tbuckley/cabot-search huggingface dataset:
Small GTPases: Structure, biological function and its interaction with nanoparticles
Authors: Siyang Song, Wenshu Cong, Shurong Zhou, Yujie Shi, Wenbing Dai, Hua Zhang, Xueqing Wang, Bing He, Qiang Zhang
Journal: Asian Journal of Pharmaceutical Sciences (2018)

Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic cells. It plays an important role in cytoskeletal reorganization, cell polarity, cell cycle progression, gene expression and many other significant events in cells, such as the interaction with foreign particles. Therefore, it is of great scientific significance to understand the biological properties of small GTPases as well as the GTPase-nano interplay, since more and more nanomedicine are supposed to be used in biomedical field. However, there is no review in this aspect. This review summarizes the small GTPases in terms of the structure, biological function and its interaction with nanoparticles. We briefly introduced the various nanoparticles such as gold/silver nanoparticles, SWCNT, polymeric micelles and other nano delivery systems that interacted with different GTPases. These current nanoparticles exhibited different pharmacological effect modes and various target design concepts in the small GTPases study. This will help to elucidate the conclusion that the therapeutic strategy targeting small GTPases might be a new research direction. It is believed that the in-depth study on the functional mechanism of GTPases can provide insights for the design and study of nanomedicines.
Abstract 5611: Inhibition of IL-6 trans-signaling in HNSCC
Authors: Andrean L. Simons, Rachel A. Dahl, Madelyn Espinosa-Cotton, Samuel N. Rodman, Stefan Rose-John
Journal: Cancer Research (2018)

Abstract Various types of cancers including head and neck squamous cell carcinomas (HNSCCs) are highly inflammatory, and the cytokine interleukin-6 (IL-6) is believed to be associated with this inflammatory phenotype. Unfortunately, global inhibition of IL-6 signaling has demonstrated little to no clinical efficacy in various types of cancers. Previous studies in the field have reported major differences between IL-6 classical signaling through the membrane bound IL-6R (mIL-6R) and IL-6 trans-signaling through the soluble IL-6R (sIL-6R), and the idea that these 2 pathways may have vastly different functions. Recent studies in models of inflammation have proposed that IL-6 classical signaling serves an anti-inflammatory/homeostatic role while IL-6 trans-signaling stimulates proinflammatory events. Therefore, IL-6 trans-signaling (and not classical signaling) may be associated with the proinflammatory phenotype observed in HNSCCs and may also be responsible for the increased tumor progression and treatment resistance frequently encountered with this disease. The goal of this work is to investigate if selective inhibition of IL-6 trans-signaling will demonstrate superior antitumor efficacy compared to global inhibition of IL-6 signaling in HNSCC cells and if selective inhibition of IL-6 trans-signaling will enhance the antitumor efficacy of chemo/radiotherapy in HNSCC cells. We observed that the HNSCC cell lines SQ20B, SCC-25, FaDu and Cal-27 all express mIL-6R and secrete IL-6, sIL-6R, and the natural inhibitor of sIL-6R signaling–soluble glycoprotein 130 (sgp130)–at varying levels. Simultaneous inhibition of IL-6 classical and trans-signaling using the IL-6R antagonist tocilizumab, and selective inhibition of IL-6 trans-signaling using the extracellular portion of gp130 fused to the Fc portion of human IgG1 (sgp130-Fc), showed no significant effects on cell survival in vitro. However, sgp130-Fc significantly suppressed SQ20B tumor growth in athymic nude mice while tocilizumab had no effect. Significant antitumor effects of sgp130-Fc were also observed in a murine SCCVII/C3H syngeneic mouse model. Cell lines treated with cisplatin and/or X-ray radiation (0-4 Gy) increased IL-6, sIL-6R and sgp130 in a dose-dependent manner and sgp130-Fc significantly increased SQ20B tumor response to chemo/radiotherapy in vivo. Altogether, this work suggests that selective inhibition of IL-6 trans-signaling using sgp130-Fc may be more effective than global IL-6 inhibition with respect to suppressing HNSCC tumor growth and warrants further study as an adjuvant to standard HNSCC therapy. Citation Format: Andrean L. Simons, Rachel A. Dahl, Madelyn Espinosa-Cotton, Samuel N. Rodman, Stefan Rose-John. Inhibition of IL-6 trans-signaling in HNSCC [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 5611.
Quantification of Extracellular and Intracellular Adenosine Production
Authors: AndreasDeussen, MargitStappert, StefanSchäfer, MalteKelm
Journal: Circulation (1999)

