tbuckley/cabot-search huggingface dataset:
Overexpression of amplified in breast cancer 1 (<i>AIB1</i> ) gene promotes lung adenocarcinoma aggressiveness in vitro and in vivo by upregulating C-X-C motif chemokine receptor 4
Authors: Liru He, Haixia Deng, Shiliang Liu, Jiewei Chen, Binkui Li, Chenyuan Wang, Xin Wang, Yiguo Jiang, Ningfang Ma, Mengzhong Liu, Dan Xie
Journal: Cancer Communications (2018)

We previously found that overexpression of the gene known as amplified in breast cancer 1 (AIB1) was associated with lymph node metastasis and poor prognosis in patients with lung adenocarcinoma. However, the role of AIB1 in that malignancy remains unknown. The present study aimed to investigate the function of AIB1 in the process of lung adenocarcinoma cell metastasis.A series of in vivo and in vitro assays were performed to elucidate the function of AIB1, while real-time PCR and Western blotting were utilized to identify the potential downstream targets of AIB1 in the process of lung adenocarcinoma metastasis. Rescue experiments and in vitro assays were performed to investigate whether the invasiveness of AIB1-induced lung adenocarcinoma was mediated by C-X-C motif chemokine receptor 4 (CXCR4).The ectopic overexpression of AIB1 in lung adenocarcinoma cells substantially enhanced cell migration and invasive abilities in vitro and tumor metastasis in vivo, whereas the depletion of AIB1 expression substantially inhibited lung adenocarcinoma cell migration and invasion. CXCR4 was identified as a potential downstream target of AIB1 in lung adenocarcinoma. The knockdown of AIB1 greatly reduced CXCR4 gene expression at both the transcription and protein levels, whereas the knockdown of CXCR4 in cells with AIB1 ectopic overexpression diminished AIB1-induced migration and invasion in vitro and tumor metastasis in vivo. Furthermore, we found a significant positive association between the expression of AIB1 and CXCR4 in lung adenocarcinoma patients (183 cases), and the co-overexpression of AIB1 and CXCR4 predicted the poorest prognosis.These findings suggest that AIB1 promotes the aggressiveness of lung adenocarcinoma in vitro and in vivo by upregulating CXCR4 and that it might be usable as a novel prognostic marker and/or therapeutic target for this disease.
Abstract P058: Serum Fibroblast Growth Factor-23 Does Not Have a Linear Relation to Cardiovascular Mortality
Authors: Karl Krupp, Emir Veledar, Purnima Madhivanan, Robert Cook, Khurram Nasir
Journal: Circulation (2015)

Introduction: Fibroblast Growth Factor 23 (FGF23) is bone-derived hormone regulating phosphate homeostasis as part of a newly described bone-kidney axis. Several studies have demonstrated that elevated circulating FGF23 levels are independently associated with cardiovascular mortality. Methods: A systematic review was conducted according to Meta-analysis of Observational Studies in Epidemiology Group guidelines. Six databases (PubMed-Central, Ovid-MEDLINE, EMBASE, Web of Science, BIOSIS and Cochrane Database of Systematic Reviews) were searched for articles published between 2000 and 2014 examining the longitudinal association between FGF23 and CVD mortality among populations without prior CVD, Chronic Kidney Disease, or Diabetes. The review yielded 1,961 articles, of which 982 met the inclusion criteria. About 893 abstracts were excluded during the title and abstract screen, and an additional 92 after full text review. Only three articles met the review criteria and were included in the meta-analysis. Data from selected articles were abstracted and independently assessed for quality by two reviewers. Summary estimates and associated 95% confidence intervals were included in fixed and random-effects models. The presence of heterogeneity was evaluated using a Q-statistic with a conservative p-value of 0.10. All analyses were performed using R library meta. Results: Data for 15,379 participants were included in the meta-analysis. The hazard ratio for quartiles two and four when compared with quartile one,the reference category, were 1.29 (1.06- 1.58; p=0.01) and 1.31 (1.077-1.59; p=0.0068) respectively. There was no significant difference in CVD mortality between the third and first quartile. There was also no evidence of heterogeneity observed (I2 = 0%, p = 0.611). Conclusions: This study found a U-shaped association between FGF23 and CVD mortality suggesting that either low or high serum levels increase risk for CVD mortality. Current strategies focus on lowering high levels of circulating FGF23, but little attention has been given to understanding optimal levels necessary to prevent CVD mortality. If this U-shaped relationship between FGF23 and CVD mortality is real, the possible links, causes, and mechanisms require additional research.
Distinct genomic profile and specific targeted drug responses in adult cerebellar glioblastoma
Authors: Hee Jin Cho, Junfei Zhao, Sang Won Jung, Erik Ladewig, Doo-Sik Kong, Yeon-Lim Suh, Yeri Lee, Donggeon Kim, Sun Hee Ahn, Mykola Bordyuh, Hyun Ju Kang, Jason K Sa, Yun Jee Seo, Sung Tae Kim, Do Hoon Lim, Yun-Sik Dho, Jung-Il Lee, Ho Jun Seol, Jung Won Choi, Woong-Yang Park, Chul-Kee Park, Raul Rabadan, Do-Hyun Nam
Journal: Neuro-Oncology (2018)

