tbuckley/cabot-search huggingface dataset:
Abstract 14305: Functional Genomics Implicates Decreased Fam13B Expression as Causal for the Chromosome 5q31 Atrial Fibrillation Risk Locus
Authors: Jeffrey Hsu, Shamone Gore-Panter, Gregory Tchou, Laurie Castel, Beth Lovano, Christine S Moravec, John Barnard, David R Van Wagoner, Mina K Chung, Jonathan D Smith
Journal: Circulation (2016)

Introduction: Genome wide association studies (GWAS) identified an atrial fibrillation (AF) risk locus on chr. 5q31 near the WNT8A gene, but the mechanism for this association is unknown. Objective: To use functional genomics to identify the SNP and gene responsible for the chr. 5q31 AF GWAS locus. Methods and Results: RNAseq and SNP microarray analyses were performed on 265 left atrial appendages (LAA) from a biracial cohort. Global gene expression was ascertained by RNAseq and adjusted using surrogate variable analysis. For each gene we calculated the effect of every cis-SNP on gene expression to derive expression quantitative trait loci. At the 5q31 AF GWAS locus, we observed that WNT8A was not expressed in the LAA; however, the expression of an adjacent gene, FAM13B, was strongly associated with the AF susceptibility SNP rs2040862 (in European descent subjects p=4.83E-27, with each AF risk allele lowering expression by 15%). FAM13B encodes for a poorly characterized member of the Rho GTPase activation...
Enhanced Capillary Formation Stimulated by a Chimeric Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor-C Silk Domain Fusion Protein
Authors: SallaKeskitalo, TuomasTammela, JohannesLyytikka, TerhiKarpanen, MichaelJeltsch, JohannaMarkkanen, SeppoYla-Herttuala, KariAlitalo
Journal: Circulation Research (2007)

Vascular endothelial growth factor (VEGF)-C and VEGF-D require proteolytic cleavage of the carboxy terminal silk-homology domain for activation. To study the functions of the VEGF-C propeptides, we engineered a chimeric growth factor protein, VEGF-CAC, composed of the amino- and carboxy-terminal propeptides of VEGF-C fused to the receptor-activating core domain of VEGF. Like VEGF-C, VEGF-CAC underwent proteolytic cleavage, and like VEGF, it bound to and activated VEGF receptor-1 and VEGF receptor-2, but not the VEGF-C receptor VEGF receptor-3. VEGF-CAC also bound to neuropilins in a heparin-dependent manner. Strikingly, when VEGF-CAC was expressed via an adenovirus vector in the ear skin of immunodeficient mice, it proved to be a more potent inducer of capillary angiogenesis than VEGF. The VEGF-CAC–induced vessels differed greatly from those induced by VEGF, as they formed a very dense and fine network of pericyte and basement membrane–covered capillaries that were functional, as shown by lectin perfusion...
Abstract 4303: Modulation of protein interaction states through the cell cycle
Authors: Lingyun Dai, Tianyun Zhao, Xavier Bisteau, Wendi Sun, Nayana Prabhu, Yan Ting Lim, Radoslaw Sobota, Philipp Kaldis, Pär Nordlund
Journal: Cancer Research (2018)

