Translational Medical Research Commons^™

The Histone Deacetylase Inhibitor Tubacin Mitigates Endothelial Dysfunction By Up-Regulating The Expression Of Endothelial Nitric Oxide Synthase., Jihui Chen, Jian Zhang, Noor F. Shaik, Bing Yi, Xin Wei, Xiao-Feng Yang, Ulhas P. Naik, Ross Summer, Guijun Yan, Xinyun Xu, Jianxin Sun

Center for Translational Medicine Faculty Papers

Endothelial nitric oxide (NO) synthase (eNOS) plays a critical role in the maintenance of blood vessel homeostasis. Recent findings suggest that cytoskeletal dynamics play an essential role in regulating eNOS expression and activation. Here, we sought to test whether modulation of cytoskeletal dynamics through pharmacological regulation of histone deacetylase 6 (HDAC6)-mediated tubulin deacetylation affects eNOS expression and endothelial function in vitro and in vivo.Wefound that tubulin acetylation inducer (tubacin), a compound that appears to selectively inhibit HDAC6 activity, dramatically increased eNOS expression in several different endothelial cell lines, as determined by both immunoblotting and NO production assays. Mechanistically, we found …

A Drive To Driven Model Of Mapping Intraspecific Interaction Networks., Libo Jiang, Jian Xu, Mengmeng Sang, Yan Zhang, Meixia Ye, Hanyuan Zhang, Biyin Wu, Youxiu Zhu, Peng Xu, Ruyu Tai, Zixia Zhao, Yanliang Jiang, Chuanju Dong, Lidan Sun, Christopher H. Griffin, Claudia Gragnoli, Rongling Wu

Division of Endocrinology, Diabetes and Metabolic Diseases Faculty Papers

Community ecology theory suggests that an individual's phenotype is determined by the phenotypes of its coexisting members to the extent at which this process can shape community evolution. Here, we develop a mapping theory to identify interaction quantitative trait loci (QTL) governing inter-individual dependence. We mathematically formulate the decision-making strategy of interacting individuals. We integrate these mathematical descriptors into a statistical procedure, enabling the joint characterization of how QTL drive the strengths of ecological interactions and how the genetic architecture of QTL is driven by ecological networks. In three fish full-sib mapping experiments, we identify a set of genome-wide QTL …

Twenty Novel Disease Group-Specific And 12 New Shared Macrophage Pathways In Eight Groups Of 34 Diseases Including 24 Inflammatory Organ Diseases And 10 Types Of Tumors., Bin Lai, Jiwei Wang, Alexander Fagenson, Yu Sun, Jason Saredy, Yifan Lu, Gayani Nanayakkara, William Y Yang, Daohai Yu, Ying Shao, Charles Drummer, Candice Johnson, Fatma Saaoud, Ruijing Zhang, Qian Yang, Keman Xu, Kevin Mastascusa, Ramon Cueto, Hangfei Fu, Susu Wu, Lizhe Sun, Peiqian Zhu, Xuebin Qin, Jun Yu, Daping Fan, Ying H Shen, Jianxin Sun, Thomas Rogers, Eric T Choi, Hong Wang, Xiaofeng Yang

Center for Translational Medicine Faculty Papers

The mechanisms underlying pathophysiological regulation of tissue macrophage (Mφ) subsets remain poorly understood. From the expression of 207 Mφ genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 Mφ markers and 45 Mφ TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) Mφ in lung, liver, spleen, and intestine (LLSI-Mφ) express higher M1 Mφ …

Gsk3Β-Dependent Phosphorylation Of Cypd And Regulation Of Mptp Opening During Myocardial Infarction, Stephen Hurst, Ludovic Gomez, Shey-Shing Sheu

