tbuckley/cabot-search huggingface dataset:
DOCK180 Is a Rac Activator That Regulates Cardiovascular Development by Acting Downstream of CXCR4
Authors: FumiyukiSanematsu, MasanoriHirashima, MélanieLaurin, RyosukeTakii, AkihikoNishikimi, KeikoKitajima, GuoDing, MamikoNoda, YuzoMurata, YoshihikoTanaka, SadahikoMasuko, ToshioSuda, ChikaraMeno, Jean-FrançoisCôté, TakashiNagasawa, YoshinoriFukui
Journal: Circulation Research (2010)

Rationale:During embryogenesis, the CXC chemokine ligand (CXCL)12 acts on endothelial cells to control cardiac development and angiogenesis. Although biological functions of CXCL12 are exerted in part through activation of the small GTPase Rac, the pathway leading from its receptor CXC chemokine receptor (CXCR)4 to Rac activation remains to be determined. Objective:DOCK180 (dedicator of cytokinesis), an atypical Rac activator, has been implicated in various cellular functions. Here, we examined the role of DOCK180 in cardiovascular development. Methods and Results:DOCK180 associates with ELMO (engulfment and cell motility) through the N-terminal region containing a Src homology 3 domain. We found that targeted deletion of the Src homology 3 domain of DOCK180 in mice leads to embryonic lethality with marked reduction of DOCK180 expression at the protein level. These mutant mice, as well as DOCK180-deficient mice, exhibited multiple cardiovascular abnormalities resembling those seen in CXCR4-deficient mice....
Abstract 3666: Diagnostic application of novel ACE technology: Treatment response monitoring via quantification of cell-free DNA (cfDNA) in plasma from late-stage cancer patients
Authors: Robert Kovelman, Juan Pablo Hinestrosa, Delia Ye, Patrick Desmond, Michelle Nguyen, Robert Turner, David Searson, Suren Uswatta, James Madsen, David Bodkin, Lyudmila Bazhenova, Afshin Bahador, Rajaram Krishnan
Journal: Cancer Research (2018)

Abstract We have developed a novel microfluidic technology that makes use of Alternating Current Electrokinetics (ACE) to isolate macromolecules such as high-molecular-weight DNA and protein complexes as well as nanoparticles, including cell-derived exosomes. As one of the first applications of this novel technology, we have developed procedures and assays for the isolation and quantification of cell-free DNA (cfDNA) in plasma. We show that this methodology allows for the rapid, robust, and highly quantitative assay of cfDNA in undiluted plasma. Analytical studies indicate that these ACE assays are sensitive, have a very broad dynamic range, and allow for highly effective calibration strategies, thereby enabling comparison of results over time and between laboratories. Importantly, we show correspondence between the results of ACE assays and those that employ traditional technologies such as PCR. We have applied this technology to the quantification of cfDNA in plasma from cancer patients, with an initial focus on stage III and IV non-small cell lung cancer (NSCLC). With a goal of enabling less invasive, more frequent, and lower-cost treatment response monitoring in cancer patients, we have conducted clinical studies showing that the results generated from ACE assays provide informative and useful findings related to disease progression and therapeutic alternatives. We are conducting laboratory and clinical studies oriented toward the development of this technology for in vitro diagnostic use. Citation Format: Robert Kovelman, Juan Pablo Hinestrosa, Delia Ye, Patrick Desmond, Michelle Nguyen, Robert Turner, David Searson, Suren Uswatta, James Madsen, David Bodkin, Lyudmila Bazhenova, Afshin Bahador, Rajaram Krishnan. Diagnostic application of novel ACE technology: Treatment response monitoring via quantification of cell-free DNA (cfDNA) in plasma from late-stage 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 3666.
Abstract 5148: Secreted ccdc80 from hepatic stellate cell promote invasion and epithelial-mesenchymal transition in hepatocellular carcinoma
Authors: Kwang Seock Kim, SaeHwan Lee, Nayoung Jun, Hyog Young Kwon
Journal: Cancer Research (2018)

