Life Sciences Commons^™

Targeting The Brd4/Foxo3a/Cdk6 Axis Sensitizes Akt Inhibition In Luminal Breast Cancer, Jingyi Liu, Weijie Guo, Zhibing Duan, Lei Zeng, Yadi Wu, Yule Chen, Fang Tai, Yifan Wang, Yiwei Lin, Qiang Zhang, Yanling He, Jiong Deng, Rachel L. Stewart, Chi Wang, Pengnian Charles Lin, Saghi Ghaffari, B. Mark Evers, Suling Liu, Ming-Ming Zhou, Binhua P. Zhou, Jian Shi

Molecular and Cellular Biochemistry Faculty Publications

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or …

Macrophage-Derived Netrin-1 Promotes Abdominal Aortic Aneurysm Formation By Activating Mmp3 In Vascular Smooth Muscle Cells, Tarik Hadi, Ludovic Boytard, Michele Silvestro, Dornazsadat Alebrahim, Samson Jacob, Jordyn Feinstein, Krista Barone, Wes Spiro, Susan Hutchison, Russell Simon, Debra L. Rateri, Florence Pinet, David Fenyo, Mark Adelman, Kathryn J. Moore, Holger K. Eltzschig, Alan Daugherty, Bhama Ramkhelawon

Physiology Faculty Publications

Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) …

Proteomics Of Human Liver Membrane Transporters: A Focus On Fetuses And Newborn Infants., Bianca D. Van Groen, Evita Van De Steeg, Miriam G. Mooij, Marola M H Van Lipzig, Barbara A E De Koning, Robert M. Verdijk, Heleen M. Wortelboer, R Gaedigk, Chengpeng Bi, J Steven Leeder, Ron H N Van Schaik, Joost Van Rosmalen, Dick Tibboel, Wouter H. Vaes, Saskia N. De Wildt

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Hepatic membrane transporters are involved in the transport of many endogenous and exogenous compounds, including drugs. We aimed to study the relation of age with absolute transporter protein expression in a cohort of 62 mainly fetus and newborn samples.

METHODS: Protein expressions of BCRP, BSEP, GLUT1, MCT1, MDR1, MRP1, MRP2, MRP3, NTCP, OCT1, OATP1B1, OATP1B3, OATP2B1 and ATP1A1 were quantified with LC-MS/MS in isolated crude membrane fractions of snap-frozen post-mortem fetal and pediatric, and surgical adult liver samples. mRNA expression was quantified using RNA sequencing, and genetic variants with TaqMan assays. We explored relationships between protein expression and age …

Rationale, Design And Methods Of "Set The Rules": A Tailored Peer-To-Peer Health Information Intervention, Jennifer R. Warren, Brandi M. White

Health and Clinical Sciences Faculty Publications

Ensuring equitable access to health information is one strategy to promote health equity for underserved communities, especially for low-income African Americans (AAs). Childcare centers are one viable site to deliver health information to address this disparity. This paper describes the methods used in a community-based participatory research project with a childcare facility that aimed to reduce environmental tobacco smoke (ETS) exposure among low-income AA children. Through collaboration and multiple data collection methods, partners identified communication strategies to overcome informational barriers. These initial findings indicated a peer-to-peer health information intervention, entitled “Set the Rules”, as the best strategy to increase awareness. …

Collagen Prolyl 4-Hydroxylase 1 Is Essential For Hif-1Α Stabilization And Tnbc Chemoresistance, Gaofeng Xiong, Rachel L. Stewart, Jie Chen, Tianyan Gao, Timothy L. Scott, Luis M. Samayoa, Kathleen L. O'Connor, Andrew N. Lane, Ren Xu

Markey Cancer Center Faculty Publications

Collagen prolyl 4-hydroxylase (P4H) expression and collagen hydroxylation in cancer cells are necessary for breast cancer progression. Here, we show that P4H alpha 1 subunit (P4HA1) protein expression is induced in triple-negative breast cancer (TNBC) and HER2 positive breast cancer. By modulating alpha ketoglutarate (α-KG) and succinate levels P4HA1 expression reduces proline hydroxylation on hypoxia-inducible factor (HIF) 1α, enhancing its stability in cancer cells. Activation of the P4HA/HIF-1 axis enhances cancer cell stemness, accompanied by decreased oxidative phosphorylation and reactive oxygen species (ROS) levels. Inhibition of P4HA1 sensitizes TNBC to the chemotherapeutic agent docetaxel and doxorubicin in xenografts and patient-derived …

