tbuckley/cabot-search huggingface dataset:
Abstract 996: Host-derived MCP-1 dictates prostate cancer skeletal metastasis in vivo
Authors: Jie Meng, Weiping Liang, Haibo Tong, Evan T. Keller, Jian Zhang, Yi Lu
Journal: Cancer Research (2018)

Abstract Overexpression of the tumor-derived monocyte chemotactic protein-1 (MCP-1) has been suggested to partially promote prostate cancer bone metastasis, but the function for host-derived MCP-1 in these processes is not well established. To understand the function of host-derived MCP-1 on bone metastasis, we developed a mouse model using intracardiac injection and in vivo selection to obtain tumor cell subpopulations with a higher propensity for bone metastasis. Here, we found that a loss of host MCP-1 (MCP-1 knockout) retarded tumor growth in bone and prolonged survival of mice by intracardiac injection of tumor cells in vivo. Moreover, a decrease in osteolytic bone lesion was observed in MCP-1 knockout mice by bone density analysis, as compared to wild-type control. Systemically, MCP-1 deficiency inhibited the proportion of PMN-and M-MDSC populations with immunosuppressive function. Together, this study indicates that the dysregulated immunity resulting from a loss of host MCP-1 signaling is sufficient to drive PCa bone metastasis, and provides a new perspective for targeting the endogenous MCP-1 pathway as an antimetastatic strategy. Supported by NSFC Key Project 81130046; NSFC projects 81773146, 81272415; JCYJ20170412152943794, JCYJ20170412154619484, JCYJ20170307105128101, JCYJ2017030711041760; Guangxi Key Projects 2013GXNSFEA053004. Citation Format: Jie Meng, Weiping Liang, Haibo Tong, Evan T. Keller, Jian Zhang, Yi Lu. Host-derived MCP-1 dictates prostate cancer skeletal metastasis in vivo [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 996.
Abstract 17484: MG53 Modulates KChIP2 Expression through Regulation of NF-κB Activity
Authors: WenjuanLiu, CuicuiZhang, JianxinDeng, jieliu
Journal: Circulation (2014)

Background: The fast transient outward K+ current (Ito,f) is an important repolarizing component in heart. Ito,f is formed by specific interaction of the pore-forming Kv4-subunits and obligatory ancillary subunits K+ channel interacting protein 2 (KChIP2). Recent study shows that MG53, a muscle-specific TRIM-family protein is critical for maintaining cardiac electrical stability. In this study, we investigated the possible role of MG53 in regulation of Ito,f activity and the underlying mechanisms. Methods: Bidirectional manipulations of MG53 expression were performed by adenoviral overexpression of MG53 or knockdown of MG53 with RNA interference in neonatal and adult rat ventricular myocytes. Ito,f was recorded with patch clamp in whole-cell mode 48 h after adenoviral transfection. Results: Overexpression of MG53 by 100% increased the amplitude of Ito,f by 112%, whereas knockdown of MG53 by 58% decreased it by 38% in neonatal cardiomyocytes. MG53 overexpression slowed the kinetics of inactivation and posi...
Abstract 16699: Chitinase-3-like-1 Reduces Reparative Inflammatory Cells and Exacerbates Cardiac Dysfunction After Myocardial Infarction
Authors: Sujith Dassanayaka, Senthilkumar Muthusamy, Yi Kang, Hong Li, Steven P Jones, Marcin Wysoczynski
Journal: Circulation (2016)

Introduction: Chitinase-3-like-1 (CHI3L1), a putative marker of inflammation and acute-phase reactant, is upregulated in human heart failure. Although elevated CHI3L1 serum levels correlate with ca...
<i>BMI1</i> Drives Metastasis of Prostate Cancer in Caucasian and African-American Men and Is A Potential Therapeutic Target: Hypothesis Tested in Race-specific Models
Authors: Arsheed A. Ganaie, Firdous H. Beigh, Matteo Astone, Marina G. Ferrari, Raihana Maqbool, Syed Umbreen, Aijaz S. Parray, Hifzur R. Siddique, Tabish Hussain, Paari Murugan, Colm Morrissey, Shahriar Koochekpour, Yibin Deng, Badrinath R. Konety, Luke H. Hoeppner, Mohammad Saleem
Journal: Clinical Cancer Research (2018)