Background—Inhibitors of adenosine membrane transport cause vasodilation and enhance the plasma adenosine concentration. However, it is unclear why the plasma adenosine concentration rises rather than falls when membrane transport is inhibited. We tested the hypothesis that the cytosolic adenosine concentration exceeds the interstitial concentration under well-oxygenated conditions. Methods and Results—In isolated, isovolumically working guinea pig hearts (n=50), the release rate of adenosine and accumulation of S-adenosylhomocysteine (after 20 minutes of 200 μmol/L homocysteine), a measure of the free cytosolic adenosine concentration, were determined in the absence and presence of specific and powerful blockers of adenosine membrane transport (nitrobenzylthioinosine 1 μmol/L), adenosine deaminase (erythro-9-hydroxy-nonyl-adenine 5 μmol/L), and adenosine kinase (iodotubericidine 10 μmol/L). Data analysis with a distributed multicompartment model revealed a total cardiac adenosine production rate of 2294 ...
Abstract 1822: Emergence of MET D1228N mutation as a resistance mechanism following an exceptional response to crizotinib in a MET-amplified triple-negative breast cancer patient
Authors: Benjamin M. Parsons, David R. Meier, Grzegorz T. Gurda, Kristopher A. Lofgren, Paraic A. Kenny
Journal: Cancer Research (2018)

Abstract The MET proto-oncogene encodes a receptor tyrosine kinase which is activated by Hepatocyte Growth Factor binding. Recent reports have described single agent activity for crizotinib in MET-amplified or mutant lung adenocarcinoma, squamous cell carcinoma and papillary renal cell carcinoma. Here we describe a stage IV triple-negative breast cancer patient in her early forties, previously treated with doxorubicin/cyclophosphamide, carboplatin/paclitaxel and with capecitabine. PET/CT imaging after progression on capecitabine revealed extensive metastatic disease including a large left pleural effusion, bilateral hypermetabolic nodular pleural implants, innumerable bilateral lung nodules and widespread mildly hyper-metabolic skeletal metastases in the ribs, spine and pelvis. A next-generation sequencing assay detected a 30-fold amplification of MET. MET amplification, overexpression and hyperactivity was confirmed by FISH and by immunohistochemistry for total MET and phospho-MET, respectively. Single agent crizotinib (250 mg, twice daily) was well-tolerated. Immunostaining of a biopsy taken after 9 days of treatment showed elimination of active phosphorylated MET, demonstrating in-tumor crizotinib efficacy at the clinical dose. CT imaging at 10 weeks showed a resolution of her metastatic disease, meeting RECIST 1.1 criteria for a complete response. This response was sustained at 22 weeks. At 37 weeks, the patient progressed in the pleura. An ultrasound guided biopsy revealed a robust resurgence of MET phosphorylation while still taking crizotinib, suggesting an alteration rendering MET recalcitrant to crizotinib. Next generation sequencing revealed a MET D1228N mutation, previously implicated in crizotinib resistance in lung cancer. This mutation was not detected in the pre-crizotinib biopsy (locus sequenced at 6300x) suggesting de novo acquisition in response to crizotinib. Transition from this type I MET inhibitor to a type II inhibitor (cabozantinib, initially 60 mg/day, later 100 mg/day) resulted in clinically stable disease for a period of 7 weeks, at which point the patient again progressed. Although MET-amplification is rare in breast cancer (~0.6% of cases), these data indicate that substantial clinical benefit may be achieved using single agent MET inhibition however the optimal selection of second-line agents to use upon progression will be critical. Citation Format: Benjamin M. Parsons, David R. Meier, Grzegorz T. Gurda, Kristopher A. Lofgren, Paraic A. Kenny. Emergence of MET D1228N mutation as a resistance mechanism following an exceptional response to crizotinib in a MET-amplified triple-negative breast cancer patient [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 1822.
Abstract 3232: Circulating sCD27 and sCD30 in samples collected fifteen years apart and non-Hodgkin lymphoma risk: Findings from the CLUE-I and CLUE-II cohorts
Authors: Mark P. Purdue, Qing Lan, Judith Hoffman-Bolton, Allan Hildesheim, Paul Strickland, Kala Visvanathan, Nathaniel Rothman
Journal: Cancer Research (2018)

