and response to therapy are influenced by the extracellular matrix (ECM) density and composition of the surrounding tumour microenvironment (TME), the development of a three-dimensional in vitro model mimicking the in vivo tumors is necessary to better understand the dynamic interactions between tumor cells and TME elements, including fibroblasts, endothelial cells and the ECM, regulated by ET-1R. With this in mind, we have developed HG-SOC tumoroids by engineering a dense central artificial cancer mass (ACM) containing HG-SOC cells, nested within a compressed hydrogel representing the stromal compartment comprising type I collagen, laminin, fibronectin, and stromal cells (fibroblasts and endothelial cells). After 21 days, ET-1-stimulated HG-SOC cells showed an altered migration pattern and formed cellular aggregates, mimicking micrometastases that invaded the stroma. As compared to control cells, ET-1 treated cells showed a higher number of cellular aggregates, which were reduced by treatment with the dual receptor antagonist macitentan. In addition, ET-1 increased the size of the invading aggregates compared to control cells. These findings suggest that HG-SOC tumoroids might be useful to investigate the cross-talk between HG-SOC cells and TME in cancer progression and the response to combinatorial treatment, including ET-1R antagonist. Note: This abstract was not presented at the meeting. Citation Format: Laura Rosanò, Judith Pape, Umber Cheema, Marilena Loizidou, Anna Bagnato. ET-1 receptor blockade in engineered 3D high-grade serous ovarian cancer tumoroids [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 49.