tbuckley/cabot-search huggingface dataset:
Abstract 15181: Female Sex Hormones Are Protective of Vascular Cognitive Impairment in Aortic-Banded Mini-Swine
Authors: T. Dylan Olver, Jessica A Hiemstra, Jenna C Edwards, Jan R Ivey, Pamela K Thorne, Todd R Schactman, Paul J Fadel, Cheryl M Heesch, M. Harold Laughlin, Craig A Emter
Journal: Circulation (2016)

Introduction:  The prevalence of heart failure with preserved ejection fraction (HFpEF) increases disproportionately following menopause, and is associated with systemic vascular dysfunction and accelerated cognitive decline. The purpose of this study was to examine the relationship between cerebrovascular function and cognition in intact (CON) and ovariectomized (OVX) aortic-banded (AB; model of HFpEF) mini-swine. We hypothesized that the combination of OVX and AB, reflecting postmenopausal HFpEF, would result in pathological cerebral vasoconstriction associated with vascular cognitive impairment.   Methods:  Female Yucatan mini-swine were divided into 4 groups; CON (n=6), OVX (n=7), AB (n=6) and AB-OVX (n=7). OVX and AB procedures occurred at 7 and 8 mo. of age, respectively. Memory performance was tested using a spatial-holeboard task 4 mo. post-surgery. Carotid and cerebral blood flow (CBF; Doppler ultrasound) were measured  in vivo  during vena cava occlusion (autoregulation task) or at rest 6 mo. post-surgery, respectively. Myogenic tone and vasomotor responses to neuropeptide Y (NPY) were examined  in vitro  (pressurized myography) in cerebral resistance arteries. Significance is reported at P   Results:  Working and reference memory were impaired and CBF decreased in OVX animals (OVX main effect), with group differences in the AB-OVX vs. AB group. Average memory scores and CBF were positively correlated (R=0.54). Vascular resistance was increased (group main effect) and carotid blood flow decreased (group X time interaction) following vena cava occlusion in the AB-OVX group vs. CON. Vasoconstrictor responses to NPY in isolated cerebral resistance arteries were increased in AB-OVX vs. CON animals at all doses (group X dose interaction). Increased vasoconstriction to NPY was observed in the OVX and AB groups at higher doses only. Myogenic tone was similar between groups.   Conclusion:  Cognitive deficits were associated with reduced CBF and increased vasoconstriction to NPY in the AB-OVX group. AB alone did not cause cerebrovascular or cognitive impairment, suggesting female sex hormones protect against developing vascular cognitive impairment in a translational model of pressure-overload HF with potential relevance to human HFpEF.
Upregulation of E3 Ubiquitin Ligase CBLC Enhances EGFR Dysregulation and Signaling in Lung Adenocarcinoma
Authors: Shiao-Ya Hong, Yu-Rung Kao, Te-Chang Lee, Cheng-Wen Wu
Journal: Cancer Research (2018)

CBLC (CBL proto-oncogene c) belongs to the CBL protein family, which has E3 ubiquitin ligase activity toward activated receptor tyrosine kinases. CBLC is frequently upregulated in non-small cell lung cancer (NSCLC), yet very little is known about the functions of CBLC in tumorigenesis. Here we show that CBLC is an epigenetically demethylated target and its expression can be upregulated in NSCLC after treatment with the DNA methylation inhibitor 5'-azacytidine. Depletion of CBLC significantly inhibited cell viability and clonogenicity in vitro and reduced tumor growth in a xenograft model. CBLC silencing further sensitized EGFR-mutated NSCLC cells to treatment with tyrosine kinase inhibitors. Conversely, ectopic expression of CBLC enhanced the activation of EGFR and downstream ERK1/2 signaling after ligand stimulation by competing with CBL for EGFR binding. Analysis of ubiquitin linkages on activated EGFR (aEGFR) revealed that CBLC ubiquitinated and positively regulated aEGFR stability through the conjugation of polyubiquitin by K6 and K11 linkages. This CBLC-mediated polyubiquitination promoted either preferential recycling of aEGFR back to the plasma membrane or trafficking to the cell nucleus. IHC analyses revealed a positive correlation between phospho-EGFR and CBLC in lung adenocarcinoma. In summary, we demonstrate a novel mechanism by which aEGFR escapes lysosomal degradation in a CBLC/ubiquitin-dependent manner to sustain its activation. Our work identifies CBLC as a potential diagnostic biomarker and also points to its utilization as a novel therapeutic target for NSCLC therapy.Significance: This work demonstrates the role of CBLC expression as a diagnostic biomarker and potential therapeutic target in lung adenocarcinoma. Cancer Res; 78(17); 4984-96. ©2018 AACR.
Non-classical monocytes as mediators of tissue destruction in arthritis
Authors: Antonia Puchner, Victoria Saferding, Michael Bonelli, Yohei Mikami, Melanie Hofmann, Julia S Brunner, Michael Caldera, Eliana Goncalves-Alves, Nikolaus B Binder, Anita Fischer, Elisabeth Simader, Carl-Walter Steiner, Harald Leiss, Silvia Hayer, Birgit Niederreiter, Thomas Karonitsch, Marije I Koenders, Bruno K Podesser, John J O’Shea, Jörg Menche, Josef S Smolen, Kurt Redlich, Stephan Blüml
Journal: Annals of the Rheumatic Diseases (2018)