Abstract Liver cirrhosis is the most important risk factor for hepatocellular carcinoma (HCC) and hepatic stellate cell (HSC) has pivotal role in developing cirrhosis by producing various extracellular matrix (ECM). HSC are essential mediators of tumor microenvironment of HCC through remodeling of ECM and angiogenesis. We found that CCDC80 expression is upregulated in activated HSCs from RNA-sequencing with human fetal stellate cell. However, the role of CCDC80 was not well known in hepatocarcinogenesis. First, we validated mRNA expression of CCDC80 was increased in activated HSC lines and protein expression was also increased in cultured media. Functional analysis of knockdown CCDC80 was investigated in both HCC and HSC cell lines, and HCC cell lines were analyzed for proliferation (MTT assay), migration (using transwell), invasion (using Matrigel-coated transwell), and wound healing assay with condition media of CCDC80 knockdown HSCs. Expression of epithelial-mesenchymal transition (EMT) markers in HCC was evaluated with conditioned media. Knockdown of CCDC80 resulted in reduced cell proliferation and significantly reduced invasion, migration and wound healing behaviors of HCC cell lines. Expression of E-cadherin was increased and snail and vimentin expression were decreased in HCC cell lines cultured with conditioned media of CCDC80 knockdown HSCs. The associations between CCDC80 and EMT markers were validated in CCDC80 transfected HSC cell line compared with control. Taken together, secreted CCDC80 from HSCs affected the aggressiveness and EMT of HCC cell lines. CCDC80 might be a novel biomarker and therapeutic target for patients with HCC. Citation Format: Kwang Seock Kim, SaeHwan Lee, Nayoung Jun, Hyog Young Kwon. Secreted ccdc80 from hepatic stellate cell promote invasion and epithelial-mesenchymal transition in hepatocellular 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 5148.
Abstract 1058: CRLF1 promotes proliferation and metastasis in papillary thyroid carcinoma via activating MAPK/ERK and PI3K/AKT pathway
Authors: QIAN ZHONG, Shitong Yu, Xiaoming Huang, Musheng Zeng
Journal: Cancer Research (2018)

Abstract Papillary thyroid cancer (PTC) is the most common cancer in endocrine system which accounts for the majority component of thyroid cancer during the past decades. PTCs usually are indolent and curable with 5-year survival rate over 95%. However, some of PTCs will dedifferentiate and become aggressive with a poor prognosis. Current established biomarkers may not fully explain the mechanisms of the development of PTC. Therefore, it is still urgent to find novel biomarkers of PTC to better predict patients' prognosis and lead to the personalized therapies for PTC patients. By analyzing The Cancer Genome Altas (TCGA) database, we identified Cytokine Receptor Like Factor-1(CRLF1) as a potential oncogene. We identified CRLF1 is highly expressed in papillary thyroid carcinoma (PTC) compared with normal thyroid tissues both at mRNA and protein level. High CRLF1 level was associated with aggressive clinicopathological features and worse disease-free survival rate. By loss-of-function and gain-of-function assays, we found that CRLF1 not only boosts capacity of cell migration and invasion in vitro, but promotes tumor growth both in vitro and in vivo. Besides, CRLF1 can induce epithelial-mesenchymal transitions. Overexpressing CRLF1 could activate ERK1/2 and AKT pathways. The oncogenic effects induced by CRLF1 were suppressed by treating the cells with the MEK inhibitor U0126 or the AKT inhibitor MK-2206. These results suggest an oncogenic role CRLF1 plays in PTC tumorigenesis by regulating MAPK/ERK and PI3K/AKT signaling pathways. These results suggest that CRLF1 is a potential biomarker in PTC patients and it may be a valuable therapeutic target for PTC in the future. Citation Format: QIAN ZHONG, Shitong Yu, Xiaoming Huang, Musheng Zeng. CRLF1 promotes proliferation and metastasis in papillary thyroid carcinoma via activating MAPK/ERK and PI3K/AKT pathway [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 1058.
Abstract 17031: Intracoronary Liquid Keratin (Keraplast) Injection Prevents Post-infarction Left Ventricular Remodeling in a Porcine Infarct Model
Authors: Yousi A Oquendo, Tetsushi Takayama, Chikashi Aoki, Tomonori Kawamura, Akito Imai, Matthew J Gillespie, Joseph H Gorman, Robert C Gorman
Journal: Circulation (2016)

Introduction: Myocardial infarction (MI) leads to adverse LV remodeling and heart failure. Approximately 50% of MI survivors develop congestive heart failure (CHF) despite rarely suffering another ...
Smartphone measures of day-to-day behavior changes in children with autism
Authors: Rebecca M. Jones, Thaddeus Tarpey, Amarelle Hamo, Caroline Carberry, Catherine Lord
Journal: npj Digital Medicine (2018)