Metastasis is the major cause of mortality in prostate cancer patients. Factors such as genetic makeup and race play critical role in the outcome of therapies. This study was conducted to investigate the relevance of BMI1 in metastatic prostate cancer disease in Caucasian and African-Americans.We employed race-specific prostate cancer models, clinical specimens, clinical data mining, gene-microarray, transcription-reporter assay, chromatin-immunoprecipitation (ChIP), IHC, transgenic-(tgfl/fl) zebrafish, and mouse metastasis models.BMI1 expression was observed to be elevated in metastatic tumors (lymph nodes, lungs, bones, liver) of Caucasian and African-American prostate cancer patients. The comparative analysis of stage III/IV tumors showed an increased BMI1 expression in African-Americans than Caucasians. TCGA and NIH/GEO clinical data corroborated to our findings. We show that BMI1 expression (i) positively correlates to metastatic (MYC, VEGF, cyclin D1) and (ii) negative correlates to tumor suppressor (INKF4A/p16, PTEN) levels in tumors. The correlation was prominent in African-American tumors. We show that BMI1 regulates the transcriptional activation of MYC, VEGF, INKF4A/p16, and PTEN. We show the effect of pharmacological inhibition of BMI1 on the metastatic genome and invasiveness of tumor cells. Next, we show the anti-metastatic efficacy of BMI1-inhibitor in transgenic zebrafish and mouse metastasis models. Docetaxel as monotherapy has poor outcome on the growth of metastatic tumors. BMI1 inhibitor as an adjuvant improved the taxane therapy in race-based in vitro and in vivo models.BMI1, a major driver of metastasis, represents a promising therapeutic target for treating advanced prostate cancer in patients (including those belonging to high-risk group).
Correspondence to viewpoint ‘Defining refractory rheumatoid arthritis’ by Buch
Authors: Nadia MT Roodenrijs, Maria JH de Hair, Marlies C van der Goes, Johannes WG Jacobs
Journal: Annals of the Rheumatic Diseases (2018)

With great interest, we read the clinically highly relevant viewpoint on ‘Defining refractory rheumatoid arthritis’ by Professor Maya H. Buch.1 The author classifies refractory rheumatoid arthritis (RA) into ‘intrinsic refractory’ (persistent inflammation, no antidrug antibodies (ADA)), ‘pharmacokinetic refractory’ (persistent inflammation, presence of ADA) or ‘false positive refractory’ (no persistent inflammation, no ADA). Professor Buch highlights the gap of knowledge in the understanding of refractory RA and states that consistent definitions and criteria are required for future research. We fully agree with the author that this subpopulation of patients with RA is facing unmet needs, …
Treatment of Acute Myocardial Infarction by Primary Coronary Angioplasty or Intravenous Thrombolysis in the “Real World”
Authors: NicolasDanchin, LaurentVaur, NathalieGenès, SylvieEtienne, MichaëlAngioï, JeanFerrières, Jean-PierreCambou
Journal: Circulation (1999)

Background—Recent randomized trials comparing primary coronary angioplasty and intravenous thrombolysis at the acute stage of myocardial infarction have shown a limited but definite advantage for primary angioplasty. The aim of this study was to document 1-year outcome in patients receiving either thrombolysis or primary angioplasty for acute myocardial infarction in the “real world.” Methods and Results—We used a nationwide prospective registry of all patients admitted for acute myocardial infarction in French intensive care units in November 1995. Of the 721 patients who received reperfusion therapy, 152 were treated with primary angioplasty and 569 received intravenous thrombolysis. The two groups were remarkably similar with respect to all baseline descriptors, except that a higher proportion of patients in the angioplasty group had a history of cerebrovascular accident (10% versus 2%, P<0.01). In-hospital outcome was not different in the 2 groups. One-year survival was 85.5% in the angioplasty group ...
Abstract 12845: Renal Biomarkers Predict Long-Term Adverse Events in Patients With Type 2 Diabetes Mellitus and Recent Acute Coronary Syndrome: Insights From the EXAMINE Trial
Authors: Muthiah Vaduganathan, William B White, David M Charytan, David A Morrow, Yuyin Liu, Craig Wilson, Stuart Kupfer, Faiez Zannad, Christopher P Cannon, George L Bakris
Journal: Circulation (2016)

