tbuckley/cabot-search huggingface dataset:
Abstract 14172: Abrogation of S100A1 Exacerbates Right Ventricular Dilation and Fetal Gene Expression in the Sugen/hypoxia Model of Pulmonary Arterial Hypertension in Mice
Authors: Krystyna Teichert-Kuliszewska, James N Tsoporis, Jean F Desjardins, Shehla Izhar, Thomas G Parker
Journal: Circulation (2015)

Background: S100A1, a Ca 2+ -sensor protein, is expressed in myocardium and endothelial cells and regulates cardiac muscle contractility. Previously, we demonstrated that under basal conditions in vivo , S100A1 knockout mice (KO) exhibited a significant elevation in right ventricular systolic pressure (RVSP), accompanied by an increase in RV hypertrophy. Since RV dysfunction occurs with progression of pulmonary arterial hypertension (PAH), we aimed to determine the impact of deleting S100A1 on progression of PAH in the Sugen-hypoxia (SUHx) model in mice. Methods and Results: C57BL6 (WT) and S100A1 KO mice (n=10 per group) were injected once weekly subcutaneously with SU (20mg/kg) and exposed to chronic Hx (10% O 2 ) for 3 weeks. PAH was assessed by hemodynamic parameters, RV morphology and echocardiography. RV and lung tissue were collected for molecular analysis. In WT and S100A1 KO mice exposed to SUHx, RVSP was similar 31.0±1.90 vs.31.4±2.08, respectively. In RV and lung tissue of WT mice, S100A1 mRNA and protein decreased approximately 40% in response to SUHx. SUHx induced similar increases in RV weight calculated as the Fulton index (0.43±0.06 in WT vs. 0.41±0.04 in S100A1KO) but in contrast to WT, S100A1 KO demonstrated a 3.7- and 1.5- fold increase in the mRNA levels of the hypertrophic genes, atrial natriuretic factor and beta-myosin heavy chain, respectively (p&lt;0.05). In S100A1 KO mice SUHx reduced heart rate (S100A1KO - 305.41±54.69 vs. WT- 443 ±54.82 bpm, p&lt; 0.001) compared to WT. Furthermore, serial echocardiographic assessment indicated increased RV dilation in the S100A1KO compared to the WT in response to SUHx as assessed by increases in RV internal diameter in both diastole (S100A1KO, 1.92±0.08 vs. WT, 1.53 ±0.08, p=0.004) and systole (S100A1KO, 1.34±0.1 vs. WT, 0.97±0.01, p=0.02). Conclusion: Our results show that PAH is associated with decreased expression of S100A1 in the RV and lack of S100A1 increases RV dilation and expression of fetal gene markers in the SUHx model. S100A1 may serve to limit severity of RV structural changes in PAH and represents a potential therapeutic target in this disease.
Abstract 4097: Maintenance of primary human colorectal cancer microenvironment using a perfusion bioreactor-based 3D culture system
Authors: Celeste Manfredonia, Manuele Giuseppe Muraro, Christian Hirt, Valentina Mele, Valeria Governa, Adam Papadimitropoulos, Silvio Daester, Savas D. Soysal, Raoul A. Droeser, Robert Mechera, Daniel Oertli, Raffaele Rosso, Martin Bolli, Luigi M. Terracciano, Giulio C. Spagnoli, Ivan Martin, Giandomenica Iezzi
Journal: Cancer Research (2018)