Smartphones offer a flexible tool to collect data about mental health, but less is known about their effectiveness as a method to assess variability in children's problem behaviors. Caregivers of children with autism completed daily questions about irritability, anxiety and mood delivered via smartphones across 8-weeks. Smartphone questions were consistent with subscales on standard caregiver questionnaires. Data collection from 7 to 10 days at the beginning and 7 to 10 days at the end of the study were sufficient to capture similar amounts of variance as daily data across 8-weeks. Other significant findings included effects of caregiver socioeconomic status and placebo-like effects from participation even though the study included no specific treatment. Nevertheless, single questions via smartphones collected over relatively brief periods reliably represent subdomains in standardized behavioral questionnaires, thereby decreasing burden on caregivers.
Abstract 200: FOXD1 promotes stromal investment in clear cell renal cell carcinoma
Authors: Kyle H. Bond, Jennifer Fetting, Ashwani Gupta, Christine W. Duarte, Michele Karolak, Clare B. Congdon, Ivette Emery, Eoghainín Ó hAinmhire, Benjamin D. Humphreys, Leif Oxburgh
Journal: Cancer Research (2018)

Abstract Forkhead transcription factors (FOX) play a role in the development of many cancers, including clear cell renal cell carcinoma (ccRCC). FOXD1, essential for angiogenesis in the developing kidney, has not previously been implicated in ccRCC. Tumor microarrays (TMAs) containing 41 patient-derived ccRCC tumors and 26 healthy cortex samples were stained for FOXD1, with 65% of tumor samples staining positively. Due to the effect of FOXD1 on angiogenesis, staining for stromal markers PECAM, αSMA, PDGFRβ and NG2 was also performed. A direct correlation was found only between FOXD1 and PDGFRβ (p&amp;lt;4.5x10-6), suggesting interstitial fibroblast recruitment by FOXD1+ cancer cells. Increased expression of FOXD1 was found to correlate with increased stage (p=9.1x10-5) and reduced survival (FOXD1 low= 2830 days; FOXD1 high= 1913 days) from a Kaplan-Meier analysis of RNA-seq data from The Cancer Genome Atlas (TCGA). Potential FOXD1 target binding sites were determined using the TRANSFAC FOXD1 binding site matrix. SLIT2, a factor known to inhibit migration of pericytes, was uncovered from the analysis and was further found to be downregulated in response to FOXD1 overexpression in renal proximal tubule cells (RPTECs). To test the influence of SLIT2 on interstitialfibroblast migration, scratch assays on NRK-49F (rat kidney fibroblast) and Gli-1 (cardiac fibroblast) cells were performed and showed that SLIT2 reduced PDGFBB-induced cell migration (p&amp;lt;0.027). A multiplex proximity ligation assay for multiple signaling pathways showed that SLIT2 treatment reduced the STAT signaling response to PGDFBB. To model the influence of SLIT2 on ccRCC stromal invasion in vitro, we devised a novel 3D invasion assay. In summary, 786-O ccRCC cancer cells were seeded into a 200um thick silk scaffold and cultured for 3 days to allow deposition of ECM. Scaffolds were then placed on top of a monolayer of interstitial fibroblasts and invasion into the cancer cell-filled scaffold was measured using confocal microscopy. The results showed a significant reduction of cell invasion into the cancer-filled matrix with the addition of recombinant SLIT2 to media (5µm p=1.34x10-4; 50µm p=1.64x10-2). In conclusion, we show that FOXD1 expression has prognostic relevance to patient survival in ccRCC, and that this may be due to modulation of SLIT2 expression. Citation Format: Kyle H. Bond, Jennifer Fetting, Ashwani Gupta, Christine W. Duarte, Michele Karolak, Clare B. Congdon, Ivette Emery, Eoghainín Ó hAinmhire, Benjamin D. Humphreys, Leif Oxburgh. FOXD1 promotes stromal investment in clear cell renal 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 200.
Abstract 2332: Necroptosis induction in triple negative breast cancer therapy
Authors: Angelique Nyinawabera, Smiti Gupta, Karthikeyan Chandrabose, Amit K. Tiwari
Journal: Cancer Research (2018)

