tbuckley/cabot-search huggingface dataset:
Abstract 4727: MicroRNA-155 as a regulator of NK cell mediated solid tumor rejection
Authors: Aman Prasad, Wing Keung Chan
Journal: Cancer Research (2018)

Abstract Natural Killer (NK) cells are granular innate lymphocytes that orchestrate immune response by releasing interferon gamma (IFN-γ): a critical cytokine heavily involved in intercellular immune and inflammatory processes. Prior work from our lab has linked microRNA-155 (miR-155) to significant cell proliferation and NK cell mediated IFN-γ release. Previously, our lab has also shown that miR-155 can increase hematological malignancy rejection and NK cell cytotoxicity in T-cell lymphomas. However, it is unclear how miR-155 can affect NK cell cytotoxicity in solid tumor models. IFN-γ has been reported in the literature to directly induce apoptosis in glioblastoma solid tumors. We therefore hypothesize that miR-155 induction can increase NK cell mediated cytotoxicity and IFN-γ mediated apoptosis for solid tumor rejection. To test this, 10x106 GL261 cells were injected subcutaneously into the flanks of both wild type (WT) littermates and miR-155 transgenic (miR-155Tg) mice. CD3(-)NK1.1(+) effector splenic NK cells were isolated from WT and miR-155Tg mice for total RNA extraction and subsequent gene expression profiling on NK cell activation pathways. We found that tumor growth in WT mice was at least 2-fold greater than that of miR-155Tg mice (average 2cmx2cm vs 0.7cmx0.7cm, n=6). Tumor weights from WT and miR-155 mice were 1052 mg vs 340 mg, respectively, with an average of 2 mice per group. Furthermore, we have successfully created an IFN-γ receptor 1 (IFN-γR1) shRNA knock-down (KD) lentiviral construct in a stable glioblastoma cell line. IFN-γR1 knockdown was measured to be 90% as determined by real-time PCR analysis. Future experiments will be performed wherein IFN-γR1 KD glioblastoma cells will be injected in miR-155Tg and WT mice to evaluate tumor rejection. In summary, we demonstrate a model system to investigate the effect of miR-155 on solid tumor glioblastoma multiforme. Further characterization of gene expression profiles of purified NK cells from both WT and miR-155 mice will provide important insights on the mechanisms of NK cell medicated tumor rejection. Citation Format: Aman Prasad, Wing Keung Chan. MicroRNA-155 as a regulator of NK cell mediated solid tumor rejection [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 4727.
Abstract 5902: RNA sequencing analysis of taxane-resistant prostate cancer cells reveals potential candidate genes for therapeutic targeting
Authors: Christina K. Cajigas-Du Ross, Leanne Woods-Burnham, Joshua Ramirez, Xin Chen, Charles Wang, Carlos A. Casiano
Journal: Cancer Research (2018)

Abstract There is no cure for metastatic prostate cancer (PCa), the most commonly diagnosed cancer and third leading cause of cancer mortality among U.S. men. Patients with advanced PCa often develop resistance to conventional therapies resulting in metastatic castration-resistant PCa (mCRPC). Docetaxel (DTX) chemotherapy is the standard-of-care for mCRPC, followed by secondary chemotherapy with cabazitaxel (CBZ), yet chemoresistance and death inevitably occurs. While pharmacological agents targeting single survival pathways have shown promise at the bench side, clinical trials have failed. This is mostly due to the presence of redundant pathways utilized by PCa tumor cells to maintain chemoresistance. Therefore, we are interested in further defining molecular pathways associated with DTX-resistance in order to identify novel therapeutic targets to overcome this resistance. We hypothesized that RNA sequencing (RNAseq) analysis comparing the transcriptomes of chemosensitive and chemoresistant mCRPC cells will reveal potential targets for combinatorial therapies. RNAseq analysis of DTX-sensitive and -resistant PC3 and DU145 cells revealed a number of differentially regulated genes that were either unique to each cell line or common to both. We found that dipeptidyl peptidase 4 (DPP4), fatty acid binding protein 5 (FABP5), nestin (NES), and tetraspanin 8 (TSPAN8) were among the top most robustly and significantly upregulated genes in both DTX-resistant PC3 and DU145 cell lines. In-house qPCR studies validated the RNAseq results for these genes, and Western blotting analysis showed increased expression of these proteins in DTX-resistant cells, which correlated with increased mRNA expression. Interestingly, NES, TSPAN8, DPP4 are genes associated with development of the cancer stem-cell (CSC) phenotype. Other genes associated with CSCs were also upregulated in the DTX-resistant cells, suggesting that in vitro selection of mCRPC cells for DTX resistance may enrich for CSCs. This novel finding is consistent with recent studies implicating CSCs in PCa chemoresistance. Further analysis and validation of our RNAseq data will increase our understanding of DTX-resistance mechanisms in PCa cells, including the yet undefined functional role of CSC-related genes. These studies also reveal potential therapeutic targets to circumvent DTX resistance in PCa. Citation Format: Christina K. Cajigas-Du Ross, Leanne Woods-Burnham, Joshua Ramirez, Xin Chen, Charles Wang, Carlos A. Casiano. RNA sequencing analysis of taxane-resistant prostate cancer cells reveals potential candidate genes for therapeutic targeting [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 5902.
Abstract 11021: Cardiac Rehabilitation Improves Risk Factors, Quality of Life and Exercise Capacity in Extreme Old Age
Authors: Hardik Mehta, Shannon St.Clair, Matthew Sacrinty, Dominic Johnson, Danylo Zorin, Theresa Addison, DonTressica Greer, Beverly Martin, Cynthia Hayes, Connie Paladenech, Killian Robinson
Journal: Circulation (2011)