Abstract Colorectal cancer (CRC) is a leading cause of cancer-related death, often diagnosed at advanced stages. Conventional chemotherapeutic regimens have limited success rates, and a major challenge is represented by the lack of adequate in vitro models predicting patient responsiveness to defined treatments, possibly guiding therapeutic decisions. Non-malignant cells, including mesenchymal and immune cells, critically affect development, progression and drug responsiveness of human CRC. However, tumor drug responses are still evaluated on culture systems, such as 2D tumor cell monocultures or on tumor xenografts, which do not preserve all cellular components of in vivo tumor microenvironment.In this work, we have investigated the suitability of a perfusion-based bioreactor for 3D culture of primary CRC samples. Freshly excised CRC specimens were cut into fragments, inserted between two collagen type I sponges in a “sandwich-like” format and cultured for three days in a perfused-based system or under static conditions.We show that cultures under perfusion result in significantly higher maintenance of tissue integrity as compared to static cultures, with preservation of whole tumor microenvironment components, including cancer cells, mesenchymal stromal cells and a fraction of immune cells. Tumor tissues cultured under perfusion displayed an almost intact architecture with viable and proliferating tumor cells. Stromal cells were also maintained in proportions similar to those of original tumors and were fully viable, as indicated by their responsiveness to microenvironmental stimuli, such as IL-17. In addition, immune cells were also partially preserved, and were capable to release effector cytokines upon activation. Importantly, perfusion-based cultures proved suitable for testing sensitivity of primary tumor cells to chemotherapies currently in use for CRC and revealed heterogeneous responsiveness across different samples. [C.M. and M.G.M. contributed equally to this work.] Citation Format: Celeste Manfredonia, Manuele Giuseppe Muraro, Christian Hirt, Valentina Mele, Valeria Governa, Adam Papadimitropoulos, Silvio Daester, Savas D. Soysal, Raoul A. Droeser, Robert Mechera, Daniel Oertli, Raffaele Rosso, Martin Bolli, Luigi M. Terracciano, Giulio C. Spagnoli, Ivan Martin, Giandomenica Iezzi. Maintenance of primary human colorectal cancer microenvironment using a perfusion bioreactor-based 3D culture system [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 4097.
Abstract 4330: Pan-cancer analysis reveals m6A modification is functionally important in cancer
Authors: Zhixiang Zuo, Yubin Xie, Yueyuan Zheng, Peng Nie, Shuai Jiang, QI Zhao, Yanyan Miao, Jian Ren
Journal: Cancer Research (2018)

Abstract N6-Methyladenosine (m6A) is the most abundant post-transcriptional modification in mammalian RNA molecules and has a critical role in many diseases, including cancer. However, the systematic investigation of the role of m6A in cancer is still lacking. We conducted a systematic analysis of the m6A-associated somatic mutations and expression of m6A writers and erasers in 3,401 cancer genomes of 12 cancer types from The Cancer Genome Atlas (TCGA) to find a potential role of the m6A machinery in cancer development. We revealed 1,973 genes with recurrent m6A-associated somatic mutations across multiple cancer types. We identified many known cancer genes, such as TP53, CTNNB1 and CDKN2A, as well as many candidate genes whose cancer-specific roles are less understood. Strikingly, liver cancer had the highest frequency of m6A-associated somatic mutations among the 12 cancer types, and these mutations were significantly enriched in metabolic pathways, such as retinol metabolism. In liver cancer, the abnormalities in m6A “writers” and m6A modification sites were significantly correlated with worse overall survival, independent of other clinical characteristics (e.g., tumor stage and race). Implications: We for the first time consider somatic mutations relevant to the m6A modification sites to identify “driver” genes, thereby uncovering additional potential cancer “drivers” with rare mutations. Our study highlights m6A modifications as an important epigenetic mechanism of cancer development. Citation Format: Zhixiang Zuo, Yubin Xie, Yueyuan Zheng, Peng Nie, Shuai Jiang, QI Zhao, Yanyan Miao, Jian Ren. Pan-cancer analysis reveals m6A modification is functionally important in 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 4330.
Abstract 20707: Macrophage Mitochondrial Fission is Essential for Continued Clearance of Apoptotic Cells and Plays a Protective Role in Advanced Atherosclerosis
Authors: YingWang, IraTabas, MasatoshiNomura
Journal: Circulation (2014)

Introduction: The mitochondrial dynamic processes of fission and fusion influence and integrate with multiple physiologic and pathophysiologic processes. Mitochondrial dynamics dysregulation has been implicated in atherosclerosis, but little is known about the role of myeloid cell specific mitochondrial dynamics in the progression of atherosclerosis. In macrophage-enriched murine atherosclerosis lesion areas, we have found that levels of mitochondrial fission protein DRP1 down-regulated as the lesion progresses. In contrast, the mitochondrial fusion protein MFN2 is up-regulated. Further, mitochondria in lesional macrophages show hyperfusion morphology as the lesion develops. These suggest that mitochondria in macrophages undergo hyperfusion during the lesion progression. Hypothesis: We hypothesize that mitochondrial hyperfusion plays a significant role in atherosclerosis. Methods: We used a model Drp1fl/fl LysmCre+/-Ldlr-/-mice who have hyperfused mitochondria in Mϕs to test the functional significance of...
Abstract 4401: Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and novel therapeutic nanomedicine in head and neck cancer
Authors: Anthony D. Saleh, Robert F. Place, Hui Cheng, Rita Das, Thomas M. Harris, Geoffrey Childs, Gordon A. Robertson, Kathleen F. Pirollo, Esther H. Chang, Zhong Chen, Carter Van Waes
Journal: Cancer Research (2018)