Despite extensive efforts on the genomic characterization of gliomas, very few studies have reported the genetic alterations of cerebellar glioblastoma (C-GBM), a rare and lethal disease. Here, we provide a systematic study of C-GBM to better understand its specific genomic features.We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies with supratentorial glioblastoma (S-GBM). To uncover the molecular characteristics, we performed DNA and mRNA sequencing and DNA methylation arrays on 19, 6, and 4 C-GBM cases, respectively. Moreover, chemical drug screening was conducted to identify potential therapeutic options for C-GBMs.Despite differing anatomical origins of C-GBM and S-GBM, neither histological, cytological, nor patient demographics appeared significantly different between the 2 types. However, we observed striking differences in mutational patterns, including frequent alterations of ATRX, PDGFRA, NF1, and RAS and absence of EGFR alterations in C-GBM. These results show a distinct evolutionary path in C-GBM, suggesting specific therapeutic targeted options. Targeted-drug screening revealed that C-GBMs were more responsive to mitogen-activated protein kinase kinase (MEK) inhibitor and resistant to epidermal growth factor receptor inhibitors than S-GBMs. Also, differential expression analysis indicated that C-GBMs may have originated from oligodendrocyte progenitor cells, suggesting that different types of cells can undergo malignant transformation according to their location in brain. Master regulator analysis with differentially expressed genes between C-GBM and proneural S-GBM revealed NR4A1 as a potential therapeutic target.Our results imply that unique gliomagenesis mechanisms occur in adult cerebellum and new treatment strategies are needed to provide greater therapeutic benefits for C-GBM patients.1. Distinct genomic profiles of 19 adult cerebellar GBMs were characterized. 2. MEK inhibitor was highly sensitive to cerebellar GBM compared with supratentorial GBM. 3. Master regulator analysis revealed NR4A1 as a potential therapeutic target in cerebellar GBM.
Human Cardiac Troponin T: Cloning and Expression of New Isoforms in the Normal and Failing Heart
Authors: LaurenceMesnard, DamienLogeart, SylvieTaviaux, SylvieDiriong, Jean-JacquesMercadier, FrançoiseSamson
Journal: Circulation Research (1995)

Abstract Troponin T, like many myofibrillar proteins, exists as multiple isoforms encoded by distinct genes or generated by splicing of the same primary RNA transcript. We have previously cloned the first human cardiac troponin T (cTnT) cDNA and showed the differential expression of cTnT in cardiac and skeletal muscle during ontogenic development. In this work we located the human cTnT gene by means of fluorescent in situ hybridization to 1q32 and, by sequencing thirteen cDNAs isolated from a human fetal heart cDNA library, identified three new isoforms resulting from specific combinations of three variable regions in human cTnT cDNA. The first variable region is a 30-bp box located at the 5′ end of the cDNA, which can be excised either totally or only from the first 3 bp onwards; the second is a codon which can be completely excised; and the third is a 9-bp box in the 3′ half of the cDNA, which can also be excised either totally or only from the first 3 bp. The existence of the corresponding RNAs in feta...
Paradoxical Effects of Epinephrine on Excitation-Contraction Coupling in Cardiac Muscle
Authors: FredericKavaler, MartinMorad
Journal: Circulation Research (1966)