Identification Of Susceptibility Pathways For The Role Of Chromosome 15q25.1 In Modifying Lung Cancer Risk, Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella De Biasi, Younghun Han, Olga Gorlova, Rayjean J. Hung, Xifeng Wu, James Mckay, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Susanne M. Arnold

Markey Cancer Center Faculty Publications

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated …

Association Between Bone-Specific Physical Activity Scores And Pqct-Derived Measures Of Bone Strength And Geometry In Healthy Young And Middle-Aged Premenopausal Women., Sojung Kim, Breanne S Baker, Pragya Sharma-Ghimire, Debra A Bemben, Michael G Bemben

Faculty Scholarship for the College of Science & Mathematics

The aim of this study was to determine if bone-specific physical activity questionnaire (BPAQ) scores were positively related to bone health in healthy young and middle-aged premenopausal women. The total BPAQ was a stronger predictor of bone strength and bone mineral density of hip in young women as compared to middle-aged premenopausal women.

PURPOSE: The purpose of this study was to determine whether the BPAQ scores were predictive indices of volumetric BMD (vBMD), bone strength, and bone geometry in young and middle-aged premenopausal women.

METHODS: Healthy young (n = 60) and middle-aged premenopausal women (n = 54) between the ages …

Age Adjusted Hematopoietic Stem Cell Transplant Comorbidity Index Predicts Survival In A T-Cell Depleted Cohort, Hayder Saeed, Swati Yalamanchi, Meng Liu, Emily Van Meter, Zartash Gul, Gregory Monohan, Dianna Howard, Gerhard C. Hildebrandt, Roger Herzig

Markey Cancer Center Faculty Publications

Objectives: Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria.

Methods: A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was …

Analysis Of The Immunological Biomarker Profile During Acute Zika Virus Infection Reveals The Overexpression Of Cxcl10, A Chemokine Linked To Neuronal Damage., Felipe Gomes Naveca, Gemilson Soares Pontes, Aileen Yu-Hen Chang, George Allan Villarouco Da Silva, Valdinete Alves Do Nascimento, Dana Cristina Da Silva Monteiro, +Several Additional Authors

Medicine Faculty Publications

BACKGROUND: Infection with Zika virus (ZIKV) manifests in a broad spectrum of disease ranging from mild illness to severe neurological complications and little is known about Zika immunopathogenesis.

OBJECTIVES: To define the immunologic biomarkers that correlate with acute ZIKV infection.

METHODS: We characterized the levels of circulating cytokines, chemokines, and growth factors in 54 infected patients of both genders at five different time points after symptom onset using microbeads multiplex immunoassay; comparison to 100 age-matched controls was performed for statistical analysis and data mining.

FINDINGS: ZIKV-infected patients present a striking systemic inflammatory response with high levels of pro-inflammatory mediators. Despite …

Human Cancer And Platelet Interaction, A Potential Therapeutic Target, Shike Wang, Zhenyu Li, Ren Xu

Markey Cancer Center Faculty Publications

Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect interaction of platelets induces cancer cell plasticity and enhances survival and extravasation of circulating cancer cells during dissemination. In vivo and in vitro experiments also demonstrate that cancer cells induce platelet aggregation, suggesting that platelet-cancer interaction is bidirectional. Therefore, understanding how platelets crosstalk with cancer cells may identify potential strategies to inhibit cancer metastasis and to reduce …

Profiling Prostate Cancer Therapeutic Resistance, Cameron A. Wade, Natasha Kyprianou

Urology Faculty Publications

The major challenge in the treatment of patients with advanced lethal prostate cancer is therapeutic resistance to androgen-deprivation therapy (ADT) and chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our …

Treated Hypothyroidism Is Associated With Cerebrovascular Disease But Not Alzheimer's Disease Pathology In Older Adults, Willa D. Brenowitz, Fang Han, Walter A. Kukull, Peter T. Nelson

Pathology and Laboratory Medicine Faculty Publications

Thyroid hormone (TH) disease is common among older adults and is associated with cognitive impairment. However, pathologic correlates are not well understood. We studied pathologic and clinical factors associated with hypothyroidism, the most common form of TH disease, in research subjects seen annually for clinical evaluations at U.S. Alzheimer’s Disease Centers. Thyroid disease and treatment status were assessed during clinician interviews. Among autopsied subjects, there were 555 participants with treated hypothyroidism and 2,146 with no known thyroid disease; hypothyroidism was associated with severe atherosclerosis (OR=1.35 95% CI: 1.02, 1.79) but not Alzheimer’s disease (AD) pathologies (amyloid plaques or neurofibrillary tangles). …