Introduction: Octogenarians are the fastest growing segment of the US population but data concerning cardiac rehabilitation (CR) in this patient group are sparse. Hypothesis: A 36-session CR program improves risk factor profile, quality of life (QOL) and exercise capacity in patients older than 80 years of age. Methods: A total of 945 patients were prospectively enrolled in an outpatient CR program. Baseline demographics and risk factors were recorded. Lipid profiles, BMI and QOL scores were documented pre and post CR. Steady state exercise levels (metabolic equivalents - METs) were calculated at each session. Results: There were 873 patients <80 years (male 73%, mean age 61 ± 10.6) and 72 patients ≥ 80 years (male 64%, mean age 83 ± 2.3). Risk factors were similar in the older and the younger groups. At baseline, octogenarians had lower BMI (Δ3.4, p<0.05), higher mean QOL score (Δ2.2, p<0.05) and lower mean MET levels (Δ0.5, p<0.05) than those <80 years. In both groups, risk factors and QOL improved (see...
Transcriptional activation of glucose transporter 1 in orthodontic tooth movement-associated mechanical response
Authors: Yu Wang, Qian Li, Fuliang Liu, Shanshan Jin, Yimei Zhang, Ting Zhang, Yunyan Zhu, Yanheng Zhou
Journal: International Journal of Oral Science (2018)

Abstract The interplay between mechanoresponses and a broad range of fundamental biological processes, such as cell cycle progression, growth and differentiation, has been extensively investigated. However, metabolic regulation in mechanobiology remains largely unexplored. Here, we identified glucose transporter 1 (GLUT1)—the primary glucose transporter in various cells—as a novel mechanosensitive gene in orthodontic tooth movement (OTM). Using an in vivo rat OTM model, we demonstrated the specific induction of Glut1 proteins on the compressive side of a physically strained periodontal ligament. This transcriptional activation could be recapitulated in in vitro cultured human periodontal ligament cells (PDLCs), showing a time- and dose-dependent mechanoresponse. Importantly, application of GLUT1 specific inhibitor WZB117 greatly suppressed the efficiency of orthodontic tooth movement in a mouse OTM model, and this reduction was associated with a decline in osteoclastic activities. A mechanistic study suggested that GLUT1 inhibition affected the receptor activator for nuclear factor-κ B Ligand (RANKL)/osteoprotegerin (OPG) system by impairing compressive force-mediated RANKL upregulation. Consistently, pretreatment of PDLCs with WZB117 severely impeded the osteoclastic differentiation of co-cultured RAW264.7 cells. Further biochemical analysis indicated mutual regulation between GLUT1 and the MEK/ERK cascade to relay potential communication between glucose uptake and mechanical stress response. Together, these cross-species experiments revealed the transcriptional activation of GLUT1 as a novel and conserved linkage between metabolism and bone remodelling.
Abstract 3113: Expression of autophagy- and mitophagy-related genes in clear cell renal cell carcinoma
Authors: Adrian G. Simon, Joerg Ellinger, Yuri Tolkach, Stefan C. Mueller, Glen Kristiansen, Marieta I. Toma
Journal: Cancer Research (2018)