Abstract Global profiling of protein expression through the cell cycle has revealed subsets of periodically expressed proteins. However, expression levels alone only give a partial view of processes determining cellular events. The cell cycle progression events are to a large extent controlled by the dynamic biochemical interactions of proteins with physiological ligands such as other proteins, metabolites, lipids, nucleic acids or low molecular weight effectors. Using a proteome-wide implementation of the Cellular Thermal Shift Assay (CETSA) to study specific cell cycle phases in K562 cell, we uncover modulations of interaction states for more than 750 proteins along the cell cycle. Notably, many protein complexes are modulated in specific cell cycle phases, reflecting their roles in processes such as DNA replication, chromatin remodeling, transcription, translation, and nuclear membrane decomposition. Surprisingly, only small differences in interaction states were seen between G1 and G2 phases, suggesting similar hardwiring of biochemical processes in these two phases. The present work reveals novel molecular details of the cell cycle. CETSA, therefore emerge as a novel approach to discover cellular modulations during cancer development and therapy. Citation Format: Lingyun Dai, Tianyun Zhao, Xavier Bisteau, Wendi Sun, Nayana Prabhu, Yan Ting Lim, Radoslaw Sobota, Philipp Kaldis, Pär Nordlund. Modulation of protein interaction states through the cell cycle [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 4303.
Abstract 5752: Protumoral and pro-metastatic effects of TLR7 in lung cancer
Authors: Marion Dajon, Kristina Iribarren, Marco Alifano, Diane Damotte, Isabelle Cremer
Journal: Cancer Research (2018)

Abstract TLR7 agonists are currently under investigations for their ability to enhance anti-tumor immune responses. However, in some tumor models, these agonists also stimulate tumor cells, which can express high levels of TLR7, a receptor for single-stranded RNA [1]. We have demonstrated that stimulation of lung tumor cell lines expressing TLR7 with synthetic TLR7 agonists led to upregulation of the antiapoptotic protein Bcl-2, tumor cell survival and chemoresistance [2]. In Non-Small-Cell Lung Carcinoma (NSCLC) cohorts of patients, we have observed high expression of TLR7 on tumor cells of 70% of patients, which conferred poor clinical outcome and was strongly associated with resistance to chemotherapy [3]. This pro-tumoral effect of TLR7 has been validated in murine models in which the injection of TLR7 agonists in NOD/SCID mice, in C57BL/6 wild-type or in TLR7-deficient mice grafted with lung adenocarcinoma tumor cells led to increased tumor progression, increased lung metastasis, and resistance to chemotherapy. On the contrary, we demonstrated that TLR7 antagonist injection led to antitumoral effect. Additionally, TLR7 stimulation resulted in a significant increase of Myeloid-Derived Suppressor Cells (MDSC) in the tumor microenvironment. Depletion experiments of MDSC indicated that these cells are involved in the pro-tumoral effect induced upon TLR7 stimulation. Finally, we have demonstrated that the pro-tumoral effect of TLR7 stimulation, mediated by the MDSC recruitment, was independent of TLR7 stimulation on immune cells. Our results reveal the mechanism by which TLR7 stimulation induce the pro-tumoral effect in mice, and open the way to the development of novel cancer therapeutics including TLR7 inhibitors, for NSCLC patients. This results demonstrate the important role of TLR7 in lung tumor progression. Knowing that natural ligands of TLR7 are ssRNA, we suppose that this effect could be linked to viral infections or RNA released in the tumor microenvironment. [1] Dajon, et al. Immunobiologie. 2016 [2] Cherfils-Vicini J, et al. J Clin Invest. 2010 [3] Chatterjee J, et al. Cancer Res. 2014 Citation Format: Marion Dajon, Kristina Iribarren, Marco Alifano, Diane Damotte, Isabelle Cremer. Protumoral and pro-metastatic effects of TLR7 in lung 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 5752.
Abstract 4012: SAG/RBX2/ROC2 regulates pancreatic cancer initiation, cystic formation in mice driven by KrasG12D
Authors: Mingjia Tan, Qiang Zhang, Yi Sun
Journal: Cancer Research (2018)