Introduction: Prediction of cardiovascular (CV) risk in patients with type 2 diabetes mellitus (T2DM) remains incomplete. Measurement of renal biomarkers may facilitate early risk stratification in high-risk patients with T2DM. Methods: We evaluated the prognostic performance of 4 urinary and 1 serum renal biomarkers for major cardiovascular events in 5,380 patients with T2DM and recent acute coronary syndrome (ACS, within 15-90d) enrolled in the EXAMINE trial. Patients requiring dialysis within 14d of screening were excluded. Cystatin C, markers of kidney injury, including neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule (KIM)-1 protein, and indices of urinary protein excretion were measured at randomization (a median of 45 days after ACS). CV events at 24-mo were estimated by the Kaplan-Meier method. Single- and multi-biomarker covariate-adjusted Cox proportional hazards models were created to predict times to events. Results: In EXAMINE, median age was 61y, 68% were male, and median baseline estimated glomerular filtration rate (eGFR) was 71.2 ml/min/1.73 m 2 . During follow-up, 326 (6.1%) patients had died. All renal biomarkers were robustly associated with long-term adverse CV events in graded fashion (P≤0.006 for all trends; Table ). Risk prediction for all 5 renal biomarkers was independent of major covariates including baseline eGFR for all major clinical endpoints ( Table ). However, when simultaneously accounting for all biomarkers, only Cystatin C (standardized) was predictive of all-cause mortality (HR 1.51 [1.30, 1.74]; p≤0.001), heart failure hospitalization (HR 1.20 [0.96, 1.49]; p=0.107), and major CV events (HR 1.28 [1.14, 1.45]; p≤0.001). Conclusions: These data from the EXAMINE trial represent one of the largest experiences to support the prognostic value of multiple novel and traditional renal biomarkers in predicting long-term adverse CV events in high-risk patients with T2DM, beyond baseline eGFR.
Long-Term Clinical Outcome of Major Adverse Cardiac Events in Survivors of Infective Endocarditis
Authors: Chia-JenShih, HsiChu, Pei-WenChao, Yi-JungLee, Shu-ChenKuo, Szu-YuanLi, Der-CherngTarng, Chih-YuYang, Wu-ChangYang, Shuo-MingOu, Yung-TaiChen
Journal: Circulation (2014)

Background—Substantial infective endocarditis (IE)–related morbidity and mortality may occur even after successful treatment. However, no previous study has explored long-term hard end points (ie, stroke, myocardial infarction, heart failure, cardiovascular death) in addition to all-cause mortality in IE survivors. Methods and Results—A nationwide population-based cohort study was conducted among IE survivors identified with the use of the Taiwan National Health Insurance Research Database during 2000 to 2009. IE survivors were defined as those who survived after discharge from first hospitalization with a diagnosis of IE. A total of 10 116 IE survivors were identified. IE survivors were matched to control subjects without IE at a 1:1 ratio through the use of propensity scores. The primary outcomes were stroke, myocardial infarction, readmission for heart failure, and sudden cardiac death or ventricular arrhythmia. The secondary outcomes were repeat IE and all-cause mortality. Compared with the matched co...
Abstract 1041: XenofilteR: Computational dissection of mouse and human reads in PDX and xenograft sequence data
Authors: Oscar Krijgsman, Roelof JC Kluin, Kristel Kemper, Thomas Kuilman, Julian R. de Ruiter, Vivek Iyer, Josep V. Forment, Paulien Cornelissen-Steijger, Iris de Rink, Petra ter Brugge, Ji-Ying Song, Sjoerd Klarenbeek, Ultan McDermott, Jos Jonkers, Arno Velds, David J. Adams, Daniel S. Peeper
Journal: Cancer Research (2018)