Abstract Objectives: First objective of this study was to establish primary cell cultures from renal cell carcinoma (RCC). Second objective was to analyze mRNA and protein expression of PINK1, PARK2, PACRG and a-Synuclein, genes involved in cell survival, apoptosis and mitophagy. Methods: Tumor and non-neoplastic tissue from 15 patients undergoing surgery for clear cell renal cell carcinoma (ccRCC, n=9), papillary renal cell carcinoma (pRCC, n=3) as well as three retroperitoneal metastases (two clear cell, one papillary type) were obtained. After tissue digestion and filtration malignant and non-malignant cells were cultivated in two different media in order to establish an optimized cultivation procedure. DNA and RNA were extracted and immunohistochemical analyses (IHC) and qPCR from cultivated cells were performed for VHL and CAIX to verify tumor histotype. RNA was isolated from fresh-frozen primary ccRCC samples and corresponding non-malignant tissues from 50 patients (30 male, 20 female). Expression of PINK1, PARK2, PACRG and a-synuclein was measured by qPCR in the cultivated ccRCC cell lines as well as in the patient samples. Results: All tumor specimens were successfully cultivated to first confluence. Six out of nine ccRCC cell lines and all other tumor specimens could be passaged more than two times. Cultivated RCC cells showed protein expression matching to their tumor of origin in IHC analyses, confirming tumor identity. QPCR demonstrated VHL expression downregulated or lost in all ccRCC cell lines and CA9 highly upregulated in most cases, which is both typical for ccRCC. The mRNA expression of PINK1, PARK2 and PACRG was downregulated in ccRCC cultures as well as in the 50 patient tumors in comparison to normal tissue. A-synuclein expression was highly variable. Conclusions: We successfully established primary cell cultures from various renal tumor entities suitable for further investigation. Loss of PACRG and PARK2 are common events in ccRCC. PACRG and PARK2 might function as tumor suppressors in ccRCC and their loss may be involved in tumor progression as reported before for other tumor entities. Further investigation of PINK1, PARK2 and PACRG might allow new therapeutic approaches. Citation Format: Adrian G. Simon, Joerg Ellinger, Yuri Tolkach, Stefan C. Mueller, Glen Kristiansen, Marieta I. Toma. Expression of autophagy- and mitophagy-related genes 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 3113.
The Ballistocardiogram in Overweight Young Adults
Authors: Samuelstern, MissAjaLipavsky
Journal: Circulation (1958)

The ability to record the mechanical function of the heart is the principal value of the ballistocardiogram. In young healthy individuals the ballistocardiogram is consistently normal. Since overweight is apparently an important factor in the development of degenerative heart diseases, a study was undertaken to correlate excess weight in otherwise healthy young students with their respective ballistocardiograms, obtained on a direct-body ballistocardiograph.
Abstract A66: The tissue transglutaminase 2–fibronectin protein complex: A new target in ovarian cancer
Authors: Livia Elena Sima, Bakhtiyor Yakubov, Salvatore Condello, Horacio Cardenas, Zhong Yin Zhang, Lan Chen, Daniela Elena Matei
Journal: Clinical Cancer Research (2018)

Abstract Here we describe a small-molecule inhibitor (SMI) that disrupts the tissue transglutaminase 2 (TG2)-fibronectin (FN) interaction. TG2 is a multifunctional protein, with enzymatic (transglutaminase, isopeptidase, protein disulfide isomerase), GTPase, and extracellular matrix (ECM) scaffold activities. TG2 directly interacts with FN through its N-terminus domain, playing an important role in stabilizing ternary TG2/FN/integrin complexes, which regulate cell adhesion to the matrix. Our group has previously shown that TG2 overexpressed in ovarian cancer (OC) promotes epithelial-to-mesenchymal transition (EMT) contributing to OC cell invasiveness and metastatic behavior. We showed that the interaction with FN is critical to these functions. Proximity ligation assay was used to measure TG2/integrin beta 1 interaction in OC tumors and identified TG2/integrin beta 1 complex in &amp;gt;50% of ovarian tumors, irrespective of histologic type. Based on those findings, we conducted the high-throughput screening and identified TG53 as the lead TG2/FN inhibitory compound. Structure-activity relationship-based approach was used to optimize the physicochemical properties of TG53, leading to design and chemical synthesis of 6 analogues (MT1-6). All analogues blocked TG2/FN interaction, as measured by an ELISA assay, and OC cell adhesion to FN, as measured by a solid phase assay, MT4 being the most potent inhibitor. MT4 downregulates integrin-initiated signaling in OC cells, leading to downstream inhibition of FAK and ERK. Immunofluorescence staining demonstrated that the actin cytoskeleton adopts a cortical localization pattern in MT4-treated cells. MT4 caused membrane ruffling delaying the formation of stable focal contacts and mature adhesions points. Pretreatment with MT4 sensitized OC cells to paclitaxel, as measured by colony-forming assay. In an intraperitoneal OC mouse model, MT4 caused decreased OC cell adhesion to the peritoneum, inhibiting peritoneal dissemination. Hence, MT4 is a potential candidate to be developed and used in combination with current chemotherapeutics to target OC tumor progression. Further studies will continue to optimize this new class of TG2/FN SMIs for potential clinical use in OC. Citation Format: Livia Elena Sima, Bakhtiyor Yakubov, Salvatore Condello, Horacio Cardenas, Zhong Yin Zhang, Lan Chen, Daniela Elena Matei. The tissue transglutaminase 2–fibronectin protein complex: A new target in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr A66.
Prostacyclin-Deficient Mice Develop Ischemic Renal Disorders, Including Nephrosclerosis and Renal Infarction
Authors: ChiekoYokoyama, TomokoYabuki, ManabuShimonishi, MasayukiWada, ToshihisaHatae, SusumuOhkawara, JunjiTakeda, TarohKinoshita, MasaruOkabe, TadashiTanabe
Journal: Circulation (2002)