Abstract Elevated serum levels of the immune activation markers sCD27 and sCD30 have been consistently associated with increased future risk of non-Hodgkin lymphoma (NHL). However, past studies could not clarify patterns of these markers over time preceding diagnosis, given their use of a single banked sample per participant. To address this question, we conducted a nested case-control study within the CLUE-I and CLUE-II cohorts including 102 case-control matched pairs with two banked samples per participant, collected fifteen years apart. The CLUE-II sCD27 concentrations among cases were higher than in the earlier CLUE-I samples (P&amp;lt;0.0001), whereas no systematic difference was observed for controls (P=0.89). The sCD27 increase was greater for cases diagnosed less than 10 years vs. 10+ years after CLUE-II enrollment (P = 0.0007). For sCD30, an increase between samples was observed for both cases (P = 0.0002) and controls (P=0.02), and the magnitude of increase among cases did not significantly differ across the two follow-up periods (P = 0.12). In comparison to having low (below-median) sCD27 levels in both CLUE-I and CLUE-II samples, associations with NHL were observed for having low CLUE-I sCD27 and high CLUE-II sCD27 (“low / high”; odds ratio 2.4, 95% confidence interval 1.0-6.2) as well as having high sCD27 levels in both samples (“high / high”; 2.1, 1.0-4.4). For sCD30, only the “high-high” category was associated with NHL (2.1, 0.9-5.0). The “low-high” sCD27 association was apparent only for cases diagnosed less than 10 years after CLUE-II (4.1, 1.3-13.0), while the “high-high” associations were consistent across follow-up periods. Our findings suggest that multiple factors may underlie NHL associations with these markers; rising sCD27 closer to diagnosis is likely driven by occult disease, whereas associations with stable elevated analyte levels may reflect etiologically relevant effects. Citation Format: Mark P. Purdue, Qing Lan, Judith Hoffman-Bolton, Allan Hildesheim, Paul Strickland, Kala Visvanathan, Nathaniel Rothman. Circulating sCD27 and sCD30 in samples collected fifteen years apart and non-Hodgkin lymphoma risk: Findings from the CLUE-I and CLUE-II cohorts [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 3232.
SAT0155 Traditional and nontraditional cardiovascular risk factors in patients with early onset arthritis of the panlar-eoa
Authors: I. Acosta Colman, P. Delgadillo, G. Avila-Pedretti, S. Cabrera-Villalba, P. Melgarejo, G. Elizaur, M. Franco, A. Ramagli, J. Mazzoleni, P. Abreu
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Inflammation plays a significant role in atherosclerosis and cardiovascular disease (CVD). Patients with chronic inflammatory diseases are at increased risk of CVD, but it is debated whether this association is causal or dependent on shared risk factors or inflammatory pathways. <h3>Objectives:</h3> Identify the mScore value and the association between traditional and nontraditional cardiovascular risks factors (CVRF) in an early onset arthritis (PANLAR-EOA) <h3>Methods:</h3> Prospective, longitudinal cohort study. Patients were protocoled according to the PANLAR-EOA project. For this analysis only patients with 12 and 24 months follow up were included. Patients were registered in REPANARC (www.panlareoa.org) database. The mScore evolution and the nontraditional CVRF linked to the disease (i.e. DAS28) association with the traditional CVRF (i.e. obesity) were studied. The Wilcoxon Test and the Spearman correlation test, depending on wether the variables were categorical or numerical, were utilized. <h3>Results:</h3> Initially 136 patients with early onset arthritis were included, out of which 88 completed the 12 months follow up and 58 the 24 months one. There was a female predominance 86% (117/136) of patients, with a median age of 44.80±14,47 years. When comparing the change ratio of the values obtained with the mScore on the initial, the 12 months and 24 months visit, the results were not statistically significant (p=0.106 at 12 months and p=0.175 at 24 months). An association between the elevated erithrosedimentation rate and obesity(p=5.807e-03) and diabetes (p=3.739e-02) was found in the initial visit. An association between elevated prednisone doses and high levels of total cholesterol (2.084e-02), high levels of diastolic blood pressure (p=1.967e-02) and low HDL values were observed (7.706e-03). At 12 months a significant association between obesity and high CRP (p=3.649e-02) and between high glycaemia levels with elevated prednisone doses and high CRP levels (p=2.549e-02). In the 24 months visit analysis, an association between elevated HDL-chol with high prednisone doses (p=5.016e-03) and elevated CRP levels (3.492e-02). <h3>Conclusions:</h3> An increment in Cardiovascular Risk (CVR) was not found at 12 and 24 months follow up according to the mScore. We have observed that there is an association between traditional and nontraditional CVRF. Therefore, the prevention strategies should be aimed not only towards the control of traditional CVRF, but also against the nontraditional CVRF associated with disease activity, which in a certain way could influence over the previous ones and modify the global CVR of patients with EOA <h3>Disclosure of Interest:</h3> None declared
Abstract 1809: Expression of genes in the nuclear receptor superfamily defines a set of prognostic biomarkers in endometrial cancer
Authors: Erling A. Hoivik, Ingvild L. Tangen, Karen M. Mauland, Mari K. Halle, Henrica J. Werner, Jone Trovik, Camilla Krakstad
Journal: Cancer Research (2018)