Abstract BACKGROUND &amp; AIMS: SAG, a small ring finger protein, a component of CRLs, might be involved in pancreatic tumorigenesis. SAG overexpression in human pancreatic ductal adenocarcinomas indicating that SAG could be promotes pancreatic tumorigenesis. We investigated how manipulated SAG (overexpression or disruption of SAG) cooperate KRAS to regulate pancreatic cancer progression in mice. METHODS: We disrupted or overexpressed SAG specifically in pancreata of mice (Sagfl/fl;P48-Cre or SagTG;P48-Cre mice) and crossed them with LSL-KRASG12D mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Sagfl/fl;LSL-KRASG12D;P48-Cre or SagTG;LSL-KRASG12D;P48-Cre mice were monitored; Pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. Protein was isolated from mouse tissues and primary acinar cells were prepared and cultured in 3D condition. Human PDA TMA was analyzed by immunohistochemistry. RESULTS: Overexpression of Sag with KRASG12D in pancreata of mice increased the proliferation of pancreatic epithelial cells, lead to formation of acinar to ductal metaplasia and pancreatic intraepithelial neoplasias (mPanINs) and shorten mice survival. Disruption of Sag in LSL-KRASG12D;P48-Cre mice accelerated the growth of pancreatic cystic lesions compared to LSL-KRASG12D;P48-Cre mice, but did not change mouse survival. In mechanism, Sag promotes pancreatic tumorigenesis by regulating Deptor/mTOR/S6K axis and EGFR signaling pathway. CONCLUSION: Sag is an oncogenic cooperator of activated KRAS for pancreatic tumorigenesis. Targeting SAG E3 ligase may, therefore, have therapeutic value for the treatment of prostate cancer associated with mutant KRAS. Citation Format: Mingjia Tan, Qiang Zhang, Yi Sun. SAG/RBX2/ROC2 regulates pancreatic cancer initiation, cystic formation in mice driven by KrasG12D [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 4012.
Abstract 17982: Patterns of 30-Day Readmissions Following Acute Myocardial Infarction in the United States: Analysis of the Nationwide Readmission Database
Authors: Rohan Khera, Snigdha Jain, Ambarish Pandey, Nilay Kumar, Saket Girotra
Journal: Circulation (2016)

Background: Readmissions following an acute myocardial infarction (AMI) are common among Medicare beneficiaries (≥65 years), and associated with significant costs to the health care system. However...
Abstract 5891: ABCG2 expression contributes to CC-115 resistance
Authors: Jenny Beebe
Journal: Cancer Research (2018)

Abstract Introduction: A major obstacle in the treatment of cancers is innate or acquired resistance. Multi-drug resistance proteins such as MDR1, ABCG2, MRP1, and LRP have been shown to be involved in resistance and are predictors of clinical outcomes. Expression of ABCG2, an ATP-binding cassette efflux transporter, may be responsible for observed variability of the efficacy of CC-115, a dual mTOR/DNA-PK inhibitor, currently in clinical trials. Here we evaluate the role of ABCG2 in CC-115 resistance. Methods: Western blots, methylene blue and MTT assays, and FACS were used to determine ABCG2 expression, cell survival/viability with and without inhibitors, and accumulation of CC-115 respectively. Results: MCF7/AdVp3000 (M3K) cells have been shown to have a significant increase in ABCG2 as compared to parental MCF7 cells. M3K cells had a 50-fold increase in IC50 to CC-115 compared to MCF7. Use of ABCG2 inhibitors FTC and C8 (1uM), decreased the IC50 of CC-115 in M3K cells by 10-fold. Accumulation studies using FACS showed that M3K cells had significantly lower accumulation of CC-115 as compared to MCF7 and addition of FTC and C8 (1uM) significantly enhanced accumulation of CC-115 to the same extent as seen in MCF7 cells. Next, HEK293/ABCG2 stable clone with overexpression of ectopic ABCG2 and its control HEK293/vec cells were used to determine ABCG2's direct impact on CC-115 resistance. HEK293/ABCG2 cells had a 10-fold increase in resistance to CC-115 with an IC50 of 2.05 uM as compared to 0.23 uM in HEK293/vec cells. Addition of FTC and C8 (1uM) decreased the IC50 by 10-fold in HEK293/ABCG2 cells. Accumulation of CC-115 in HEK293/ABCG2 cells was also significantly lower than that in HEK293/vec cells and addition of FTC and C8 (1uM) significantly increased its accumulation only in HEK293/ABCG2 cells. Discussion: The results from this study suggest that ABCG2 contributes to and possibly is responsible for CC-115 resistance and that inhibiting ABCG2 could lead to reversal of CC-115 resistance, increased response rate, highlights the importance of personalized therapies, and has the potential to increase patient survival. Citation Format: Jenny Beebe. ABCG2 expression contributes to CC-115 resistance [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 5891.
A method of elevated temperatures coupled with magnetic stirring to predict real time release from long acting progesterone PLGA microspheres
Authors: Mingzhu Ye, Hongliang Duan, Lixia Yao, Yicheng Fang, Xiaoyu Zhang, Ling Dong, Feifei Yang, Xinggang Yang, Weisan Pan
Journal: Asian Journal of Pharmaceutical Sciences (2018)