The possibility that the inotropic action of epinephrine might be mediated through an effect on the excitation-contraction coupling process was explored, using techniques for measurement of isometric tension, together, in some experiments, with recording of the transmembrane potential time course from short lengths of cat papillary muscle. Four observations relevant to this question, have been made: (1) Extracellular calcium concentration can be raised and extracellular sodium concentration lowered to a point at which contraction cannot be further augmented by the addition of epinephrine. (2) The early relaxation induced by epinephrine occurs well in advance of membrane repolarization. This effect is antagonized by increasing calcium concentration, although the action of epinephrine in augmenting developed tension appears to be synergistic with that of calciumion. (3) The length-tension relationship is undiminished in the calcium-rich (8.1 mmoles /liter), sodium-poor (75 mEq/liter) medium. (4) Epinephrine...
Abstract 9597: Differential Effects of Strong and Regular Statins on Clinical Outcome in Patients With Chronic Kidney Disease Following Coronary Stent Implantation - The Kumamoto Intervention Conference Study (kics) Registry -
Authors: Masanobuishii, SeijiHokimoto, TomonoriAkasaka, KoichiKaikita, HisaoOgawa
Journal: Circulation (2014)

Introduction: Practice guidelines recommend the use of intensive statin treatment for secondary prevention in high-risk patients with clinical atherosclerotic cardiovascular disease regardless of the value of LDL-C. Objectives: The aim of this study was to examine the effects of different statins on the clinical outcome of Japanese patients with coronary stent implants. Methods: This prospective study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with either strong statins (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). Clinical events were monitored and compared between the two groups and patients were followed up for 12 months. Primary endpoints included cardiovascular death, nonfatal MI, including stent thrombosis and ischemic stroke. Results: Compared with regular stati...
Abstract 4761: Joint model of longitudinal tumor size and overall survival (OS) in non-small cell lung cancer (NSCLC): A Bayesian approach
Authors: Nidal Al-Huniti, Hongmei Xu, Diansong Zhou, Helena Edlund, Sergey Aksenov, Gabriel Helmlinger, James Dunyak
Journal: Cancer Research (2018)

Abstract Objective: The methodology of joint modeling longitudinal tumor size and OS data is very promising and provides the opportunity of survival prediction in individual patients. However, current joint modeling software are restricted in terms of distributions/parameterizations available and non-linear mixed effects models are not supported. The objective of this work was to develop a joint model in Bayesian framework to relax these restrictions and enable investigation of additional (continuous and/or discrete) biomarkers. Methods: Longitudinal tumor size and OS data from gefitinib Phase 3 study in NSCLC (‘IPASS', NCT00322452) was used in the modeling analysis. Joint model was developed in JM package in R and the Bayesian formulation of the joint modeling was implemented in STAN. Different parametrizations were investigated for both sub-models and the impact of lag-times was explored. The parameter estimates and model fit were compared between models by JM package and STAN. The final Bayesian joint model was validated on an independent dataset from a Phase 4 study (‘IFUM', NCT01203917, EGFR positive patients only) by simulating individual survival based on their tumor size data and compared with observed survival. Results: The estimated parameter values were similar to those from the fit from JM package. The different parametrizations provided similar fits for the tumor size model, while the survival model was improved by using a b-spline model. The association parameters indicate a strong association between tumor size and survival and introduction of lag-times did not impact the association parameters to a great extent. Posterior predictive simulations of OS in phase 4 study were consistent with observed data. Conclusions: Bayesian formulation further improved the joint model of tumor size and OS which would enable investigation of additional biomarkers (e.g. new lesions). Citation Format: Nidal Al-Huniti, Hongmei Xu, Diansong Zhou, Helena Edlund, Sergey Aksenov, Gabriel Helmlinger, James Dunyak. Joint model of longitudinal tumor size and overall survival (OS) in non-small cell lung cancer (NSCLC): A Bayesian approach [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 4761.
Publisher Correction: Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing
Authors: Xinyi Guo, Yuanyuan Zhang, Liangtao Zheng, Chunhong Zheng, Jintao Song, Qiming Zhang, Boxi Kang, Zhouzerui Liu, Liang Jin, Rui Xing, Ranran Gao, Lei Zhang, Minghui Dong, Xueda Hu, Xianwen Ren, Dennis Kirchhoff, Helge Gottfried Roider, Tiansheng Yan, Zemin Zhang
Journal: Nature Medicine (2018)
Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non–Small Cell Lung Cancer: A Phase Ib Study
Authors: Edward S. Kim, Karen Kelly, Luis G. Paz-Ares, Pilar Garrido, Shadia Jalal, Daruka Mahadevan, Martin Gutierrez, Mariano Provencio, Eric Schaefer, Monte Shaheen, Erica L. Johnston, P. Kellie Turner, Siva Rama Prasad Kambhampati, Richard Beckmann, Anwar Hossain, William J. John, Jonathan W. Goldman
Journal: Clinical Cancer Research (2018)

