tbuckley/cabot-search huggingface dataset:
Abstract 4356: SIRT2-deacetylase activity is a potential predictive and prognostic marker in lung cancer patients
Authors: Yang Guo, Ha Yong Song, Kirtee Raparia, Athanassios Vassilopoulos
Journal: Cancer Research (2018)

Abstract Background: SIRT2 has been described as a tumor suppressor, whereas our previous study using an LSL-KRASG12D mouse model showed that Sirt2 loss induced lung tumorigenesis in vivo through increased KRAS acetylation (K147) and activity. However, there is limited information about the clinical significance of SIRT2 expression and/or activity in lung cancer patients. Purpose: The aim of this study was to investigate the associations between SIRT2 levels and activity with clinical-pathological characteristics and patient outcomes in lung cancer. Materials and Methods: SIRT2 expression and activity was analyzed using a tissue microarray of 162 resected lung cancer samples from Northwestern Memorial Hospital. To assess SIRT2 expression, we used an antibody against SIRT2 for immunohistochemistry. To assess SIRT2 activity, we evaluated acetylated levels of two specific deacetylation targets, α-tubulin (K40) and KRAS (K147). For all tested markers, staining intensity of each tissue sample was scored as 0 (no signal), + 1 (weak), + 2 (distinct), + 3 (strong). The percentage of each positive staining was categorized as A (&amp;lt;25%), B (25~50%), C (&amp;gt;50%). Following statistical analysis, it was determined whether SIRT2 expression and activity were associated with several clinical parameters or outcomes. p &amp;lt; 0.05 was assumed statistically significant. Results: Acetylated α-tubulin and acetylated KRAS in lung tumor samples were significantly correlated with each other (p&amp;lt;0.05), but not with SIRT2 expression. Of note, acetylated α-tubulin was significantly associated with TTF1 expression (p&amp;lt;0.05), staging (p&amp;lt;0.005), pleural metastasis (p&amp;lt;0.005), surgery (p&amp;lt;0.001), and chemotherapy (p&amp;lt;0.005). Acetylated KRAS had significant associations with surgery (p&amp;lt;0.005), lymph nodal status (p&amp;lt;0.05) and pleural metastasis (p&amp;lt;0.05). Kaplan-Meier analysis further indicated that both TTF1 and acetylated α-tubulin were independent predictors of patient survival (p=0.005 and p=0.028, respectively). Conclusions: Our data implicated that SIRT2 deacetylation activity, but not SIRT2 expression levels, could represent an optimal predictive and prognostic factor in lung cancer. Based on this finding, strategies to increase SIRT2 activity might be favorable in clinical treatment protocols for lung cancer. Citation Format: Yang Guo, Ha Yong Song, Kirtee Raparia, Athanassios Vassilopoulos. SIRT2-deacetylase activity is a potential predictive and prognostic marker in lung 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 4356.
Immunolocalization of β2-Glycoprotein I (Apolipoprotein H) to Human Atherosclerotic Plaques
Authors: JacobGeorge, DrorHarats, BorisGilburd, ArnonAfek, YairLevy, JacobSchneiderman, IrisBarshack, JuriKopolovic, YehudaShoenfeld
Journal: Circulation (1999)

Background—β2-Glycoprotein I (β2GPI) is a major antigenic target of antiphospholipid antibodies, which possesses natural anticoagulant properties. The aim of the present study was to determine its presence and localization within human atherosclerotic plaques and to study its association with endothelial cells and monocyte macrophages in vitro. Methods and Results—Human atherosclerotic lesions were obtained after carotid endarterectomies and studied immunohistochemically with anti-β2GPI as well as antibodies to CD4/CD8, macrophages, and adhesion molecules. In vitro, human umbilical vein endothelial cells (HUVECs) and U937 (myelomonocytic cell line) cells were investigated for their ability to associate with radiolabeled β2GPI. We found β2GPI to be abundantly expressed within the subendothelial regions and intimal-medial borders of human atherosclerotic plaques and to colocalize with CD4-positive lymphocytes. This observation was confirmed by Western blot applied on homogenates of atherosclerotic lesions w...
The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity
Authors: Laura L. Swystun, Jesse D. Lai, Colleen Notley, Ilinca Georgescu, A. Simonne Paine, Jeff Mewburn, Kate Nesbitt, Kai Schledzewski, Cyrill Géraud, Julia Kzhyshkowska, Sergij Goerdt, Wilma Hopman, Robert R. Montgomery, Paula D. James, David Lillicrap
Journal: Journal of Clinical Investigation (2018)

Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.
Abstract 14694: Combined Assessment of Urinary Liver-Type Fatty-Acid Binding Protein and Albumin Improves Prediction of Acute Kidney Injury in Patients Hospitalized to Coronary Care Units
Authors: Shigeru Matsui, Junnichi Ishiii, Hiroshi Takahashi, Ryuunosuke Okuyama, Hideki Kawai, Takahashi Muramatsu, Akira Yamada, Sadako Motoyama, Hiroyuki Naruse, Mutsuharu Hayashi, Hideo Izawa, Yukio Ozaki
Journal: Circulation (2016)

Background: Urinary concentration of liver-type fatty-acid binding protein (L-FABP) reflects tubulointerstitial damage, and urinary albumin concentration (UAC) reflects glomerular damage. We prospectively investigated the predictive value of urinary L-FABP, both independently and in combination with UAC for acute kidney injury (AKI) which develops after admission to coronary care units (CCUs). Methods: We studied 1139 patients (mean age of 69 yrs) who admitted to CCUs. Baseline urinary L-FABP and UAC were measured on admission. Among these patients, heart failure was present in 43%, and acute coronary syndrome in 45%. AKI was diagnosed and classified according to the KDIGO criteria. Results: Urinary L-FABP levels moderately correlated with UAC (r = 0.42, p < 0.0001). AKI occurred in 223 (19.6%) patients. Comparably, patients with AKI were older (73 vs. 71 yrs, p = 0.01), had a higher prevalence of heart failure (51 vs. 41%, p = 0.007), higher levels of B-type natriuretic peptide (377 vs. 206 pg/ml, p < 0....
Abstract 16895: Relationship of Activity Energy Expenditure With Autonomic Balance and Liver Congestion in Patients With Fontan Circulation
Authors: Akiko Yana
Journal: Circulation (2016)

Background: CVP increases with physical activity (PA) in Fontan circulation; therefore, excessive PA can be deleterious as it causes organ congestion. Contrarily, moderate exercise has beneficial effects in patients with heart failure, including improvement in autonomic nerve balance, resulting in better prognosis. However, no data are available regarding whether and how the intensity of PA affects the pathophysiology of Fontan patients. To our knowledge, this is the first study that assessed the effects of daily PA on hepatic congestion and autonomic balance in patients with Fontan circulation and determined the ideal intensity of PA for them. Methods: Daily PA was assessed by activity energy expenditure (AEE) in 37 Fontan patients (3.8-42 years) who wore a high-accuracy accelerometer (Actical®) continuously for 2 weeks. We examined the relationship of the AEE values with γ-GTP, as an indicator of hepatic congestion, and heart rate variability (HRV), as an indicator of autonomic balance. Additionally, AE...
L-Type Calcium Channel C Terminus Autoregulates Transcription
Authors: ElizabethSchroder, MirandaByse, JonathanSatin
Journal: Circulation Research (2009)

Calcium homeostasis is critical for cardiac myocyte function and must be tightly regulated. The guiding hypothesis of this study is that a carboxyl-terminal cleavage product of the cardiac L-type calcium channel (CaV1.2) autoregulates expression. First, we confirmed that the CaV1.2 C terminus (CCt) is cleaved in murine cardiac myocytes from mature and developing ventricle. Overexpression of full-length CCt caused a 34±8% decrease of CaV1.2 promoter activity, and truncated CCt caused an 80±3% decrease of CaV1.2 promoter (n=12). The full-length CCt distributes into cytosol and nucleus. A deletion mutant of CCt has a greater relative affinity for the nucleus than full-length CCt, and this is consistent with increased repression of CaV1.2 promoter activity by truncated CCt. Chromatin immunoprecipitation analysis revealed that CCt interacts with the CaV1.2 promoter in adult ventricular cardiac myocytes at promoter modules containing Nkx2.5/Mef2, C/EBp, and a cis regulatory module. The next hypothesis tested wa...
Repair Processes in Arterial Tissue. Biochemical Alterations in Rabbit Aorta Induced by Norepinephrine
Authors: Iblorenzen
Journal: Circulation Research (1963)