Abstract We have developed an integrative approach to elucidate the functional role of deregulated microRNAs (miRs) and identify candidates for miR replacement therapy in cancer, applied here to head and neck squamous cell carcinomas (HNSCC). Our method involves integration of results from TCGA and other validation databases of genetic and expression data, including: miR expression, mRNA expression, copy number variation, DNA methylation. This data is then intersected with functional in vitro genome-wide miR screening for anti-proliferative miR mimics. We report that the miR-30-5p family is commonly repressed and correlates with overexpression of a broad network of proliferative and metastasis-related oncogenic mRNAs, including the growth receptors EGFR, MET and IGF1R. We show that re-expression of miR-30a-5p repressed this gene program, downstream signaling, proliferation, migration, and invasion in vitro. We have developed a chemically modified mimic of miR-30-5p with 50x improved stability in human serum, and 5X improvement in IC50 in vitro by XTT assay. We have formulated our novel miR-30a-5p mimic into Transferrin Receptor targeted nanoparticles which strongly inhibited HNSCC xenograft tumor growth, and regulated miR-30-5p family targets in vivo. Together with data linking decreased miR-30 family expression with DNA copy loss and promoter hypermethylation, and clinical disease-specific survival, for the first time, we have reported a more global picture of the function of this important tumor suppressor and identified a subset of patients that may benefit from miR replacement therapy with our novel miR-30-5p based nanomedicine. This research was supported by NIDCD intramural projects ZIA-DC-000073, 74, and NCI grant U43CA22156701. Citation Format: Anthony D. Saleh, Robert F. Place, Hui Cheng, Rita Das, Thomas M. Harris, Geoffrey Childs, Gordon A. Robertson, Kathleen F. Pirollo, Esther H. Chang, Zhong Chen, Carter Van Waes. Integrated genomic and functional microRNA analysis identifies miR-30-5p as a tumor suppressor and novel therapeutic nanomedicine in head and neck 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 4401.
Abstract 3168A: S100A4 mediates paracrine interactions with breast tumor cells
Authors: Natalya G. Dulyaninova, Adriana Levine, Jonathan M. Backer, Anne R. Bresnick
Journal: Cancer Research (2018)

Abstract S100A4, a member of the S100 family of Ca2+-binding proteins, has a direct and causative role in tumor metastasis. In murine models of breast cancer, S100A4 overexpression in tumor cells promotes an aggressive metastatic phenotype, while inhibition of S100A4 expression significantly reduces metastatic burden. We have now evaluated the contribution of stromal S100A4 to mammary tumor progression. The growth of E0771 orthotopic mammary tumors was reduced in S100A4-/- mice as compared to wild type mice. In addition, in a 3D collagen assay that recapitulates macrophage-tumor cell paracrine interactions that drive metastasis in vivo, S100A4-/- bone marrow-derived macrophages failed to stimulate breast tumor cell invasion. Our cell biological studies on bone marrow-derived macrophages from wild type and S100A4-/- mice show that loss of S100A4 produces two mechanistically distinct phenotypes in macrophages: a myosin-IIA-dependent defect in matrix degradation, due to an inhibition of podosome rosettes (actin-rich degradative structures that allow macrophages to penetrate through endothelial layers and their associated basement membranes), and a defect in invasion, due to a myosin-IIA-independent increase in microtubule acetylation and stability. These studies suggest that S100A4, which has well described pro-metastatic functions in tumor cells, also plays a critical role in immune cells in the tumor microenvironment. Citation Format: Natalya G. Dulyaninova, Adriana Levine, Jonathan M. Backer, Anne R. Bresnick. S100A4 mediates paracrine interactions with breast tumor cells [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 3168A.
Abstract A10: Fatty acid synthesis inhibitor, orlistat, potentiates cisplatin-induced toxicity in ovarian cancer cells
Authors: Bennett Van Houten, Molly Heft-Neal, Wei Qian, Vera Roginskaya
Journal: Clinical Cancer Research (2018)