Purpose: Abemaciclib, a dual inhibitor of cyclin-dependent kinases 4 and 6, has demonstrated preclinical activity in non-small cell lung cancer (NSCLC). A multicenter, nonrandomized, open-label phase Ib study was conducted to test safety, MTD, pharmacokinetics, and preliminary antitumor activity of abemaciclib in combination with other therapies for treatment in patients with metastatic NSCLC.Patients and Methods: An initial dose escalation phase was used to determine the MTD of twice-daily oral abemaciclib (150, 200 mg) plus pemetrexed, gemcitabine, or ramucirumab, followed by an expansion phase for each drug combination. Pemetrexed and gemcitabine were administered according to label. The abemaciclib plus ramucirumab study examined two dosing schedules.Results: The three study parts enrolled 86 patients; all received ≥1 dose of combination therapy. Across arms, the most common treatment-emergent adverse events were fatigue, diarrhea, neutropenia, decreased appetite, and nausea. The trial did not identify an abemaciclib MTD for the combination with pemetrexed or gemcitabine but did so for the combination of abemaciclib with days 1 and 8 ramucirumab (8 mg/kg). Plasma sample analysis showed that abemaciclib did not influence the pharmacokinetics of the combination agents and the combination agents did not affect abemaciclib exposure. The disease control rate was 57% for patients treated with abemaciclib-pemetrexed, 25% for abemaciclib-gemcitabine, and 54% for abemaciclib-ramucirumab. Median progression-free survival was 5.55, 1.58, and 4.83 months, respectively.Conclusions: Abemaciclib demonstrated an acceptable safety profile when dosed on a continuous twice-daily schedule in combination with pemetrexed, gemcitabine, or ramucirumab. Abemaciclib exposures remained consistent with those observed in single-agent studies. Clin Cancer Res; 24(22); 5543-51. ©2018 AACR.
Abstract 723: Targeting phosphorylated p53 to elicit tumor-reactive T helper responses against head and neck squamous cell carcinoma
Authors: Kenzo Ohara, Takumi Kumai, Tatsuya Hayashi, Takayuki Ohkuri, Nobuyuki Bandoh, Hiroya Kobayashi, Yasuaki Harabuchi
Journal: Cancer Research (2018)

Abstract The p53 is a DNA-binding and transcription activation domain containing tumor suppressor that upregulates growth arrest and apoptosis-related genes. In response to DNA damage, p53 is phosphorylated at multiple sites including serine 33 or 37. Additionally, abnormal phosphorylation of cellular proteins is a hallmark of malignant transformation. The human immune system is capable of distinguishing between the normal components and these posttranslational modifications. Therefore, the existence of posttranslational modifications increases the diversity of potential immune reactions to a determinant antigen. We identified phosphorylated peptide epitopes from tumor protein p53 that could elicit effective T helper-cell responses. Two epitope peptides, p5322-41/Phospho-S33 and p5322-41/Phospho-S37, induced T helper responses against tumor cells expressing phosphorylated p53 protein. Moreover, cisplatin and doxorubicin augmented the responses of such CD4+ T cells via upregulation of phosphorylated p53. Importantly, we elucidated the presence of peripheral blood lymphocytes specific for these peptide epitopes in the PBMCs of head and neck squamous cell cancer patients. These results predict that epitopes p5322-41/Phospho-S33 and p5322-41/Phospho-S37 are immunogenic for anti-tumor responses and could be beneficial for cancer immunotherapy. Citation Format: Kenzo Ohara, Takumi Kumai, Tatsuya Hayashi, Takayuki Ohkuri, Nobuyuki Bandoh, Hiroya Kobayashi, Yasuaki Harabuchi. Targeting phosphorylated p53 to elicit tumor-reactive T helper responses against head and neck squamous cell carcinoma [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 723.
Abstract 170: Targeting colorectal cancer stem cells with the anticancer molecule thymoquinone
Authors: Farah R. Ballout, Maamoun Fatfat, Rana Abdel-Samad, Nadine Darwiche, Regine Schneider-Stock, Wassim Abou-Kheir, Hala-Gali Muhtasib
Journal: Cancer Research (2018)