Center for Translational Medicine Posters

Background

Mitochondrial calcium overload and oxidative stress during ischemia reperfusion (I/R) injury remains a major obstacle during percutaneous coronary intervention after acute myocardial infarction. It often leads to an increased susceptibility for mitochondria permeability transition pore (mPTP) opening leading to cell death. Mitochondrial calcium overload and ROS have been identified as key triggers to open the mPTP for over 30 years, yet the exact mechanism has remained elusive. Additionally, glycogen synthase kinase 3β; (GSK-3β;) is proposed as one of the key molecules that regulate mitochondrial dysfunction and injury during I/R. Indeed inhibition of GSK-3β has been shown to be required …

Pyk2 Expression And Localization In Cardiac Mitochondria And Its Role In Mitochondrial Calcium Regulation, Ariele Baggett, Celia Fernandez-Sanz, Sergio De La Fuente, Johannes Hoek, Shey-Shing Sheu

Center for Translational Medicine Posters

TRPM2 is a non-selective cation channel located in the plasma membrane of the cell. Upon activation, the channel opens, allowing calcium to enter into the cytosol of the cell, leading ultimately to the phosphorylation and activation of the enzyme Pyk2 (proline-rich tyrosine kinase 2). Once phosphorylated, Pyk2 translocates from the cytosol to the mitochondria, where it regulates the formation of the pore component of the mitochondrial calcium uniporter (MCU) complex. Consequently, this interaction is a key factor in mitochondrial calcium uptake and therefore mitochondrial bioenergetics.

Insights Into The Hiv Latency And The Role Of Cytokines., Joseph Hokello, Adhikarimayum Lakhikumar Sharma, Manjari Dimri, Mudit Tyagi

Center for Translational Medicine Faculty Papers

Human immunodeficiency virus-1 (HIV-1) has the ability to infect latently at the level of individual CD4+ cells. Latent HIV-1 proviruses are transcriptionally silent and immunologically inert, but are still capable of reactivating productive lytic infection following cellular activation. These latent viruses are the main obstacle in the eradication of HIV-1, because current HIV-1 treatment regimens are ineffective against them. Normal immunological response against an antigen activates CD4+ naïve T cells. The activated CD4+ naïve T cells undergo cell cycle, resulting in further transformation and profound proliferation to form effector CD4+ T-cells. Notably, in HIV-1 infected individuals, some of the effector …

Mechanisms Of Simvastatin Myotoxicity: The Role Of Autophagy Flux Inhibition., Arya Emami, Shahla Shojaei, Simone C. Da Silva Rosa, Mahmoud Aghaei, Ehsan Samiei, Amir Reza Vosoughi, Forouh Kalantari, Philip Kawalec, James Thliveris, Pawan Sharma, Amir A. Zeki, Mohsen Akbari, Joseph W. Gordon, Saeid Ghavami

Center for Translational Medicine Faculty Papers

Statins are some of the most widely used drugs worldwide, but one of their major side effects is myotoxicity. Using mouse myoblast (C2C12) and human alveolar rhabdomyosarcoma cell lines (RH30) in both 2-dimensional (2D) and 3-dimensional (3D) cell culture, we investigated the mechanisms of simvastatin's myotoxicity. We found that simvastatin significantly reduced cell viability in C2C12 cells compared to RH30 cells. However, simvastatin induced greater apoptosis in RH30 compared to C2C12 cells. Simvastatin-induced cell death is dependent on geranylgeranyl pyrophosphate (GGPP) in C2C12 cells, while in RH30 cells it is dependent on both farnesyl pyrophosphate (FPP) and GGPP. Simvastatin inhibited …

Spg7 Targets The M-Aaa Protease Complex To Process Mcu For Uniporter Assembly, Ca2 Influx, And Regulation Of Mitochondrial Permeability Transition Pore Opening, Stephen Hurst, Ariele Baggett, György Csordás, Shey-Shing Sheu

Center for Translational Medicine Faculty Papers

The mitochondrial matrix ATPase associated with diverse cellular activities (m-AAA) protease spastic paraplegia 7 (SPG7) has been recently implicated as either a negative or positive regulatory component of the mitochondrial permeability transition pore (mPTP) by two research groups. To address this controversy, we investigated possible mechanisms that explain the discrepancies between these two studies. We found that loss of the SPG7 gene increased resistance to Ca²-induced mPTP opening. However, this occurs independently of cyclophilin D (cyclosporine A insensitive) rather it is through decreased mitochondrial Ca² concentrations and subsequent adaptations mediated by impaired formation of functional mitochondrial Ca …