Genotype-Phenotype Study In Patients With Valosin-Containing Protein Mutations Associated With Multisystem Proteinopathy, Ebaa Al-Obeidi, Sejad Al-Tahan, Abhilasha Surampalli, Namita Goyal, Annabel K. Wang, Andreas Hermann, Molly Omizo, Charles D. Smith, Tahseen Mozaffar, Virginia Kimonis

Neurology Faculty Publications

Mutations in valosin‐containing protein (VCP), an ATPase involved in protein degradation and autophagy, cause VCP disease, a progressive autosomal dominant adult onset multisystem proteinopathy. The goal of this study is to examine if phenotypic differences in this disorder could be explained by the specific gene mutations. We therefore studied 231 individuals (118 males and 113 females) from 36 families carrying 15 different VCP mutations. We analyzed the correlation between the different mutations and prevalence, age of onset and severity of myopathy, Paget's disease of bone (PDB), and frontotemporal dementia (FTD), and other comorbidities. Myopathy, PDB and FTD was present in …

Cetuximab Plus Carboplatin And Paclitaxel With Or Without Bevacizumab Versus Carboplatin And Paclitaxel With Or Without Bevacizumab In Advanced Nsclc (Swog S0819): A Randomised, Phase 3 Study, Roy S. Herbst, Mary W. Redman, Edward S. Kim, Thomas J. Semrad, Lyudmila Bazhenova, Gregory Masters, Kurt Oettel, Perry Guaglianone, Christopher Reynolds, Anand Karnad, Susanne M. Arnold, Marileila Varella-Garcia, James Moon, Philip C. Mack, Charles D. Blanke, Fred R. Hirsch, Karen Kelly, David R. Gandara

Markey Cancer Center Faculty Publications

Background

EGFR antibodies have shown promise in patients with advanced non-small-cell lung cancer (NSCLC), particularly with squamous cell histology. We hypothesised that EGFR copy number by fluorescence in-situ hybridisation (FISH) can identify patients most likely to benefit from these drugs combined with chemotherapy and we aimed to explore the activity of cetuximab with chemotherapy in patients with advanced NSCLC who are EGFR FISH-positive.

Methods

We did this open-label, phase 3 study (SWOG S0819) at 277 sites in the USA and Mexico. We randomly assigned (1:1) eligible patients with treatment-naive stage IV NSCLC to receive paclitaxel (200 mg/m ²; every …

Nanoparticle Orientation To Control Rna Loading And Ligand Display On Extracellular Vesicles For Cancer Regression, Fengmei Pi, Daniel W. Binzel, Tae Jin Lee, Zhefeng Li, Meiyan Sun, Piotr G. Rychahou, Hui Li, Farzin Haque, Shaoying Wang, Carlo M. Croce, Bin Guo, B. Mark Evers, Peixuan Guo

Markey Cancer Center Faculty Publications

Nanotechnology offers many benefits, and here we report an advantage of applying RNA nanotechnology for directional control. The orientation of arrow-shaped RNA was altered to control ligand display on extracellular vesicle membranes for specific cell targeting, or to regulate intracellular trafficking of small interfering RNA (siRNA) or microRNA (miRNA). Placing membrane-anchoring cholesterol at the tail of the arrow results in display of RNA aptamer or folate on the outer surface of the extracellular vesicle. In contrast, placing the cholesterol at the arrowhead results in partial loading of RNA nanoparticles into the extracellular vesicles. Taking advantage of the RNA ligand for …

Baseline White Matter Hyperintensities And Hippocampal Volume Are Associated With Conversion From Normal Cognition To Mild Cognitive Impairment In The Framingham Offspring Study., Katherine J Bangen, Sarah R Preis, Lisa Delano-Wood, Philip A Wolf, David J Libon, Mark W Bondi, Rhoda Au, Charles Decarli, Adam M Brickman

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

INTRODUCTION: We examined associations between magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration with mild cognitive impairment (MCI) diagnosis at baseline and conversion from normal cognition to MCI at follow-up.

METHODS: Framingham Offspring participants underwent brain MRI and neuropsychological assessment at baseline (n=1049) and follow-up (n=561). Participants were classified at baseline and at follow-up as cognitively normal or MCI using sensitive neuropsychological criteria. White matter hyperintensity (WMH) volume, covert brain infarcts, hippocampal volume, and total cerebral brain volume were quantified.

RESULTS: Baseline measures of WMH and hippocampal volume were associated with MCI status cross-sectionally and also with conversion …