Abstract Introduction: 5-fluorouracil (5-Fu) remains the standard chemotherapy for metastatic colorectal cancer (CRC), but drug resistance and unpredictable cardiotoxicity limit its effectiveness. The high recurrence rates and the common resistance are thought to be due to a population of self-renewing cancer stem cells (CSCs). The black seed extract Thymoquinone (TQ) is a promising anticancer molecule known to inhibit cancer cell growth and progression in numerous cancer systems both in vitro and in vivo. This project aims to investigate the effect and mechanism of action of TQ on colon cancer stem/progenitor cells using two isogenic HCT116 colon cancer cell lines that differ in their 5-Fu drug sensitivity. Methods: Sphere-formation and propagation assays were used to assess the efficacy of TQ on targeting self-renewal capacity of colon CSCs enriched from the sensitive and resistant cell lines in 3D cultures over several generations in comparison to 2D monolayers. In addition, xenotransplantation experiments were used to assess for the tumor initiation of 2D vs. 3D cells. Results: Our results of TQ efficacy in 2D cell culture system showed that it reduced the viability of both cell lines. Importantly, our 3D results showed that TQ inhibits HCT116 colonosphere growth at 10-fold lower concentrations than those required to inhibit the growth of 2D monolayer cells. Interestingly, the injection of 100 spheres derived from HCT116 sensitive cell line and not the 2D equivalent cell density into NOD-SCID immunocompromised mice resulted in tumor development, suggesting that spheres are rich in cells with stem-like properties. Conclusion: In summary, our data suggests that TQ might be an effective treatment strategy and may prevent colorectal cancer recurrence by targeting CSCs. Citation Format: Farah R. Ballout, Maamoun Fatfat, Rana Abdel-Samad, Nadine Darwiche, Regine Schneider-Stock, Wassim Abou-Kheir, Hala-Gali Muhtasib. Targeting colorectal cancer stem cells with the anticancer molecule thymoquinone [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 170.
Abstract 1488: Inter-individual variation in hTERT regulation pathway genes in normal bronchial epithelial cells
Authors: Rose Zolondek, Daniel J. Craig, Erin L. Crawford, James C. Willey
Journal: Cancer Research (2018)

Abstract Background: Genome-wide association studies (GWAS) and candidate gene studies suggest that telomere maintenance genes participate in etiology of lung cancer, idiopathic pulmonary fibrosis, and COPD. Telomeres are nucleoprotein structures located at the end of chromosomes that are maintained by telomerase encoded by hTERT. Telomerase is active in cancers, has the ability to aid in rapid cell division, and is dysfunctional in chronic conditions induced by inflammation as such as diabetes, renal failure, and COPD. hTERT is a known downstream target of β-catenin and WNT signaling. However, little is known regarding expression levels of these genes in normal bronchial epithelial cells (NBEC). The purpose of this study is to investigate inter-individual variation in regulation of β-catenin and WNT in NBEC, and if present, identify variants in regulatory region of human telomerase reverse transcriptase (hTERT) that could be used as candidate biomarkers for lung cancer risk. Methods: NBEC specimens from subjects with COPD (n=5) or without COPD (n=9) were obtained by bronchoscopy brush under IRB approved protocol. β-catenin, and WNT4 were measured by competitive multiplex-RT-PCR. Results: Both β-catenin and WNT4 displayed significant inter-individual variation as measured by Intra-Class Correlation (ICC) analysis (β-catenin ICC = 0.47, 95% Confidence Interval (0.2, 0.55), p &amp;lt; 0.05; WNT4 ICC = 0.60, 95% Confidence Interval (0.35, 0.85), p &amp;lt; 0.05). In patients with COPD, WNT4 expression was significantly higher in current smokers compared to former smokers (p&amp;lt;0.05). Conclusions: Inter-individual variation in NBEC expression of β-catenin and/or WNT4 was observed and it is reasonable to test the hypothesis that these genes and related pathway genes may contribute to variation in regulation of hTERT in NBEC and risk for lung cancer, COPD, and/or other lung diseases. Citation Format: Rose Zolondek, Daniel J. Craig, Erin L. Crawford, James C. Willey. Inter-individual variation in hTERT regulation pathway genes in normal bronchial epithelial 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 1488.