Matrix Metalloproteinase Activity In The Lung Is Increased In Hermansky-Pudlak Syndrome., Ross Summer, Rachana Krishna, Deleila Schriner, Karina Cuevas-Mora, Dominic Sales, Rachel Para, Jesse Roman, Carl Nieweld, Bernadette R. Gochuico, Freddy Romero

Center for Translational Medicine Faculty Papers

BACKGROUND: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF). Although the activities of various matrix metalloproteinases (MMPs) are known to be dysregulated in IPF, it remains to be determined whether similar changes in these enzymes can be detected in HPS.

RESULTS: Here, we show that transcript and protein levels as well as enzymatic activities of MMP-2 and -9 are markedly increased in the lungs of mice carrying the HPS …

Glucocorticoids And Airway Smooth Muscle: A Few More Answers, Still More Questions, Ajay P. Nayak

Center for Translational Medicine Faculty Papers

No abstract provided.

C1q/Tnf-Related Protein 3 (Ctrp3) And 9 (Ctrp9) Concentrations Are Decreased In Patients With Heart Failure And Are Associated With Increased Morbidity And Mortality., Chao Gao, Shasha Zhao, Kun Lian, Baibing Mi, Rui Si, Zhijun Tan, Feng Fu, Shuai Wang, Rutao Wang, Xin-Liang Ma, Ling Tao

Center for Translational Medicine Faculty Papers

BACKGROUND: Biochemical marker has revolutionized the approach to the diagnosis of heart failure. However, it remains difficult to assess stability of the patient. As such, novel means of stratifying disease severity are needed. C1q/TNF-Related Protein 3 (CTRP3) and C1q/TNF-Related Protein 9 (CTRP9) are novel adipokines that contribute to energy homeostasis with additional anti-inflammatory and anti-ischemic properties. The aim of our study is to evaluate concentrations of CTRP3 and CTRP9 in patients with HFrEF (heart failure with reduced ejection fraction) and whether associated with mortality.

METHODS: Clinical data and plasma were obtained from 176 healthy controls and 168 patients with HFrEF. …

Increasing Upstream Chromatin Long-Range Interactions May Favor Induction Of Circular Rnas In Lysopc-Activated Human Aortic Endothelial Cells., Angus Li, Yu Sun, Charles Drummer, Yifan Lu, Daohai Yu, Yan Zhou, Xinyuan Li, Simone J. Pearson, Candice Johnson, Catherine Yu, William Y. Yang, Kevin Mastascusa, Xiaohua Jiang, Jianxin Sun, Thomas Rogers, Wenhui Hu, Hong Wang, Xiaofeng Yang

Center for Translational Medicine Faculty Papers

Circular RNAs (circRNAs) are non-coding RNAs that form covalently closed continuous loops, and act as gene regulators in physiological and disease conditions. To test our hypothesis that proatherogenic lipid lysophosphatidylcholine (LPC) induce a set of circRNAs in human aortic endothelial cell (HAEC) activation, we performed circRNA analysis by searching our RNA-Seq data from LPC-activated HAECs, and found: (1) LPC induces significant modulation of 77 newly characterized cirRNAs, among which 47 circRNAs (61%) are upregulated; (2) 34 (72%) out of 47 upregulated circRNAs are upregulated when the corresponding mRNAs are downregulated, suggesting that the majority of circRNAs are upregulated presumably via …

Lipid Uptake By Alveolar Macrophages Drives Fibrotic Responses To Silica Dust., Xiaomin Hou, Ross Summer, Ziying Chen, Ying Tian, Jingjing Ma, Jie Cui, Xiaohui Hao, Lingli Guo, Hong Xu, Hongli Wang, Heliang Liu