The object of the study was to develop a quick and reproducible accelerated
Regulation of Cardiac Ca2+ Release Channel (Ryanodine Receptor) by Ca2+, H+, Mg2+, and Adenine Nucleotides Under Normal and Simulated Ischemic Conditions
Authors: LeXu, GeoffreyMann, GerhardMeissner
Journal: Circulation Research (1996)

In myocardial ischemia, pHi and [ATP] fall, whereas the free [Ca2+] and [Mg2+] rise. The effects of these changes on cardiac Ca2+ release channel (ryanodine receptor) activity were investigated in [3H]ryanodine binding and single-channel measurements, using isolated membrane and purified channel preparations. In the absence of the two channel ligands Mg2+ and ATP, cardiac Ca2+ release channels were half-maximally activated at pH 7.4 by ≈4 μmol/L cytosolic Ca2+ and half-maximally inhibited by ≈9 mmol/L cytosolic Ca2+. Regulation of channel activity by Ca2+ was modulated by Mg2+ and ATP. Single-channel activities were more sensitive to a change of cytosolic pH than SR lumenal pH. Reduction in lumenal and/or cytosolic pH from 7.3 to 6.5 and 6.0 resulted in decreased single-channel activities without a change in single-channel conductance. [3H]Ryanodine binding measurements also indicated that acidosis impairs cardiac Ca2+ release channel activity. Mg2+ and adenine nucleotide concentrations regulated the exte...
Abstract 3065: Role of noncoding RNA miR 146 alpha and let 7c in epithelial mesenchymal transition, proliferation, and cancer stem cell-like transformation analyzed by gene expression studies in a cohort of prostate cancer patients
Authors: Hirendra N. Banerjee, Fazlul Sarkar, Myla Worthington, Sasha Hodge, Mukesh Verma, Santosh Mandal
Journal: Cancer Research (2018)

Abstract Mir 146 alpha and let 7c are considered tumor suppressor miRs and are responsible for downregulating polycomb repressor proteins like EZH2, SUZ12, etc., and thereby prevent epithelial-mesenchymal transition (EMT),proliferation, spheroid formation and metastasis in prostate cancer cells. In this study, we investigated the role of these microRNAs in a cohort of 105 patients, both White (CA) and African American (AA), by gene expression studies using real-time PCR techniques. Our results showed definite downregulation of these noncoding RNAs in the cDNAs obtained from the matched biopsy samples of normal and cancer tissues. We further transfected these miR full-length constructs in PC3 prostate cancer cell lines and validated their effects by downregulation of their target 3'UTR target mRNAs. Our results showed decrease in EMT markers ALDH, increase in EMT marker E-cadherin, decrease in cell proliferation and spheroid formation; fluorescence microscopy studies showed a decrease in CD44-positive cells in the spheroids, signifying a possible hindrance in the growth of cancer stem cells (CSCs). Thus, miR 146 alpha and let7c could be ideal targets for diagnosis, prognosis and therapeutic intervention. Citation Format: Hirendra N. Banerjee, Fazlul Sarkar, Myla Worthington, Sasha Hodge, Mukesh Verma, Santosh Mandal. Role of noncoding RNA miR 146 alpha and let 7c in epithelial mesenchymal transition, proliferation, and cancer stem cell-like transformation analyzed by gene expression studies in a cohort of prostate cancer patients [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 3065.
Characterization and Changes of Lymphocyte Subsets in Baricitinib‐Treated Patients With Rheumatoid Arthritis
Authors: Yoshiya Tanaka, Iain B. McInnes, Peter C. Taylor, Nicole L. Byers, Lei Chen, Stephanie de Bono, Maher Issa, William L. Macias, Veronica Rogai, Terence P. Rooney, Douglas E. Schlichting, Steven H. Zuckerman, Paul Emery
Journal: Arthritis & Rheumatology (2018)