Abstract The nuclear receptor (NR) superfamily in humans consists of 48 transcription factors that form a network to sense lipophilic molecules from the diet, metabolism and hormone production, which ultimately regulate development, circadian rhythm, metabolism, proliferation and differentiation in the normal state. In cancer, biomarker signatures that provide either prognostic or predictive information are useful when suggesting therapeutic strategies. However, when performing differential gene expression analysis on global datasets, there is little overlap among the gene sets identified, even among similar datasets of same cancers. The fourth-eight NRs in cancers could represent a unique predefined pan-cancer subset of potential biomarkers in gynecologic cancers. Of note, NRs, in particular, estrogen, progesterone and androgen receptors (ESR1, PGR, AR), are strongly involved in the progression of gynecologic cancers, as revealed by us and others exemplified by endometrial cancer. Further, NRs are appealing targets, as they are regulated by ligand-receptor interactions, and approximately 15% of all pharmacologic drugs target factors within this group. We investigate the association of NR expressions and clinical outcome, and reveal NR signatures that may provide useful information as a biomarker in gynecologic cancers, with emphasis on endometrial cancer. Citation Format: Erling A. Hoivik, Ingvild L. Tangen, Karen M. Mauland, Mari K. Halle, Henrica J. Werner, Jone Trovik, Camilla Krakstad. Expression of genes in the nuclear receptor superfamily defines a set of prognostic biomarkers in endometrial 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 1809.
Evidence-based treatment algorithm for BCLC C advanced hepatocellular carcinoma: A comprehensive review and meta-analysis.
Authors: Hasmukh J. Prajapati, Hyun S. "Kevin" Kim
Journal: Journal of Clinical Oncology (2017)

e15649 Background: Barcelona clinic liver cancer (BCLC) C advanced hepatocellular carcinoma (aHCC) has a poor prognosis. Different treatment methods have shown a survival benefit. The purpose of the study is to suggest the treatment algorithm based on a comprehensive review of the literature on aHCC treated with different methods. Methods: Studies were identified by searching Google Scholar using the following keywords: ‘‘advanced hepatocellular carcinoma’’ or ‘‘advanced HCC’’ or “BCLC C” in a time period from 2008 to 2017. Search identified more than 700 articles. Then, articles were searched manually for BCLC C HCC. Articles were excluded if they dealt with only liver metastases or portal vein thrombosis, or if they did not report median survival. A total of 3 randomized control studies (RCT) and 21 non-RCT studies met the inclusion criteria and were reviewed. Results:Overall median survivals (OS) according to different methods is shown in table 1. OSs of aHCC treated with TACE, Yittrium 90 transarterial radioembolization (Y90 TARE) and sorafenib were not significantly different (p&gt;0.5). The pooled results of NRCT demonstrated that Child Pugh class A or without portal vein thrombosis (PVT) or ECOG PS 0 treated with TACE had best median survivals of 15 months(m), 17 m and 20 m respectively. Conclusions: No treatment method appears clearly better than any other. However, aHCC patients with Child Pugh class A or ECOG PS 0 or without PVT treated with TACE showed highest survival. Sorafenib/TACE or sorafenib/Y90 TARE combinations show promise as an effective and a tolerable treatment strategy for advanced HCC. Radiation therapy alone showed poor survival benefit. [Table: see text]
Abstract 681: Targeting diacylglycerol kinases for immuno-oncology
Authors: Ku-Lung Hsu
Journal: Cancer Research (2018)