Center for Translational Medicine Faculty Papers

Silicosis is a common occupational disease and represents a significant contributor to respiratory morbidity and mortality worldwide. Lipid-laden macrophages, or foam cells, are observed in the lungs of patients with silicosis but the mechanisms mediating their formation remain poorly understood. In this study, we sought to elucidate the mechanisms by which silica promotes foam cell formation in the lung, and to determine whether uptake of lipids alone is sufficient to drive TGF-β production by alveolar macrophages. Consistent with previous reports, we found that foam cells were markedly increased in the lungs of patients with silicosis and that these findings associated …

Inflammatory Serine Proteases Play A Critical Role In The Early Pathogenesis Of Diabetic Cardiomyopathy., Mikhail A Kolpakov, Kunal Sikder, Amrita Sarkar, Shaswati Chaki, Sanket K Shukla, Xinji Guo, Zhao Qi, Carlos Barbery, Abdelkarim Sabri, Khadija Rafiq

Center for Translational Medicine Faculty Papers

BACKGROUND/AIMS: Diabetic cardiomyopathy (DCM) is characterized by structural and functional alterations that can lead to heart failure. Several mechanisms are known to be involved in the pathogenesis of DCM, however, the molecular mechanism that links inflammation to DCM is incompletely understood. To learn about this mechanism, we investigated the role of inflammatory serine proteases (ISPs) during the development of DCM.

METHODS: Eight weeks old mice with deletion of dipeptidyl peptidase I (DPPI), an enzyme involved in the maturation of major ISPs, and wild type (WT) mice controls were injected with streptozotocin (50 mg/kg for 5 days intraperitoneally) and studied after …

Nkx2-1-As1 Negatively Regulates Cd274/Pd-L1, Cell-Cell Interaction Genes, And Limits Human Lung Carcinoma Cell Migration., Hasmeena Kathuria, Guetchyn Millien, Liam Mcnally, Adam C. Gower, Jean-Bosco Tagne, Yuxia Cao, Maria I. Ramirez

Center for Translational Medicine Faculty Papers

The function of most long noncoding RNAs (lncRNAs) is unknown. However, recent studies reveal important roles of lncRNAs in regulating cancer-related pathways. Human antisense lncRNA-NKX2-1-AS1 partially overlaps the NKX2-1/TTF1 gene within chromosomal region 14q13.3. Amplification of this region and/or differential expression of genes therein are associated with cancer progression. Herein we show higher levels of NKX2-AS1 and NKX2-1 in lung adenocarcinomas relative to non-tumor controls but no correlation between NKX2-1-AS1 and NKX2-1 levels across specimens, or with amplification of the 14q13.3 region, suggesting that NKX2-1-AS1 and NKX2-1 are independently regulated. Loss-and-gain of function experiments showed that NKX2-1-AS1 does not regulate …

The Anti-Cancer Effect Of Retinoic Acid Signaling In Crc Occurs Via Decreased Growth Of Aldh+ Colon Cancer Stem Cells And Increased Differentiation Of Stem Cells, Shirin R. Modarai, Anindita Gupta, Lynn M. Opdenaker, Ryan Kowash, Gabriel Masters, Vignesh Viswanathan, Tao Zhang, Jeremy Z. Fields, Bruce M. Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and …

Pepducin-Mediated Cardioprotection Via Β-Arrestin-Biased Β2-Adrenergic Receptor-Specific Signaling, Laurel A. Grisanti, Toby P. Thomas, Rhonda L. Carter, Claudio De Lucia, Erhe Gao, Walter J. Koch, Jeffrey L. Benovic, Douglas G. Tilley

Department of Biochemistry and Molecular Biology Faculty Papers

Reperfusion as a therapeutic intervention for acute myocardial infarction-induced cardiac injury itself induces further cardiomyocyte death. β-arrestin (βarr)-biased β-adrenergic receptor (βAR) activation promotes survival signaling responses in vitro; thus, we hypothesize that this pathway can mitigate cardiomyocyte death at the time of reperfusion to better preserve function. However, a lack of efficacious βarr-biased orthosteric small molecules has prevented investigation into whether this pathway relays protection against ischemic injury in vivo. We recently demonstrated that the pepducin ICL1-9, a small lipidated peptide fragment designed from the first intracellular loop of β2AR, allosterically engaged pro-survival signaling cascades in a βarr-dependent manner in …