Abstract Mouse xenografts from (patient-derived) tumors (PDX) or tumor cell lines are widely used as models to study various biological and preclinical aspects of cancer. However, analysis of their RNA and DNA profiles is challenging, because they comprise reads not only from the grafted human cancer but also from the murine host. The reads of murine origin can result both in the generation of false positives in mutation analysis of DNA samples and obscure gene expression levels when sequencing RNA. Therefore, we developed the open-source R-package XenofilteR, which separates mouse from human sequence reads based on the number of discordant base pairs between each read and the reference genomes. To assess the accuracy of XenofilteR, we generated sequence data by in silico mixing of mouse and human whole genome and whole exome DNA sequence data. This analysis revealed that XenofilteR removes &amp;gt;99.9% of sequence reads of mouse origin while retaining sequence reads of human origin. The filtering allowed for mutation analysis of PDX samples with accurate variant allele frequencies, and retrieved all non-synonymous somatic mutations present in the original tumor. These findings were further validated in breast cancer and melanoma PDX samples, confirming the retrieval of accurate variant allele frequencies and somatic mutations. In conclusion, XenofilteR accurately dissects sequence reads from mouse and human origin in PDX sequence data, thereby outperforming currently available tools. Citation Format: Oscar Krijgsman, Roelof JC Kluin, Kristel Kemper, Thomas Kuilman, Julian R. de Ruiter, Vivek Iyer, Josep V. Forment, Paulien Cornelissen-Steijger, Iris de Rink, Petra ter Brugge, Ji-Ying Song, Sjoerd Klarenbeek, Ultan McDermott, Jos Jonkers, Arno Velds, David J. Adams, Daniel S. Peeper. XenofilteR: Computational dissection of mouse and human reads in PDX and xenograft sequence data [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 1041.
Recurrent hypoglycemia inhibits the counterregulatory response by suppressing adrenal activity
Authors: Yunbing Ma, Qian Wang, Debria Joe, Manqi Wang, Matthew D. Whim
Journal: Journal of Clinical Investigation (2018)

Hypoglycemia activates the counterregulatory response (CRR), a neural-endocrine reflex that restores euglycemia. Although effective if occasionally activated, repeated induction of the CRR leads to a decline in responsiveness and prolonged exposure to hypoglycemia. The mechanism underlying this impairment is not known. We found that the reduction in epinephrine release that characterizes a suppressed CRR involves a long-lasting form of sympatho-adrenal synaptic plasticity. Using optogenetically evoked catecholamine release, we show that recurrent hypoglycemia reduced the secretory capacity of mouse adrenal chromaffin cells. Single activation of the CRR increased the adrenal levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine synthesis, but this was prevented by repeated activation. In contrast, the level of neuropeptide Y (NPY), an adrenal cotransmitter, remained elevated after recurrent hypoglycemia. Inhibition of NPY or Y1 signaling, either transgenically or pharmacologically, prevented the attenuation of both TH expression and epinephrine release. These results indicate that impairment of the CRR involves suppressed activity at the adrenal level. Interfering with the peripheral NPY-dependent negative feedback loop may provide a way to avoid the pathophysiological consequences of recurrent hypoglycemia which are common in the diabetic state.
Abstract 3475: Novel correlation-based network analysis of breast tumor metabolism identifies the glycerol channel protein Aquaporin-7 as a regulator of breast cancer metastasis
Authors: Chen Dai, Jennifer Arceo, James Arnold, Junmin Wu, Norman J. Dovichi, Arun Sreekumar, Jun Li, Laurie E. Littlepage
Journal: Cancer Research (2018)