Male albino rabbits were injected intravenously with large doses of l-norepinephrine daily for 15 days. Morphological alterations in the aortae were insignificant but significant increases in the aortic content of acid muco-polysaccharides and in the uptake of S35-labeled sulfate in acid mucopolysaccharides were observed in the experimental animals in comparison to saline-injected controls. Increase in the carbazole to orcinol ratio of the acid mucopolysaccharides indicated qualitative, as well as quantitative, alterations. The alterations were interpreted as reparative processes in the arterial wall following injury produced by the intense vasoconstrictor action of norepinephrine. This interpretation finds support in the similarity between the observed alterations and those which occur during wound-healing or which follow exposure to a variety of agents known to damage blood vessels.
Abstract 4452: Musashi-2 regulates EGFR/HER3 expression in NSCLC, cell proliferation and response to EGFR inhibitors in EGFR-mutant NSCLC
Authors: Peter Makhov, Alexander Kudinov, Alexander Deneka, Brian L. Egleston, Emmanuelle Nicolas, Kathy Q. Cai, Rohan Brebion, Eleanor Avril, Mark Hitrik, Anna S. Nikonova, Ilya G. Serebriiskii, Vladimir Khazak, Hossein Borghaei, Erica A. Golemis, Yanis Boumber
Journal: Cancer Research (2018)

Abstract Musashi-2 (MSI2) is an RNA-binding protein that regulates mRNA translation. We recently established that MSI2 is elevated in a subset of non-small cell lung cancer (NSCLC) tumors upon progression and drives NSCLC metastasis, in part based on activity supporting a TGF-beta/SMAD3/claudin signaling cascade. Here, reverse phase protein array (RPPA) analysis of MSI2-depleted versus control KrasLA1/+;P53R172HΔG/+ murine NSCLC cell lines identified a significant ~2.7-fold upregulation of HER3 (ERBB3) upon MSI2 depletion. Negative MSI2-dependent regulation of ERBB3 protein was confirmed in multiple NSCLC models, based on analysis of MSI2 depletion or overexpression. Further, MSI2 positively regulated expression of the epidermal growth factor receptor (EGFR) protein in the same models. Comparing EGFR and KRAS driven models, we found that MSI2 depletion significantly impairs cell proliferation only in EGFR-mutant NSCLC cell lines. Using RNA immunoprecipitation analysis coupled with qPCR, we show that MSI2 directly binds to EGFR and, to a lesser extent, to HER3 mRNA. MSI2 mRNA binding was approximately correlating with the presence of predicted MSI2 binding sites in corresponding mRNAs. NSCLC lung tissue microarray analysis revealed that MSI2 total positivity by H-score, 2+/3+ and 3+ positivity correlated with EGFR 3+ staining. Finally, EGFR inhibitors erlotinib and afatinib synergized with MSI2 depletion in EGFR mutant models, suggesting that therapeutic targeting of MSI2 could be of clinical value, especially in EGFR-mutant lung cancer. Citation Format: Peter Makhov, Alexander Kudinov, Alexander Deneka, Brian L. Egleston, Emmanuelle Nicolas, Kathy Q. Cai, Rohan Brebion, Eleanor Avril, Mark Hitrik, Anna S. Nikonova, Ilya G. Serebriiskii, Vladimir Khazak, Hossein Borghaei, Erica A. Golemis, Yanis Boumber. Musashi-2 regulates EGFR/HER3 expression in NSCLC, cell proliferation and response to EGFR inhibitors in EGFR-mutant NSCLC [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 4452.
Abstract 3519: Disrupting glutamine metabolism depletes glutathione and sensitizes atypical teratoid/rhabdoid tumor to carboplatin
Authors: Sabrina Z. Wang, Brad Poore, Jesse Alt, Rana Rais, Sariah Allen, Brent Orr, Barbara Slusher, Charles Eberhart, Eric Raabe, Jeffrey Rubens
Journal: Cancer Research (2018)