Transcriptional Up-Regulation Of Relaxin-3 By Nur77 Attenuates Β-Adrenergic Agonist-Induced Apoptosis In Cardiomyocytes., Xiaohua You, Zhifu Guo, Fang Cheng, Bing Yi, Fan Yang, Xinzhu Liu, Ni Zhu, Xianxian Zhao, Guijun Yan, Xin-Liang Ma, Jianxin Sun

Center for Translational Medicine Faculty Papers

The relaxin family peptides have been shown to exert several beneficial effects on the heart, including anti-apoptosis, anti-fibrosis, and anti-hypertrophy activity. Understanding their regulation might provide new opportunities for therapeutic interventions, but the molecular mechanism(s) coordinating relaxin expression in the heart remain largely obscured. Previous work demonstrated a role for the orphan nuclear receptor Nur77 in regulating cardiomyocyte apoptosis. We therefore investigated Nur77 in the hopes of identifying novel relaxin regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) data indicated that ectopic expression of orphan nuclear receptor Nur77 markedly increased the expression of latexin-3 (RLN3), but not relaxin-1 …

Endorepellin Remodels The Endothelial Transcriptome Toward A Pro-Autophagic And Pro-Mitophagic Gene Signature., Thomas Neill, Eva Andreuzzi, Zi-Xuan Wang, Stephen C. Peiper, Maurizo Mongiat, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Regulation of autophagy by proteolytically cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. Endorepellin is the C-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and induces autophagy in endothelial cells. To further investigate this property, we used NanoString, a digital PCR platform for measuring pre-defined transcripts in biological samples to analyze a custom subset of 95 autophagy-related genes in human umbilical vein endothelial cells treated with ultrapure human recombinant endorepellin. We discovered an endorepellin-evoked pro-autophagic and pro-mitophagic gene expression signatures, which included two coordinately up-regulated mitochondrial-associated genes encoding the E3 ubiquitin …

High Fat Diet Upregulates Fatty Acid Oxidation And Ketogenesis Via Intervention Of Ppar-Γ., Kunal Sikder, Sanket Kumar Shukla, Neel Patel, Harpreet Singh, Khadija Rafiq

Center for Translational Medicine Faculty Papers

BACKGROUND/AIMS: Systemic hyperlipidemia and intracellular lipid accumulation induced by chronic high fat diet (HFD) leads to enhanced fatty acid oxidation (FAO) and ketogenesis. The present study was aimed to determine whether activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) by surplus free fatty acids (FA) in hyperlipidemic condition, has a positive feedback regulation over FAO and ketogenic enzymes controlling lipotoxicity and cardiac apoptosis.

METHODS: 8 weeks old C57BL/6 wild type (WT) or PPAR-γ-/- mice were challenged with 16 weeks 60% HFD to induce obesity mediated type 2 diabetes mellitus (T2DM) and diabetic cardiomyopathy. Treatment course was followed by echocardiographic measurements, glycemic and …

Apoptosis Signal-Regulating Kinase 1 Inhibition Attenuates Human Airway Smooth Muscle Growth And Migration In Chronic Obstructive Pulmonary Disease., Mathew S. Eapen, Anudeep Kota, Howard Vindin, Kielan D. Mcalinden, Dia Xenaki, Brian G. Oliver, Deepak A. Deshpande, Sukhwinder Singh Sohal, Pawan Sharma

Center for Translational Medicine Faculty Papers

Increased airway smooth muscle (ASM) mass is observed in chronic obstructive pulmonary disease (COPD), which is correlated with disease severity and negatively affects lung function in these patients. Thus, there is clear unmet clinical need for finding new therapies which can target airway remodeling and disease progression in COPD. Apoptosis signal-regulating kinase 1 (ASK1) is a ubiquitously expressed mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) activated by various stress stimuli, including reactive oxygen species (ROS), tumor necrosis factor (TNF)-α, and lipopolysaccharide (LPS) and is known to regulate cell proliferation. ASM cells from COPD patients are hyperproliferative to mitogens in vitro. …