Abstract “Triple-negative” breast cancer (TNBC), is the most aggressive form of malignant mammary tumors that do not express three cell-surface receptors (estrogen receptor-α, progesterone receptor, and HER2/ERBB3). TNBC accounts for about 15 percent of breast cancer cases, with &amp;gt;42,000 new cases each year and approximately 21,000 deaths. Currently there are no targeted treatments available for TNBC. We found an interesting target associated with TNBC, the mitochondrial fission protein GTPase, dynamin-related protein-1 (Drp1), for which one inhibitor (mdivi-1) is under active investigation. However, mdivi-1 has shown inconsistent antineoplastic activity, low potency and selectivity. This led us to use a 200,000-compound library of commercially available small molecules (Specs), in conjunction with the likely structure of the Drp1-mdivi-1 inhibitory complex, resulting in the identification of twelve thieno-pyrimidin-4-yl-hydrazinylidene class of compounds that were highly potent and selective Drp1 inhibitors. In our preliminary work we found one compound ANT4 with IC50 value of 180-220 nM that has up to 100-fold selectivity in different TNBC cells compared to normal breast cells and up to 30-fold compared to other normal cells. We discovered that ANT4 is a selective inhibitor of Drp1 and has a 100-fold greater affinity for the Drp1 complex. ANT4 inhibited TNBC colony formation, invasion and metastasis,150-fold more potently than Mdivi-1. Interestingly, we discovered that ANT4, in nanomolar range, selectively induced a unique non-apoptotic, necroptotic inducing (NANI) cell death in TNBC cells by increasing the expression of necroptotic cell death markers (RIP, p-RIP, MLKL, p-MLKL). Further, ANT4, inhibited the expression of pro-apoptotic proteins and enhanced the expression of anti-apoptotic proteins. In addition, ANT4 arrested the TNBC cells in S-phase without producing any significant nuclear condensation or release of reactive oxygen species (ROS). Further studies are underway to understand the Drp1 mediated NANI induction process in TNBC cells and to identify the structural requirements that are necessary for targeting cancers refractory to apoptosis. The findings of these studies will allow us to understand the biology of necroptosis-induced Drp1 inhibition and to develop this new class of small molecules for the treatment of TNBC patients. Citation Format: Angelique Nyinawabera, Smiti Gupta, Karthikeyan Chandrabose, Amit K. Tiwari. Necroptosis induction in triple negative breast cancer therapy [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 2332.
Abstract 20102: Time-to-Effect Based Cryoballoon Dosing to Achieve Permanent Pulmonary Vein Isolation -The First Chronic Study in Canine Model
Authors: Wilber Su, Nicole Kirchhof, Erin Grassl, Andrew Williams, Dan Wittenberger
Journal: Circulation (2016)

Background: Cryoballoon ablation (CB) is an effective treatment for Paroxysmal Atrial Fibrillation (PAF). Current time-based dosing may be inadequate to characterize the cryo-thermal energy transfe...
Multivariate Analysis of Risk Factors for Coronary Heart Disease
Authors: Larswilhelmsen, Hanswedel, Göstatibblin
Journal: Circulation (1973)

For a prospective study of risk factors for coronary heart disease (CHD), defined as acute nonfatal myocardial infarction and acute fatal CHD, 973 men, all aged 50 years, were recruited from a general Swedish urban population. Of the 855 who agreed to participate, 834 who showed no signs of CHD were selected and observed for nine years and four months. Autopsies were performed on all except two of the 55 patients who died during the study. Forty-four men developed clinical manifestations of CHD during this time; 19 of them died. Using a multiple logistic model, we analyzed nine probable risk factors. The presence of high serum cholesterol, smoking, high systolic blood pressure, dyspnea, and registration by the Temperance Board increased the risk of events related to CHD significantly. The presence of high serum triglycerides, high hematocrit readings, and increased geographic mobility did not cause a significant increase in events related to CHD. Those with sedentary jobs showed a slightly increased tende...
Abstract 13823: The Cut-off Point and Boundary Values of Waist-to-height Ratio as an Indicator for Cardiovascular Risk Factors in Chinese Adults Population From PURE Study
Authors: YaguangPeng, WeiLi
Journal: Circulation (2015)