Background— Prostacyclin (PGI2) is a short-lived endogenous inhibitor of platelet aggregation and a potent vasodilator and regulator of the growth of vascular smooth muscle cells. To study the role of PGI2 in the vascular system in vivo, PGI2-deficient (PGID) mice were established by genetic disruption of the PGI2 synthase gene. Methods and Results— PGI2 synthase–null mice were generated by replacing the exons of PGI2 synthase gene that encodes for the catalytic site of the enzyme with a neomycin resistance gene. In these mice, PGI2 levels in the plasma, kidneys, and lungs were reduced, whereas thromboxane and prostaglandin E2 levels became elevated. Blood pressure and the amounts of urea nitrogen and creatinine in plasma of the PGID mice were significantly higher than those of wild-type mice (P<0.05). They developed progressive morphological abnormalities in the kidneys, accompanied by atrophy, surface irregularity, fibrosis, cyst, arterial sclerosis, and hypertrophy of vessel walls. Thickening of the th...
Left Ventricular Ejection Fraction Normalization in Cardiac Resynchronization Therapy and Risk of Ventricular Arrhythmias and Clinical Outcomes
Authors: Martin H. Ruwald, Scott D. Solomon, Elyse Foster, Valentina Kutyifa, Anne-Christine Ruwald, Saadia Sherazi, Scott McNitt, Christian Jons, Arthur J. Moss, Wojciech Zareba
Journal: Circulation (2014)

Appropriate guideline criteria for use of implantable cardioverter-defibrillators (ICDs) do not take into account potential recovery of left ventricular ejection fraction (LVEF) in patients treated with CRT-defibrillator.Patients randomized to CRT-defibrillator from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial who survived and had paired echocardiograms at enrollment and at 12 months (n=752) were included. Patients were evaluated by LVEF recovery in 3 groups (LVEF ≤35% [reference], 36%-50%, and >50%) on outcomes of ventricular tachyarrhythmias (VTAs), VTA ≥200 bpm, ICD shock, heart failure or death, and inappropriate ICD therapy by multivariable Cox models. A total of 7.3% achieved LVEF normalization (>50%). The average follow-up was 2.2±0.8 years. The risk of VTA was reduced in patients with LVEF >50% (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.07-0.82; P=0.023) and LVEF of 36% to 50% (HR, 0.44; 95% CI, 0.28-0.68; P<0.001). Among patients with LVEF >50%, only 1 patient had VTA ≥200 bpm (HR, 0.16; 95% CI, 0.02-1.51), none were shocked by the ICD, and 2 died of nonarrhythmic causes. The risk of HF or death was reduced with improvements in LVEF (LVEF >50%: HR, 0.29; 95% CI, 0.09-0.97; P=0.045; and LVEF of 36%-50%: HR, 0.44; 95% CI, 0.28-0.69; P<0.001). For inappropriate ICD therapy, no additional risk reduction for LVEF>50% was seen compared with an LVEF of 36% to 50%. A total of 6 factors were associated with LVEF normalization, and patients with all factors present (n=42) did not experience VTAs (positive predictive value, 100%).Patients who achieve LVEF normalization (>50%) have very low absolute and relative risk of VTAs and a favorable clinical course within 2.2 years of follow-up. Risk of inappropriate ICD therapy is still present, and these patients could be considered for downgrade from CRT-defibrillator to CRT-pacemaker at the time of battery depletion if no VTAs have occurred.http://www.clinicaltrials.gov. Unique identifier: NCT00180271.
Angiogenesis Inhibitor, TNP-470, Prevents Diet-Induced and Genetic Obesity in Mice
Authors: EbbaBråkenhielm, RenhaiCao, BihuGao, BoAngelin, BarbaraCannon, PaoloParini, YihaiCao
Journal: Circulation Research (2004)