Pth1r-Casr Cross Talk: New Treatment Options For Breast Cancer Osteolytic Bone Metastases., Yanmei Yang, Bin Wang

Department of Medicine Faculty Papers

Metastatic breast cancer (BrCa) is currently incurable despite great improvements in treatment of primary BrCa. The incidence of skeletal metastases in advanced BrCa occurs up to 70%. Recent findings have established that the distribution of BrCa metastases to the skeleton is not a random process but due to the favorable microenvironment for tumor invasion and growth. The complex interplay among BrCa cells, stromal/osteoblastic cells, and osteoclasts in the osseous microenvironment creates a bone-tumor vicious cycle (a feed-forward loop) that results in excessive bone destruction and progressive tumor growth. Both the type 1 PTH receptor (PTH1R) and extracellular calcium-sensing receptor (CaSR) …

Coupling Of Smoothened To Inhibitory G Proteins Reduces Voltage-Gated K, Lan Cheng, Moza Al-Owais, Manuel Covarrubias, Walter J. Koch, David R. Manning, Chris Peers, Natalia A Riobo-Del Galdo

Department of Biochemistry and Molecular Biology Faculty Papers

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric G_i proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic G_iCT/TTA mice, in which G_i signaling is impaired, suggesting that the effect of SMO is mediated by G_i proteins. Investigation of the mechanism underlying the change …

Pepducins As A Potential Treatment Strategy For Asthma And Copd., Reynold A. Panettieri, Tonio Pera, Stephen B B. Liggett, Jeffrey L. Benovic, Raymond B. Penn

Center for Translational Medicine Faculty Papers

Current therapies to treat asthma and other airway diseases primarily include anti-inflammatory agents and bronchodilators. Anti-inflammatory agents target trafficking and resident immunocytes and structural cells, while bronchodilators act to prevent or reverse shortening of airway smooth muscle (ASM), the pivotal tissue regulating bronchomotor tone. Advances in our understanding of the biology of G protein-coupled receptors (GPCRs) and biased agonism offers unique opportunities to modulate GPCR function that include the use of pepducins and allosteric modulators. Recent evidence suggests that small molecule inhibitors of Gα _q as well as pepducins targeting G _q -coupled receptors can broadly inhibit contractile agonist-induced ASM …

New Targets For Resolution Of Airway Remodeling In Obstructive Lung Diseases., Ajay P. Nayak, Deepak A. Deshpande, Raymond B. Penn

Center for Translational Medicine Faculty Papers

Airway remodeling (AR) is a progressive pathological feature of the obstructive lung diseases, including asthma and chronic obstructive pulmonary disease (COPD). The pathology manifests itself in the form of significant, progressive, and (to date) seemingly irreversible changes to distinct respiratory structural compartments. Consequently, AR correlates with disease severity and the gradual decline in pulmonary function associated with asthma and COPD. Although current asthma/COPD drugs manage airway contraction and inflammation, none of these effectively prevent or reverse features of AR. In this review, we provide a brief overview of the features and putative mechanisms affecting AR. We further discuss recently proposed …