Objective Baricitinib is an orally administered inhibitor of JAK1 and JAK2 that has been shown to be effective in treating rheumatoid arthritis ( RA ). This study was undertaken to analyze changes in lymphocyte cell subsets during baricitinib treatment and to correlate these changes with clinical outcomes. Methods An integrated analysis was conducted by pooling data from 3 completed phase III trials comparing placebo with baricitinib treatment ( RA ‐ BEAM , RA ‐ BUILD , and RA ‐ BEACON ) and 1 ongoing long‐term extension study ( RA ‐ BEYOND ) in patients with active RA (n = 2,186). Results Baricitinib treatment was associated with an early transient increase in total lymphocyte count at week 4, which returned to baseline by week 12. Transient changes within normal reference ranges in T cells and subsets were observed with baricitinib treatment, up to week 104. B cells and relevant subpopulations increased after 4 weeks of baricitinib treatment, with no further increases noted through 104 weeks of treatment. Natural killer ( NK ) cells temporarily increased after 4 weeks of baricitinib treatment, before decreasing below baseline levels and then stabilizing over time. With baricitinib treatment, few correlations were observed between changes in lymphocyte subsets and clinical end points, and most correlations were also observed within the placebo group. A modest potential association between low NK cell numbers and treatment‐emergent infections was observed in the baricitinib 4 mg/day treatment group, but not for serious infections or herpes zoster. Conclusion Overall, these findings demonstrate that changes in lymphocyte subsets were largely within normal reference ranges across the baricitinib phase III RA clinical program and were not associated with increased risk of serious infections.
Recombinant Hirudin in Clinical Practice
Authors: AndreasGreinacher, NorbertLubenow
Journal: Circulation (2001)

Abstract—Clinical applications for recombinant hirudins have been investigated for the past 10 years. The first indication for which a hirudin—lepirudin—has been approved is treatment of heparin-induced thrombocytopenia (HIT). Also, the recently completed trials for use of lepirudin in unstable angina indicate a potentially new indication. This review describes pharmacology and clinical applications of lepirudin with an emphasis on HIT and unstable angina. An overview of usage of lepirudin in acute coronary syndromes is given, as well as a summary of rare indications for lepirudin, such as extracorporeal circulation, for which comprehensive data are lacking.
Association of frailty with short-term outcomes, organ support and resource use in critically ill patients
Authors: Fernando G. Zampieri, Theodore J. Iwashyna, Elizabeth M. Viglianti, Leandro U. Taniguchi, William N. Viana, Roberto Costa, Thiago D. Corrêa, Carlos Eduardo N. Moreira, Marcelo O. Maia, Giulliana M. Moralez, Thiago Lisboa, Marcus A. Ferez, Carlos Eduardo F. Freitas, Clayton B. de Carvalho, Bruno F. Mazza, Mariza F. A. Lima, Grazielle V. Ramos, Aline R. Silva, Fernando A. Bozza, Jorge. I. F. Salluh, Marcio Soares
Journal: Intensive Care Medicine (2018)
Abstract 15645: Carotid Artery Stenting and Endarterectomy in Patients With Stage 5 Chronic Kidney Disease: Insights of the Healthcare Cost and Utilization Project’s National Inpatient Sample
Authors: Fabio V Lima, Tzyy Y Yen, Luis Gruberg
Journal: Circulation (2015)