Adipose tissue growth has been proposed to involve recruitment of new blood vessels. Here, we test the hypothesis that delivery of an angiogenesis inhibitor in mice may prevent diet-induced obesity, the most common type of obesity in humans. We show that systemic administration of a selective angiogenesis inhibitor, TNP-470 (AGM-1470), prevents obesity in high caloric diet-fed wt mice as well as in genetically leptin-deficient ob/ob mice. Inhibition of obesity in mice by TNP-470 involves a reduction of vascularity in the adipose tissue. This therapeutic strategy appears to selectively affect the growth of adipose tissue as measured by the ratio between total fat and lean body mass. Interestingly, the treatment with TNP-470 results in decreased serum levels of low-density lipoprotein cholesterol. Furthermore, insulin levels are reduced, which indicates increased insulin sensitivity, suggesting that angiogenesis inhibitors may prevent the development of type II diabetes. Our findings suggest that similarly ...
MicroRNA 217 Modulates Endothelial Cell Senescence via Silent Information Regulator 1
Authors: RossellaMenghini, VivianaCasagrande, MarinaCardellini, EugenioMartelli, AlessandroTerrinoni, FrancescaAmati, MariucaVasa-Nicotera, ArnaldoIppoliti, GiuseppeNovelli, GerryMelino, RenatoLauro, MassimoFederici
Journal: Circulation (2009)

Background— Aging is a major risk factor for the development of atherosclerosis and coronary artery disease. Through a microarray approach, we have identified a microRNA (miR-217) that is progressively expressed in endothelial cells with aging. miR-217 regulates the expression of silent information regulator 1 (SirT1), a major regulator of longevity and metabolic disorders that is progressively reduced in multiple tissues during aging. Methods and Results— miR-217 inhibits SirT1 expression through a miR-217–binding site within the 3′-UTR of SirT1. In young human umbilical vein endothelial cells, human aortic endothelial cells, and human coronary artery endothelial cells, miR-217 induces a premature senescence-like phenotype and leads to an impairment in angiogenesis via inhibition of SirT1 and modulation of FoxO1 (forkhead box O1) and endothelial nitric oxide synthase acetylation. Conversely, inhibition of miR-217 in old endothelial cells ultimately reduces senescence and increases angiogenic activity via...
Abstract 11924: Iso-osmolar Contrast Media Superior in Chronic Kidney Disease Patients Undergoing Coronary Angiography: A Meta Analysis of Current Evidence
Authors: Bhavi P Pandya, Sainath Gaddam, Shreya Pandya, Suzanne El-Sayegh, Ruben Kandov, James Lafferty
Journal: Circulation (2015)

Background: Coronary angiography is one of the most common causes of contrast-induced nephropathy. Adequate hydration and keeping the volume of contrast media to a minimum are class 1b recommendations for preventing contrast-induced nephropathy. Current data are insufficient to justify specific recommendations about iso- and low-osmolar contrast media, and no specific guidelines on use of different contrast media have been provided by ACCF/AHA/SCAI. Objective: We performed a systematic review and meta-analysis comparing the renal safety of iso-osmolar to low-osmolar contrast media in chronic kidney disease patients with stage 3 and above who underwent coronary angiography. Methods: Randomized trials comparing iso- to low-osmolar contrast media in chronic kidney disease stage 3 and above patients undergoing coronary angiography, and reporting contrast-induced nephropathy by a rise in creatinine of 25% from baseline were included in the analysis. Meta-analysis was done using a fixed effects size model and results were expressed in terms of Odds Ratio (OR) and 95% Confidence Interval (CI) after evaluating for interstudy heterogeneity using I 2 . Results: A total of 2,007 patients were included in 7 trials, in which 1,019 patients received iso-osmolar and 988 received low-osmolar contrast media. When compared to low-osmolar contrast media, use of iso-osmolar contrast media showed statistical significant benefit in terms of preventing contrast-induced nephropathy in chronic kidney disease patients (OR=0.75, [CI: 0.58, 0.96], p=0.02, I 2 =64%). Conclusion: In chronic kidney disease patients with stage 3 and above undergoing coronary angiography, use of iso-osmolar contrast media showed benefit in terms of preventing contrast-induced nephropathy compared to low-osmolar contrast media.