Objectives Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive. Methods We investigated CCR2 −/− mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis. Results We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL. Conclusion Therefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage.
CTGF Mediates Tumor–Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression
Authors: Yuki Makino, Hayato Hikita, Takahiro Kodama, Minoru Shigekawa, Ryoko Yamada, Ryotaro Sakamori, Hidetoshi Eguchi, Eiichi Morii, Hideki Yokoi, Masashi Mukoyama, Suemizu Hiroshi, Tomohide Tatsumi, Tetsuo Takehara
Journal: Cancer Research (2018)

Abstract Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/+). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/+ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and α-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF expression, but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell–derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody. Significance: Protumor cross-talk between cancer cells and hepatic stellate cells presents an opportunity for therapeutic intervention against HCC. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4902/F1.large.jpg. Cancer Res; 78(17); 4902–14. ©2018 AACR.
Abstract 19086: Pulsatile Shear Stress-mediated Fatty Acid Metabolites Promote Anti-oxidant Effects
Authors: Nelson Jen, Jonathan Tang, Jonathan Gau, Olujimi A Ajijola, Rongsong Li, Tzung K Hsiai
Journal: Circulation (2015)

Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. While oscillatory shear stress (OSS) preferentially develops at the lateral wall of arterial bifurcations and induces oxidative stress and inflammatory states, pulsatile shear stress (PSS) develops in the straight portions of the vasculature to oppose the effects and promote “athero-protection”. In this context, we hypothesize that PSS activates PPAR-γ to produce athero-protective fatty acid metabolites to attenuate oxidative stress. Metabolomic analysis performed for 155 metabolites from human aortic endothelial cells exposed to PSS (τ avg = 23±8 dyne/cm 2 at 1 Hz for 4 hrs) revealed a significant increase in anti-inflammatory metabolites, including fatty acids such as oleic acid (OA) and dicarboxylic acids such as azelaic acid (AzA) (1.43±0.73-fold, 2.03±0.54-fold vs. control, respectively, p &lt; 0.05, n=6), and up-regulated metabolism-related genes including SCD1 and PPAR-γ (1.42±0.14-fold, 1.53±0.32-fold vs. control, respectively, p &lt; 0.001, n=6). SCD1 produces oleic acid, and SCD1 mRNA expression was down-regulated by siPPAR-γ (0.66±0.17-fold, vs. PSS, p &lt; 0.05, n=4). AzA, a known PPAR-γ agonist and a breakdown product of oleic acid, down-regulated VCAM and ICAM (0.31±.09-fold, 0.18±.01-fold vs. control, respectively, p &lt;0.05, n=4) when treated with AzA alone. AzA attenuated H 2 O 2 -induced VCAM and ICAM mRNA expression (0.36±0.10-fold, 0.38±0.20-fold, respectively, p &lt;0.05, n=4). The role PSS on PPAR- γ activation was further recapitulated in a model for paroxysmal atrial fibrillation (Afib) in New Zealand White rabbits. The right atrium was paced at 800 bpm (cycle length (CL) = 75 ms) to produce an irregular ventricular response of a mean rate of 200 bpm (CL = 300 ms) to simulate atrial fibrillation for 4 hours. p-PPAR- γ staining in the athero-prone aortic arches vs. athero-protective descending aortas was decreased in response to a reduction in time-averaged shear stress (from τ avg = 32.0±2.4 dyne/cm 2 to τ avg = 22.7±3.5 dyne/cm 2 ). Overall, pulsatile shear stress-induced fatty acid metabolites impart anti-oxidant effects to maintain endothelial homeostasis, implicating the role of PPAR-γ-SCD1-OA-AzA pathway.
Abstract LB-312: GRK5 activity mediates in vivo and in vitro prostate cancer progression and chemoresistance
Authors: Joseph B. Black, Hamsa Thayele Purayil, Iqbal Mahmud, Daiqing Liao, Yehia Daaka
Journal: Cancer Research (2018)