Abstract Background: Fatty acid synthase (FAS) is a key enzyme in the synthesis of fatty acids and has been shown to be upregulated in many cancers. Additional studies found that high levels of FAS correlated with worse prognosis and with chemoresistance in ovarian tumors. As such, FAS has become a promising target for antitumor therapies. The aim of this study was to gain mechanistic insights into the cytotoxic effects of fatty acid inhibition with orlistat treatment alone or in combination with cisplatin in the ovarian cancer cell line A2780. Methods: A2780 cells were treated with cisplatin (0.4-12 μM) for 4 hours followed by orlistat (25-100 μM, 24 hr). Cell proliferation was measured via CyQuant assay; cell apoptotic activity was measured by both caspase 3/7 assay and flow cytometry with annexin V and propidium iodide. Fatty acid β-oxidation was then characterized using a Seahorse XF24 Extracellular Flux Analyzer. ATP levels were measured with a luminescent ATP detection kit. Finally, Western blot analyses for capsase 3 and phospho-ATM were performed. Results: Cisplatin treatment (4 and 10 μM) of A2780 cells induced an increase in OXPHOS and steady-state levels of ATP 24 hr after damage. Orlistat (25 and 50 μM, 24 hr) decreased basal oxygen consumption and decreased steady-state ATP levels in cisplatin-treated cells. A2780 cells showed decreased proliferation and increased apoptotic activity (Caspase 3/7 and Annexin V) when treated with cisplatin followed by orlistat, as compared to either drug alone. Using the Chou Talaly method the combination index was found to be 0.73 indicating a synergistic relationship. Cisplatin increased the level of phospho-ATM that was reduced by orlistat. Conclusions: Orlistat in combination with cisplatin treatment of A2780 ovarian tumor cells increased apoptosis compared to either treatment alone. Orlistat caused decreased oxidative phosphorylation and prevented a cisplatin-induced increase in OXPHOS and ATP. The combination of cisplatin and orlistat decreases p-ATM, suggesting decreased activation of the DNA repair pathway after cisplatin treatment. This may represent the mechanism of synergistic action of the combination treatment. Citation Format: Bennett Van Houten, Molly Heft-Neal, Wei Qian, Vera Roginskaya. Fatty acid synthesis inhibitor, orlistat, potentiates cisplatin-induced toxicity in ovarian cancer cells. [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 A10.
Angiotensin II Activates Signal Transducer and Activators of Transcription 3 via Rac1 in Atrial Myocytes and Fibroblasts
Authors: Chia-TiTsai, Ling-PingLai, Kuan-TingKuo, Juey-JenHwang, Chia-ShanHsieh, Kuan-LihHsu, Chuen-DenTseng, Yung-ZuTseng, Fu-TienChiang, Jiunn-LeeLin
Journal: Circulation (2008)

Background— Recently, activation of the local renin-angiotensin system and mitogen-activated protein kinase pathways in atrial myocardium has been found to play an important role in atrial structural remodeling related to atrial fibrillation. Another important mediator of the angiotensin II (Ang II) effect is the Janus kinase/signal transducers and activators of transcription (STAT) pathway, which has never been characterized in the atrium. Methods and Results— In cultured atrial myocytes and fibroblasts, Ang II induced tyrosine phosphorylation of STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant-negative Rac1, losartan, and simvastatin. In atrial myocytes, activation of STAT3 by Rac1 was mediated by direct association of Rac1 with STAT3; however, in atrial fibroblasts, it was mediated by an indirect paracrine effect. Constitutively active STAT3 increased protein synthesis, and dominant-negative STAT3 abrogated Ang II–induced protein synthesis in atrial myocytes and fibroblasts. Ra...
microRNA–mRNA regulatory networks underlying chronic mucus hypersecretion in COPD
Authors: Hataitip Tasena, Alen Faiz, Wim Timens, Jacobien Noordhoek, Machteld N. Hylkema, Reinoud Gosens, Pieter S. Hiemstra, Avrum Spira, Dirkje S. Postma, Gaik W. Tew, Michele A. Grimbaldeston, Maarten van den Berge, Irene H. Heijink, Corry-Anke Brandsma
Journal: European Respiratory Journal (2018)