Background: Carotid artery stenting (CAS) has evolved into a viable alternative for the treatment of symptomatic and asymptomatic high-grade carotid artery stenosis, particularly in patients considered to be at a high surgical risk for carotid endarterectomy (CEA). Hypothesis: There is limited data on the outcomes of patients with stage 5 chronic kidney disease (CKD) (GFR&lt;15 mL/min/1.73 m 2 or dialysis) undergoing CEA or CAS. Methods: The Healthcare Cost and Utilization Project’s National Inpatient Sample was screened for hospital admissions of patients undergoing CAS and CEA from 2003-2012. Baseline clinical characteristics and outcomes were identified in patients with stage 5 CKD. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as the composite of in-hospital death, acute myocardial infarction and acute cerebrovascular accident (CVA). Results: Our study population consisted of 1,723 patients that underwent CEA and 544 patients that underwent CAS. Patients undergoing CAS were younger and had significantly lower rates of coronary artery disease, hypertension and hyperlipidemia. CAS patients experienced significantly higher rates of MACCE compared with patients that underwent CEA, mainly driven by a higher rate of in-hospital strokes (Fig. 1). In a multivariable analysis, CAS (OR 1.53, 95% CI 1.19-1.98) was an independent predictor of MACCE. Conclusions: In patients with stage 5 CKD (GFR&lt;15 mL/min/1.73 m 2 or dialysis ) undergoing internal carotid artery revascularization, CAS was associated with higher rates of in-hospital MACCE, driven by higher mortality and stroke rates when compared with CEA.
Abstract 550: One enhancer stimulates cancer cells proliferation and metastasis via the regulation of PDL1 expression
Authors: Chunyan Li, Han Chen, Han Liang
Journal: Cancer Research (2018)

Abstract Cancer cells employ multiple mechanisms to evade the recognition by the host immune system, including the expression of the negative T cell regulatory molecule PD-L1. PD-1/PD-L1-mediated immune escape plays key role during cancer development. It is crucial to unravel the regulatory mechanism of PD-1/PD-L1. In this study, we seek one enhancer (we named “enh9”) that regulates the transcription of PD-L1 by systematic exploration. First, we found that PD-L1 and enh9 were co-expressed in multiple cancer types, including both lung adenocarcinoma and lung squamous cell carcinoma, which was further validated in a cohort of 130 lung cancer cell lines from the Cancer Cell Line Encyclopedia database. Then the direct interaction between PD-L1 and enh9 was further confirmed by Hi-C dataset. To validate the transcriptional regulation of PD-L1 by enh9, we knocked out enh9 using CRISPRi (CRISPR/ clustered regularly interspaced short palindromic repeats interference) in lung adenocarcinoma cell line A549, and single cell clones with double-copy deletion of enh9 were screened out. The expression of PD-L1 was dramatically reduced at both mRNA and protein level in enh9 knockout cells. Furthermore, we found that the cell proliferation and metastasis of enh9 knockout cells were significantly decreased compared to the control cells. Based on the previous studies that PD-L1 intrinsically regulated cancer cells' proliferation in ovarian and melanoma cancer cells, ongoing work is to determine whether enh9 regulates the cancer cell hallmarks by direct regulation of the expression of PD-L1 in lung cancer cells. The regulatory mechanisms will be deeply studied. In conclusion, we found an enhancer regulated the expression of PD-L1, which was one famous immune checkpoint, and it may play key roles in the cancer cell hallmarks. Citation Format: Chunyan Li, Han Chen, Han Liang. One enhancer stimulates cancer cells proliferation and metastasis via the regulation of PDL1 expression [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 550.