Objectives: To explore a scientific boundary of WHtR to evaluate central obesity and CVD risk factors in Chinese adult population. Methods: The data from the Prospective Urban Rural Epidemiology (PURE) China study that carried out during 2005-2007. The final study analytical sample consisted of 43 841 participants (18 019 men and 25 822 women) aged 35-70 years. According to the category of CVD risk factors proposed by Joint National Committee 7 version (JNC7) and the clustering of risk factors, some diagnosis parameters, such as sensitivity, specificity, and receiver operating characteristic (ROC) curve least distance were calculated for hypertension, diabetes, high serum triglyceride (TG), high serum low density lipoprotein cholesterol (LDL-C), low serum high density lipoprotein cholesterol (HDL-C) and clustering of risk factors (number≥2) to evaluate the efficacy each value of WHtR cut-off point. The upper boundary value for severity was fixed on the point whose specificity of the point was gathered mor...
Abstract 2589: Novel predictor of FGFR1 inhibition efficacy in non-small cell lung cancer
Authors: Álvaro Quintanal-Villalonga, Irene Ferrer, Ángela Marrugal, Laura Ojeda-Márquez, Jon Zugazagoita, Laura García-Redondo, Fernando López-Ríos, Luis Montuenga, Sonia Molina-Pinelo, Sonia Molina-Pinelo, Amancio Carnero, Luis Paz-Ares
Journal: Cancer Research (2018)

Abstract Fibroblast growth factor receptor (FGFR)1 has been associated with tumorigenesis in a variety of tumors, including lung cancer. FGFR1 amplification is detected in up to 20% of lung squamous cell carcinomas, and was initially related to tumorigenesis and to response to FGFR inhibitors in preclinical models of this pathology. These data encouraged the establishment of FGFR1 amplification as the main eligibility criterion for inclusion of patients in FGFR inhibitors clinical trials. However, the use of FGFR inhibitors in FGFR1-amplified tumors has shown limited success, with only 5-10% of selected patients showing partial response, suggesting that this genomic aberration may not be a good predictive biomarker for the efficacy of these inhibitors. In this work, we provide in vitro and in vivo data showing that the oncogenic effects of FGFR1 expression depend on the expression of the adhesion molecule N-cadherin in non-small cell lung cancer (NSCLC). In line with these results, FGFR1 expression correlates with poorer prognosis only in tumors with high N-cadherin levels in two independent NSCLC patient cohorts. We observed that high FGFR1 expression alone is not sufficient to predict FGFR inhibition efficacy in lung cancer cell lines and patient-derived xenografts, with only high FGFR1- and high N-cadherin-expressing models responding to selective FGFR inhibitors. Altogether, our data show that the determination of the expression of FGFR1 alone is not sufficient to predict FGFR inhibition efficacy. The co-determination of N-cadherin expression may optimize patient selection for this therapeutic strategy. Citation Format: Álvaro Quintanal-Villalonga, Irene Ferrer, Ángela Marrugal, Laura Ojeda-Márquez, Jon Zugazagoita, Laura García-Redondo, Fernando López-Ríos, Luis Montuenga, Sonia Molina-Pinelo, Sonia Molina-Pinelo, Amancio Carnero, Luis Paz-Ares. Novel predictor of FGFR1 inhibition efficacy 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 2589.
Adaptation and modification of the immune related response criteria (IRRC): IrRECIST.
Authors: Oliver Bohnsack, Axel Hoos, Katarina Ludajic
Journal: Journal of Clinical Oncology (2014)

e22121 Background: The immune related response criteria were published in November 2009. RECIST published in 2000 had its shortcomings for targeted immunotherapy in oncology and still has with its successor version RECIST 1.1, also from 2009. Investigators may declare a patient PD too early, when the treatment effect is not yet fully evident. Methods: The irRECIST modifications represent adaptations of the published criteria based on current radiology practice and clinical trial experience and aim to provide more objective and reproducible response assessments for investigators and central independent image review. A rationale for the clarifications and modifications is provided. Results: RECIST published in 2000 and its successor version RECIST 1.1 from 2009 has its shortcomings for targeted immunotherapy in oncology. Patients with an increase in tumor burden by either ≥ 20% of measured target lesions' diameters or with an unequivocal new lesion are considered a progressor and as such a treatment failure, irrespective of time interval considerations since first treatment. Conclusions: Bearing industry demands and RECIST shortcomings in mind we introduce a modification of the irRC to better address patients' treatment and sponsors' analysis needs for targeted immunotherapy developments in oncology with irRECIST, based on adaptation of unidimensional measurements aligned with RECIST 1.1. Sponsors developing monoclonal antibodies for oncology patients are aware that with RECIST 1.1, as the most common assessment criteria, investigators may declare a patient progressive disease too early, when the compound did not have sufficient time to show its treatment effect.