Chronic mucus hypersecretion (CMH) is a common feature in chronic obstructive pulmonary disease (COPD) and is associated with worse prognosis and quality of life. This study aimed to identify microRNA (miRNA)–mRNA regulatory networks underlying CMH. The expression profiles of miRNA and mRNA in bronchial biopsies from 63 COPD patients were associated with CMH using linear regression. Potential mRNA targets of each CMH-associated miRNA were identified using Pearson correlations. Gene set enrichment analysis (GSEA) and STRING (search tool for the retrieval of interacting genes/proteins) analysis were used to identify key genes and pathways. 20 miRNAs and 539 mRNAs were differentially expressed with CMH in COPD. The expression of 10 miRNAs was significantly correlated with the expression of one or more mRNAs. Of these, miR-134-5p, miR-146a-5p and the let-7 family had the highest representation of CMH-associated mRNAs among their negatively correlated predicted targets. KRAS and EDN1 were identified as key regulators of CMH and were negatively correlated predicted targets of miR-134-5p and let-7a-5p, let-7d-5p, and let-7f-5p, respectively. GSEA suggested involvement of MUC5AC -related genes and several other relevant gene sets in CMH. The lower expression of miR-134-5p was confirmed in primary airway fibroblasts from COPD patients with CMH. We identified miR-134-5p, miR-146a-5p and let-7 family, along with their potential target genes including KRAS and EDN1 , as potential key miRNA–mRNA networks regulating CMH in COPD.
Abstract 3514: Differential metabolic targeting of PDAC cells with Zaprinast
Authors: Yi Rao, Seth Gammon, David Piwnica-Worms
Journal: Cancer Research (2018)

Abstract Many pancreatic cancers consume excessive glutamine as a preferable source for anaplerosis, maintenance of proper redox state, and synthesis of intermediates for cancer cell growth and proliferation. Abrogating glutamine metabolism is under investigation to inhibit the proliferation/ growth of glutamine-addicted cancers. In addition, inhibition of the mitochondrial pyruvate carrier (MPC1) can potentially induce cancer cells to become more dependent on glutaminolysis. In this regard, Zaprinast, originally developed as a phosphodiesterase 5 (PDE5) inhibitor, has recently been identified as an inhibitor of both glutaminase as well as MPC1. We compared the growth inhibition effect of Zaprinast against BPTES, a targeted glutaminase inhibitor, and UK5099, a targeted MPC1 inhibitor, as well as the combination of BPTES and UK5099. Using pancreatic ductal adenocarcinoma (PDAC) cells, KRAS mutant (Mia Paca2) and KRAS wildtype (Panc03.27), KRAS mutant neuroendocrine (QGP1), and normal pancreatic epithelial cells (HPNE), Zaprinast alone showed more potent growth inhibition in all tested cells lines than single agent treatment with BPTES or UK5099. Further, Zaprinast effectively depleted mitochondrial reserve respiratory capacity similar to UK5099, rendering mitochondria more vulnerable to oxidative stress or pharmacological inhibitors targeting the electron transport chain. In addition, Zaprinast treatment of cancer cells differentially elevated ROS levels greater than 10-fold compared to normal HPNE cells (ROS levels: Mia Paca2 ~ Panc03.27 &amp;gt; QGP1 &amp;gt; HPNE). However, the increase in ROS levels did not correlate with Zaprinast-induced growth inhibition (IC50: Mia Paca2=300 µM, Panc03.27=110 µM, HPNE=650 µM, QGP1 &amp;gt;1 mM). Although Zaprinast-induced growth inhibition was selective toward adenocarcinoma cells but not the neuroendocrine subtype, the selective Zaprinast-induced elevation of ROS levels toward all cancer subtypes renders possibilities for potential synthetic lethality when combined with other metabolic inhibitors. Citation Format: Yi Rao, Seth Gammon, David Piwnica-Worms. Differential metabolic targeting of PDAC cells with Zaprinast [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 3514.
Prosthetic Limbs Given Proprioception
Authors: Jennifer Abbasi
Journal: JAMA (2018)

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