Abstract Atypical teratoid rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy. Recent high-throughput molecular analyses identified 3 distinct subgroups of AT/RT. Preliminary studies show that subgroups with elevated MYC expressions are particularly aggressive, with 18.5% 5-year survival. MYC is challenging to directly target, but MYC increases tumor cells' reliance on glutamine for their metabolic demands. We hypothesize that MYC-driven ATRT can be targeted by inhibiting glutamine metabolism. 6-Diazo-5-oxo L-norleucine (DON) is a glutamine analogue that was well tolerated in a phase I pediatric clinical trial, but DON has never been tested in MYC-driven pediatric tumors. Approximately 1/3 of human AT/RT express high MYC protein (immunohistochemistry for c-MYC expression on 22 human AT/RT, H-score &amp;gt; 1 standard deviation over the median for high c-MYC expression). DON slows cell growth and induces apoptosis in high MYC-expressing AT/RT while low MYC-expressing cells are resistant (MTS assay and Western blot for c-PARP, respectively). Transducing low MYC-expressing cell lines with lentivirus with MYC plasmid to force MYC expression confers sensitivity to DON therapy (decreased cell growth per MTS assay, increased apoptosis per Western for c-PARP). DON administered intraperitoneally 30mg/kg weekly nearly doubles median survival in orthotopic xenograft models of AT/RT (p&amp;lt;0.001 by log rank test; median survival extended from 21 to 36 days). Metabolic flux experiments tracing 15N and 13C labeled glutamine reveal that DON reduces intracellular glutathione. We combine DON with carboplatin because glutathione is critical for detoxification of carboplatin and find that the combination works synergistically to further slow cell growth and induce higher rates of apoptosis (MTS assay, MUSE Cell Viability Assay). This study takes a novel approach to targeting cancer metabolism and serves as the first targeted therapeutic strategy addressing the MYC-expressing subgroup of AT/RT. These findings support the rationale for potential future clinical trials testing glutamine analogues against the MYC subgroup of AT/RT as well as other deadly MYC-driven tumors. Citation Format: Sabrina Z. Wang, Brad Poore, Jesse Alt, Rana Rais, Sariah Allen, Brent Orr, Barbara Slusher, Charles Eberhart, Eric Raabe, Jeffrey Rubens. Disrupting glutamine metabolism depletes glutathione and sensitizes atypical teratoid/rhabdoid tumor to carboplatin [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 3519.
Abstract 15598: SDPR/Cavin-2 Modulates Akt Sgnaling Involved in Regulation of Hypertrophy and Apoptosis in Cardiomyocytes
Authors: NaokiMaruyama, TakehiroOgata, NaohikoNakanishi, TetsuroHamaoka, KotaroMiyagawa, TakeruKasahara, TomomiUeyama
Journal: Circulation (2014)

Introduction: SDPR/Cavin-2 is a member of the cavins which belongs to caveolar related proteins. SDPR/Cavin-2 regulates caveolar formation in a variety of cell types.The structural role of SDPR/Cavin-2 in caveolae has been well studied. However, its functional role remains unknown. Here, we present a novel functional role of SDPR/Cavin-2 in cardiomyocytes. Methods and Results: To examine the functional role of SDPR/Cavin-2 in cardiomyocytes, we generated SDPR/Cavin-2 knock-out (SDPR-/-) mice and knocked down SDPR/Cavin-2 expression in neonatal rat cardiomyocytes using adenovirus expressing SDPR/Cavin-2 shRNA. SDPR-/- mice developed a progressive cardiac hypertrophy. At fourteen weeks of age, SDPR-/- mice had a significantly higher heart weight/body weight ratio than wild-type mice. SDPR-/- mice displayed significant concentric hypertrophy as revealed by echocardiography. In vitro study, increased cardiomyocyte surface area, which was associated with induction of hypertrophy-related fetal gene expression, ...
Abstract 3667: Technical advances in plasma genomic biomarkers for mutation detection and monitoring in cancer patients
Authors: Sandra Fitzgerald, Annette Lasham, Cherie Blenkiron, Paula Shields, Ben Lawrence, Cristin Print
Journal: Cancer Research (2018)