Abstract The complex yet interrelated connections between cancer metabolism, gene expression, and oncogenic driver genes have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. Using GC-MS, LC-MS/MS, and capillary zone electrophoresis (CZE)-MS platforms, we quantified and compared the levels of 374 metabolites in breast tumor tissue from normal tissue and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg). Comparison of the metabolite profiles from the tumors identified oncogene-induced metabolic reprogramming of the tumor tissues. To develop a higher order understanding of the driver genes and metabolites in breast cancer, we next developed a discovery-based correlation network analysis that captured interactions between both metabolite and gene expression data. This analysis uniquely identified a metabolic network of metabolites and genes with prognostic value in breast cancer patients, identifying 35 metabolite and 33 gene hubs that are likely integral to breast tumor metabolism. Further MALDI-MS based imaging revealed heterogeneous distribution of hub metabolites between stromal and epithelial tissue in breast tumors from transgenic mouse models, as well as heterogeneity within the tumor epithelium, suggesting complex metabolic landscape even within the tumor epithelium. We initially focused on the gene hub aquaporin-7 (Aqp7), a water and glycerol channel protein, as a novel regulator of breast cancer. AQP7 deficiency in animal models is associated with adipocyte hypertrophy, increased glycerol and triglyceride accumulation, insulin resistance, and obesity. We discovered that AQP7 is a prognostic marker of overall survival and metastasis in breast cancer patients. Aqp7 is expressed in the epithelium and adipocytes in normal and tumor breast tissue. Reduced Aqp7 expression in mouse breast cancer cells decreased both proliferation and lung metastatic burden. These data suggest AQP7 promotes invasive phenotypes of breast cancer progression. Using an unbiased, discovery-based approach, this study shed light on important players in breast cancer metabolism from a new perspective that complements current guided network analyses. Citation Format: Chen Dai, Jennifer Arceo, James Arnold, Junmin Wu, Norman J. Dovichi, Arun Sreekumar, Jun Li, Laurie E. Littlepage. Novel correlation-based network analysis of breast tumor metabolism identifies the glycerol channel protein Aquaporin-7 as a regulator of breast cancer metastasis [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 3475.
Abstract 1135: SOX9 regulates cancer stem-like cells and chemotherapy response in non-small cell lung cancer
Authors: Maria Voronkova, Sudjit Luanpitpong, Yon Rojanasakul
Journal: Cancer Research (2018)

Abstract Lung cancer is the leading cause of cancer-related death worldwide in both men and women. A major limitation of the lung cancer chemotherapy effectiveness is drug resistance and tumor relapse, which both have been attributed to the acquisition of cancer stem-like cells (CSCs). Thus, it is crucial to identify specific markers and drug targets for this cell population. Our work is focused on the embryonic transcription factor SOX9, which has been implicated in CSC regulation in a number of cancer types, but little is known about its role in non-small cell lung cancer (NSCLC), the predominant type of lung cancer. In addition, the regulatory mechanisms and downstream targets of SOX9 as well as its role in chemoresistance are largely unknown. We hypothesized that SOX9 plays a key role in lung cancer progression and chemoresistance by stimulating cancer stem-like properties. To test this hypothesis, we genetically manipulated SOX9 expression in various NSCLC cell lines and evaluated its effects on CSC formation, biomarkers expression, and drug resistance. Our results showed that SOX9 depletion decreases the number of tumor spheres formed by NSCLC cells, thus supporting its role in CSC regulation in lung cancer. We also showed that SOX9 depletion dramatically downregulates the expression of a functional CSC regulator ALDH1A1. Consistent with this finding, SOX9 overexpression in non-cancer lung epithelial cells promotes tumor sphere formation. Moreover, we noticed that SOX9 expression goes up in response to chemotherapy exposure. Notably, SOX9 knockdown increases cell sensitivity to the chemotherapeutic cisplatin, whereas SOX9 overexpression decreases it. Depletion of SOX9 also increases CSC sensitivity to cisplatin, as demonstrated by the tumor sphere formation assay. Analysis of the Cancer Genome Atlas (TCGA) data showed that high SOX9 expression correlates with poor survival in NSCLC patients. Taken together, our results indicate the essential role of SOX9 in the regulation of CSCs in NSCLC. Since CSCs are a key driver of chemoresistance and relapse, our findings may have important implications in the development of novel therapeutic strategies for chemoresistant and recurrent lung cancer. Citation Format: Maria Voronkova, Sudjit Luanpitpong, Yon Rojanasakul. SOX9 regulates cancer stem-like cells and chemotherapy response in non-small cell 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 1135.