Abstract Diacylglycerol kinases (DGKs) are integral components of signal transduction cascades that regulate cell biology through phosphorylation of the ubiquitous secondary messenger diacylglycerol. Emerging clinical evidence supports DGK-alpha (DGKA) as a promising target for cancer immunotherapy because of its critical role in regulating lipid signaling necessary for proper T cell activation. Methods for direct evaluation of DGK activity in native biologic systems are lacking and needed to develop chemical probes for studying isoform-specific functions. Here, I will discuss efforts from my group to utilize ATP acyl phosphate activity-based probes and quantitative mass spectrometry to map previously undefined ATP- and small molecule-binding sites of representative members from all subtypes of the DGK family. We use our chemical proteomics strategy to discover an unusual binding mode for DGKA inhibitors, including interactions at a novel binding site remote from the ATP binding pocket. I will also describe our efforts towards discovery of new lead inhibitors for future development of highly potent and selective DGKA inhibitors. Collectively, our studies illustrate the power of chemical proteomics to site-specifically profile protein-small molecule interactions and reveal key ligand binding sites for selective inactivation of the DGK family of lipid kinases. Citation Format: Ku-Lung Hsu, Hsu Lab at the University of Virginia. Targeting diacylglycerol kinases for immuno-oncology [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 681.
Abstract 4127: A tumor evolution screen in zebrafish identifies PlexinA1 as a driver of metastasis and growth in human rhabdomyosarcoma
Authors: Alessandra M. Welker, Madeline N. Hayes, Qin Tang, David M. Langenau
Journal: Cancer Research (2018)

Abstract Relapse and metastasis are major clinical problems facing patients with rhabdomyosarcoma (RMS), a devastating pediatric malignancy of the muscle. Alveolar Rhabdomyosarcoma (ARMS) is characterized by genetic translocations while Embryonal Rhabdomyosarcoma (ERMS) is characterized by Ras pathway activation. Treatment for either RMS subtype requires surgical resection, chemotherapy, and radiation with overall poor prognosis for patients with high-risk features including metastasis and relapse. Thus, there is great interest in elucidating key molecular pathways and genetic factors that are involved in continued RMS growth and tumor maintenance. In the Langenau lab, we utilize a powerful transgenic zebrafish model of kRASG12D- induced ERMS and have recently developed a p53-/- (null) zebrafish model. p53 is one of the most common tumor suppressor genes, and upwards of 1/3 of RMS patients have mutations or Loss-of-Heterozygosity (LOH) of this locus. This model accurately mimics the molecular underpinnings and histopathology of human ERMS and has been used to discover molecular pathways that drive relapse. Using our tp53-/- (null) zebrafish along with large-scale cell transplantation assays, we have assessed metastatic potential of our ERMS tumors following serial passaging and acquisition of new driver mutations. Specifically, we performed a tumor evolution screen using serial engraftment of ERMS into recipient fish followed by RNA sequencing to discover novel pathways that are associated with elevated tumor growth and metastasis. Plexin A1 was one of our top hits in this screen, being expressed at &amp;gt;8 fold in metastatic lesions of the zebrafish and expressed in &amp;gt;80% of human RMS. Plexins are a large family of receptors for transmembrane, secreted and GPI-anchored semaphorins. Knockdown of PLXNA1 decreased human ERMS cell proliferation, increased differentiation and impaired anchorage-independent growth and migration. Collectively, our data supports the hypothesis that PLXNA1 is an important moderator of tumor growth in a large fraction of human RMS and likely regulates local invasion and metastasis. This work will provide much needed data for discovery of novel therapeutically-actionable pathways for relapsed ERMS and likely inform future treatment for high-risk patients. Citation Format: Alessandra M. Welker, Madeline N. Hayes, Qin Tang, David M. Langenau. A tumor evolution screen in zebrafish identifies PlexinA1 as a driver of metastasis and growth in human rhabdomyosarcoma [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 4127.