Abstract A sea-change is imminent for cancer medicine, due to the use of non-invasive genomic biomarkers in blood to inform screening, diagnosis and the selection of treatment. This technology may be used routinely in oncology within five years. Although numerous studies, including work in our laboratory, have shown that genomic analysis of blood can detect the presence and even the type of cancer, researchers have only scratched the surface of what this technology can do. In our laboratory, we are generating new methods to improve the sensitivity and accuracy of such tests. Cell-free DNA from a metastatic colorectal cancer patient has been used to directly compare the sensitivity of mutation detection across three platforms - a custom QiaSeq Targeted amplicon sequencing panel, droplet digital PCR (ddPCR) and UltraSEEK lung panel. UltraSEEK and ddPCR platforms show better sensitivity for detection of the KRAS G12A mutation, compared to the QiaSeq Targeted DNA sequencing panel. This pilot study shows that when looking to specifically detect a small number of known mutations, UltraSEEK or ddPCR gives the highest sensitivity, but when mutations are not limited to a few or are completely unknown, the QiaSeq Targeted DNA panel allows identification of the entire repertoire of mutations in specific cancer-associated genes. Citation Format: Sandra Fitzgerald, Annette Lasham, Cherie Blenkiron, Paula Shields, Ben Lawrence, Cristin Print. Technical advances in plasma genomic biomarkers for mutation detection and monitoring in 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 3667.
Abstract 12607: Renin Angiotensin Aldosterone System Inhibition Prevents the Arterial Stiffness Elevation Resulting in the Amelioration of Inappropriate Cardiovascular Response During Exercise in Patients With Hypertension
Authors: KanaeYabu, TakashiMasuda, MisaoOgura, RyosukeShimizu, DaisukeKamekawa, AyakoAkiyama, YumiKamada, ShinyaTanaka, NobuakiHamazaki, AkihiroAoyama, TakeshiNakamura, EmiMaekawa, MinakoTojo, JunyaAko
Journal: Circulation (2015)

Introduction: Patients with hypertension (HT) are known to show an increased activity of renin-angiotensin-aldosterone system (RAAS) secondary to sympathetic hyperactivity. The RAAS hyperactivity was reported to induce vascular endothelial dysfunction and elevated functional arterial stiffness resulting in an inappropriate cardiovascular response during exercise such as an excessive blood pressure (BP) elevation. This study investigated whether a long-term RAAS inhibition ameliorated the inappropriate cardiovascular response during exercise in HT patients. Methods: Eighty HT patients (64±14 years, 48 males) were divided into two groups based on antihypertensives: angiotensin II receptor blocker (ARB) group and L-type calcium channel blocker (CCB) group. Patients were followed up for one year, after their BP was controlled below 140/90 mmHg. Patients received a cycle ergometer test, and blood examination before and after the follow-up period. We determined systolic blood pressure (SBP) elevation during the...
Abstract 42: Triple negative breast cancer cell heterogeneity in zebrafish-host microenvironment
Authors: B.Ewa Snaar-Jagalska, Arwin Groenewoud, Letizia Astrologo, Lanpeng Chen, Marianna Kruithof-de Julio
Journal: Cancer Research (2018)

Abstract Metastatic triple negative breast cancer (TNBC) can be considered as incurable endpoint in the progression of TNBC, prevention or treatment of metastasis therefore is of paramount importance. New insights into intra-tumoral heterogeneity have cast light on the existence of multiple functionally distinct cellular entities within one tumor, among others these cells can be divided based on their metastatic potential. The zebrafish provides us with the unique opportunity to study the first steps of metastatic initiation in great detail both microscopically and transcriptionally, on the side of both the host and cancer cells. Organotropic TNBC lines engrafted into this model recapitulate the tropism found in higher vertebrates. Using our zebrafish TNBC xenograft model we study these cellular sub-populations in vivo during metastatic initiation. These small metastatic lesions can be further analyzed ex vivo through the re-isolation of novel zebrafish specific organotropic cell lines. Re-engraftment of these greatly enhances the tumorigenic potential, and transcriptional analysis reveals increased EMT plasticity and an induction of stemness markers. Engraftment of these cells into murine tibia shows a significantly increased tumorigenic and osteolytic potential, further underscoring the critical role of this sub-population in cancer initiation. To determine the genetic drivers of this process we performed whole exome sequenced (NGS) of both, in vitro cultured cancer cells (maternal and re-isolated) and micro-dissected tissue samples derived from in situ zebrafish xenograft material. We are currently in the process of evaluating the candidate genes underpinning the enhanced tumorigenic potential in both the zebrafish and murine models used. Citation Format: B.Ewa Snaar-Jagalska, Arwin Groenewoud, Letizia Astrologo, Lanpeng Chen, Marianna Kruithof-de Julio. Triple negative breast cancer cell heterogeneity in zebrafish-host microenvironment [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 42.