Abstract Despite decades of research targeting the activity of the androgen receptor (AR), patients diagnosed with locally advanced and metastatic prostate cancer face an incurable disease. The Daaka lab investigates constituents of G-protein-coupled receptor signaling cascades for their ability to provide mitogenic signaling, which promotes PCa progression. We previously identified G protein-coupled receptor 5 (GRK5) for its ability to regulate PCa progression, independent of AR activity. GRK5 partially partitions to the nucleus, wherein it has been shown to regulate the transcriptome in non-PCa models. To globally elucidate the mechanistic impact of GRK5 on PCa progression, we are investigating the impact of GRK5 on the PCa transcriptome. We hypothesize that GRK5's regulation of the PCa transcriptome promotes tumor progression. To assay the effect of GRK5 on the PCa transcriptome, RNA sequencing was performed in two cell lines: PC3 Control (PC3 shGFP) and PC3 GRK5 Knockdown (PC3 shGRK5). Ontologic analysis identified the epithelial–mesenchymal transition (EMT) as being affected when GRK5 is depleted. The epithelial–mesenchymal transition (EMT) is highly associated with promoting PCa progression and chemoresistance, thus we selected this pathway for further investigation. Confirmatory western blot analysis and quantitative PCR (qPCR) validated that depleting GRK5 suppresses the expression of the mesenchymal markers Vimentin and N-Cadherin. Similarly, overexpression of GRK5 increases the expression of these mesenchymal markers. Stable overexpression of GRK5 promotes cells to develop a spindle-like morphology, indicative of a mesenchymal state. GRK5 mediates this mesenchymal transition through increasing the expression of the EMT transcription factor, Twist1. Further analysis identifies that GRK5 activity promotes in vitro invasion. Cell lines overexpressing GRK5 demonstrate an increase in resistance to docetaxel, the mainstay chemotherapy for advanced PCa. Overexpression of GRK5 promotes lymphatic intravasation. Overexpression of mutated forms of GRK5 that are relegated to the nucleus are able recapitulated all aforesaid changes, arguing that the nuclear activity of GRK5 mediates this effect. Collectively, this data presents a novel mechanism promoting PCa progression, independent of AR activity. Citation Format: Joseph B. Black, Hamsa Thayele Purayil, Iqbal Mahmud, Daiqing Liao, Yehia Daaka. GRK5 activity mediates in vivo and in vitro prostate cancer progression and chemoresistance [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 LB-312.
Bath Emollients Offer Little Added Benefit in Pediatric Eczema
Authors: Anita Slomski
Journal: JAMA (2018)

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18F-Fluciclovine Uptake by an Incidentally Detected Hepatocellular Carcinoma in a Case of Biochemically Recurrent Prostate Cancer
Authors: Bhagya Sannananja, Hardik Uresh Shah, Fatemeh Behnia
Journal: Clinical Nuclear Medicine (2018)

Prostate cancer is one of the most common cancers affecting men worldwide with a high recurrence rate following therapy. F-fluciclovine, is a US Food and Drug Administration-approved radiopharmaceutical for PET imaging in biochemically recurrent prostate cancer. It targets increased amino acid transporters in the cell membrane of cancer cells. We report a case of incidentally detected hepatocellular carcinoma showing F-fluciclovine uptake in a 71-year-old man with biochemically recurrent prostate cancer.
A pneumatosis intestinalis case diagnosed with water-immersion technique
Authors: Mesut Akarsu, Yakup Duran, Zarni Htway
Journal: Endoscopy (2018)

A 65-year-old man presented to the outpatient department with a complaint of moderate flatulence for 2 years. His personal history included coronary artery disease and type 2 diabetes mellitus, which was poorly controlled by oral antidiabetic medications. He also underwent inguinal hernia operation 2 years previously.
Flexible‐Device Injector with a Microflap Array for Subcutaneously Implanting Flexible Medical Electronics
Authors: Kwangsun Song, Juho Kim, Sungbum Cho, Namyun Kim, Dongwuk Jung, Hyuck Choo, Jongho Lee
Journal: Advanced Healthcare Materials (2018)

Abstract Implantable electronics in soft and flexible forms can reduce undesired outcomes such as irritations and chronic damages to surrounding biological tissues due to the improved mechanical compatibility with soft tissues. However, the same mechanical flexibility also makes it difficult to insert such implants through the skin because of reduced stiffness. In this paper, a flexible‐device injector that enables the subcutaneous implantation of flexible medical electronics is reported. The injector consists of a customized blade at the tip and a microflap array which holds the flexible implant while the injector penetrates through soft tissues. The microflap array eliminates the need of additional materials such as adhesives that require an extended period to release a flexible medical electronic implant from an injector inside the skin. The mechanical properties of the injection system during the insertion process are experimentally characterized, and the injection of a flexible optical pulse sensor and electrocardiogram sensor is successfully demonstrated in vivo in live pig animal models to establish the practical feasibility of the concept.
Abstract 2780: Engineering human fusion constructs for targeted delivery of granzyme B to CD33 and CEA antigens
Authors: Lawrence H. Cheung, Khalid A. Mohamedali, Walter N. Hittelman, Michael G. Rosenblum
Journal: Cancer Research (2018)