First Results On Survival From A Large Phase 3 Clinical Trial Of An Autologous Dendritic Cell Vaccine In Newly Diagnosed Glioblastoma., Linda M. Liau, Keyoumars Ashkan, David D. Tran, Jian L. Campian, John E. Trusheim, Charles S. Cobbs, Jason A. Heth, Michael Salacz, Sarah Taylor, Stacy D. D'Andre, Fabio M. Iwamoto, Edward J. Dropcho, Yaron A. Moshel, Kevin A. Walter, Clement P. Pillainayagam, Robert Aiken, Rekha Chaudhary, Samuel A. Goldlust, Daniela A. Bota, Paul Duic, Jai Grewal, Heinrich Elinzano, Steven A. Toms, Kevin O. Lillehei, Tom Mikkelsen, Tobias Walbert, Steven R. Abram, Andrew J. Brenner, Steven Brem, Matthew G. Ewend, Simon Khagi, Jana Portnow, Lyndon J. Kim, William G. Loudon, Reid C. Thompson, David E Avigan, Karen L. Fink, Francois J. Geoffroy, Scott Lindhorst, Jose Lutzky, Andrew E. Sloan, Gabriele Schackert, Dietmar Krex, Hans-Jorg Meisel, Julian Wu, Raphael P Davis, Christopher Duma, Arnold B. Etame, David Mathieu, Santosh Kesari, David Piccioni, Manfred Westphal, David S. Baskin, Pamela Z. New, Michel Lacroix, Sven-Axel May, Timothy J. Pluard, Victor Tse, Richard M. Green, John L. Villano, Michael Pearlman, Kevin Petrecca, Michael Schulder, Lynne P Taylor, Anthony E. Maida, Robert M. Prins, Timothy F. Cloughesy, Paul Mulholland, Marnix L. Bosch

Department of Medical Oncology Faculty Papers

BACKGROUND: Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax

METHODS: After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS).

RESULTS: For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly …

Visualization Of Fibronectin Assembly Using Crispr And Fluorescence Imaging, Brenda French, Sophie Astrof

Sigma Xi Student Research Day

Objectives

Surprisingly, the mechanisms of fibronectin assembly remain largely unknown. This project aims to elucidate the process by which fibronectin assembles through fluorescent labeling. Fluorescent tags allow for the visualization of fibronectin to clarify how this extracellular matrix protein may influence migration and signaling.

Pim-1 Kinase Phosphorylates Cardiac Troponin I And Regulates Cardiac Myofilament Function., Ni Zhu, Bing Yi, Zhifu Guo, Guanxin Zhang, Shengdong Huang, Yongwen Qin, Xianxian Zhao, Jianxin Sun

Center for Translational Medicine Faculty Papers

BACKGROUND/AIMS: Pim-1 is a serine/threonine kinase that is highly expressed in the heart, and exerts potent cardiac protective effects through enhancing survival, proliferation, and regeneration of cardiomyocytes. Its myocardial specific substrates, however, remain unknown. In the present study, we aim to investigate whether Pim-1 modulates myofilament activity through phosphorylation of cardiac troponin I (cTnI), a key component in regulating myofilament function in the heart.

METHODS: Coimmunoprecipitation and immunofluorescent assays were employed to investigate the interaction of Pim-1 with cTnI in cardiomyocytes. Biochemical, site directed mutagenesis, and mass spectrometric analyses were utilized to identify the phosphorylation sites of Pim1 in cTnI. …

Cyclin D1-Mediated Microrna Expression Signature Predicts Breast Cancer Outcome, Guangxue Wang, Michael Gormley, Jing Qiao, Qian Zhao, Min Wang, Gabriele Disante, Shengqiong Deng, Lin Dong, Timothy G. Pestell, Xiaoming Ju, Mathew C. Casimiro, Sankar Addya, Adam Ertel, Ayden Tozeren, Qinchuan Li, Zuoren Yu, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood.

Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes.

Results: Hierarchical clustering of …

Α-Catenin-Dependent Cytoskeletal Tension Controls Yap Activity In The Heart., Alexia Vite, Caimei Zhang, Roslyn Yi, Sabrina Emms, Glenn L. Radice

Center for Translational Medicine Faculty Papers

Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. At the same time, the N-cadherin/catenin cell adhesion complex accumulates at the cell termini, creating a specialized type of cell-cell contact called the intercalated disc (ICD). To investigate the relationship between ICD maturation and proliferation, αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes were deleted to generate cardiac-specific α-catenin double knockout (DKO) mice. DKO mice exhibited aberrant N-cadherin expression, mislocalized actomyosin activity and increased cardiomyocyte proliferation that was dependent on Yap activity. To assess effects on tension, cardiomyocytes were cultured on deformable polyacrylamide hydrogels of varying stiffness. When …