Abstract Our laboratory has developed a unique platform for the delivery of the highly pro-apoptotic serine protease granzyme B (GrB). The construct contains enzymatically active GrB and therefore does not require release from the targeting carrier by a fragile linker in contrast to conventional antibody-drug conjugates (ADCs). We employed two scFvs targeting the CD33 antigen found on AML and the juxtamembrane epitope of CEA found on numerous solid tumors. These human scFvs (designated HU33 and CEA respectively) were fused to human GrB through an engineered IgG heavy-chain fragment (hinge to Fc and designated Fc) which contains a dimerization domain. The GrB-Fc-HU33 and GrB-Fc-CEA constructs were cloned into the pSECTag vector containing an upstream 5kDa purification tag with an enterokinase (EK) cleavage site for facile removal. The molecules were expressed in transiently-transfected HEK-293E suspension cells and grown at 37°C for 3 days in 5% CO2. The molecules were isolated from culture media and purified by IMAC followed by EK cleavage and SP chromatography to remove the free tag. The yields were 6-10 mg/L for both molecules. Specific binding of each molecule to the antigen target is undergoing Biacore and/or ELISA assessment. The cytotoxicity of the GrB-Fc-HU33 against HL-60 cells showed a specific cytotoxic effect with an IC50 of 120 nM. Tests of this agent against a panel of cells expressing various levels of CD33 are ongoing. The cytotoxic effects of the GrB-Fc-CEA were assessed against HT29, HT1080-CEA and A431 cells and demonstrated IC50 values of 80, 110 and 95 nM respectively. Based on IC50 values, these data demonstrate that the fusion construct targeting CD33 is efficiently internalized and effectively delivers active serine protease to the cytosol even at relatively low antigen expression levels. In addition, the juxtamembrane epitope of the CEA antibody also allows efficient internalization for delivery of GrB to the cytosol. Immunofluorescence and confocal studies to examine the time course of internalization and the pro-apoptotic events triggered by these agents are under examination and will be presented. Research conducted, in part, by the Clayton Foundation for Research. Citation Format: Lawrence H. Cheung, Khalid A. Mohamedali, Walter N. Hittelman, Michael G. Rosenblum. Engineering human fusion constructs for targeted delivery of granzyme B to CD33 and CEA antigens [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 2780.
Neoadjuvant sipuleucel-T in localized prostate cancer: Effects on immune cells within the prostate tumor microenvironment.
Authors: Lawrence Fong, Vivian K. Weinberg, Stephen E Chan, John M Corman, Christopher L Amling, Robert A Stephenson, Carl Formaker, Jeffrey Simko, Robert Brownell Sims, Peter Carroll, Eric Jay Small
Journal: Journal of Clinical Oncology (2012)

2564 Background: Sipuleucel-T is an FDA-approved autologous cellular immunotherapy for patients with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer (mCRPC). To date, studies of sipuleucel-T in patients with mCRPC have studied immune response in peripheral blood. The effects of sipuleucel-T on prostate tumors are unknown. Methods: NeoACT (P07-1; NCT00715104) is an open-label, phase 2 study of patients with localized prostate cancer who received sipuleucel-T prior to radical prostatectomy (RP) to examine the immunologic effects of treatment on prostate tissue. Patients received 3 infusions of sipuleucel-T at approximately 2-week intervals, beginning 6-7 weeks prior to RP. The primary endpoint was the change in the frequency of lymphocytes between prostate biopsies (pre-treatment) and RP tissue (post-treatment), as assessed by immunohistochemistry (IHC). Results: The median age of the 42 enrolled patients was 61 years, and all had an ECOG performance status of 0. Thirty-eight patients received all 3 pre-RP sipuleucel-T infusions. To date, tissue IHC analysis has been completed on 32 patients. Treatment-related AEs were manageable and transient. Sipuleucel-T did not appear to impact surgery, as judged by operative complications, procedure time, and estimated blood loss. Frequent events that occurred ≤1 day after infusion (&gt;10% of patients) were fatigue, headache, and myalgia. Significant increases (≥3 fold) in CD3+ and CD4+ T cell populations were observed at the tumor interface (where benign and malignant glands interface), compared with the pre-treatment biopsy, benign RP tissue, and tumor RP tissue (ANOVA post hoc Newman-Keuls test: p&lt;0.0001 for each comparison). FoxP3+ CD4+ T cells were also increased (p=0.0005) at the tumor interface, but represented a small fraction of the observed CD4+ T cells. Conclusions: Neoadjuvant sipuleucel-T treatment is associated with an increased frequency of T cells in prostate cancer tissue at the interface of the benign and malignant glands. These data suggest that sipuleucel-T can modulate the presence of lymphocytes at the prostate tumor site. Work is ongoing to more fully characterize the immune response.