Digital Commons Network^™

Large-Scale Genome-Wide Meta-Analysis Of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture For Different Diagnosis Criteria, Felix Day, Tugce Karaderi, Michelle R. Jones, Cindy Meun, Chunyan He, Alex Drong, Peter Kraft, Nan Lin, Hongyan Huang, Linda Broer, Reedik Magi, Richa Saxena, Triin Laisk, Margrit Urbanek, M. Geoffrey Hayes, Gudmar Thorleifsson, Juan Fernandez-Tajes, Anubha Mahajan, Benjamin H. Mullin, Bronwyn G. A. Stuckey, Timothy D. Spector, Scott G. Wilson, Mark O. Goodarzi, Lea Davis, Barbara Obermayer-Pietsch, André G. Uitterlinden, Verneri Anttila, Benjamin M. Neale, Marjo-Riitta Jarvelin, Bart Fauser

Internal Medicine Faculty Publications

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related …

Als Mutations Of Fus Suppress Protein Translation And Disrupt The Regulation Of Nonsense-Mediated Decay, Marisa Kamelgarn, Jing Chen, Lisha Kuang, Huan Jin, Edward J. Kasarskis, Haining Zhu

Toxicology and Cancer Biology Faculty Publications

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid–liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed …

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 …

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 …

Structure Of The Mouse Trpc4 Ion Channel, Jingjing Duan, Jian Li, Bo Zeng, Gui-Lan Chen, Xiaogang Peng, Yixing Zhang, Jianbin Wang, David E. Clapham, Zongli Li, Jin Zhang

Molecular and Cellular Biochemistry Faculty Publications

Members of the transient receptor potential (TRP) ion channels conduct cations into cells. They mediate functions ranging from neuronally mediated hot and cold sensation to intracellular organellar and primary ciliary signaling. Here we report a cryo-electron microscopy (cryo-EM) structure of TRPC4 in its unliganded (apo) state to an overall resolution of 3.3 Å. The structure reveals a unique architecture with a long pore loop stabilized by a disulfide bond. Beyond the shared tetrameric six-transmembrane fold, the TRPC4 structure deviates from other TRP channels with a unique cytosolic domain. This unique cytosolic N-terminal domain forms extensive aromatic contacts with the TRP …

Direct Cell-To-Cell Transmission Of Respiratory Viruses: The Fast Lanes, Nicolás P. Cifuentes-Muñoz, Rebecca Ellis Dutch, Roberto Cattaneo

Molecular and Cellular Biochemistry Faculty Publications

Virus particles protect genomes from hostile environments within and outside the host, eventually delivering these genomes to target tissues to initiate infection. Complex processes requiring significant energy and time are necessary to assemble these virus particles, but only a small portion of released virus will successfully infect new target cells (Fig 1A). While the science of virology has developed based on the isolation and purification of viral particles, it is becoming increasingly clear that direct cell-to-cell transmission of viruses and/or viral components is also highly relevant [1,2].

Direct cell-to-cell spread of infections has several advantages. The first is efficiency: genomic …

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 …

Genome-Wide Association Meta-Analysis Of Circulating Odd-Numbered Chain Saturated Fatty Acids: Results From The Charge Consortium, Marcia C. De Oliveira Otto, Rozenn N. Lemaitre, Qi Sun, Irena B. King, Jason H. Y. Wu, Ani Manichaikul, Stephen S. Rich, Michael Y. Tsai, Y. D. Chen, Myriam Fornage, Guan Weihua, Stella Aslibekyan, Marguerite R. Irvin, Edmond K. Kabagambe, Donna K. Arnett, Majken K. Jensen, Barbara Mcknight, Bruce M. Psaty, Lyn M. Steffen, Caren E. Smith, Ulf Risérus, Lars Lind, Frank B. Hu, Eric B. Rimm, David S. Siscovick, Dariush Mozaffarian

Epidemiology and Environmental Health Faculty Publications

Background

Odd-numbered chain saturated fatty acids (OCSFA) have been associated with potential health benefits. Although some OCSFA (e.g., C15:0 and C17:0) are found in meats and dairy products, sources and metabolism of C19:0 and C23:0 are relatively unknown, and the influence of non-dietary determinants, including genetic factors, on circulating levels of OCSFA is not established.

Objective

To elucidate the biological processes that influence circulating levels of OCSFA by investigating associations between genetic variation and OCSFA.

Design

We performed a meta-analysis of genome-wide association studies (GWAS) of plasma phospholipid/erythrocyte levels of C15:0, C17:0, C19:0, and C23:0 among 11,494 individuals of European …

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 …

Genetic Variants In Hsd17b3, Smad3, And Ipo11 Impact Circulating Lipids In Response To Fenofibrate In Individuals With Type 2 Diabetes, Daniel M. Rotroff, Sonja S. Pijut, Skylar W. Marvel, John R. Jack, Tammy M. Havener, Aurora Pujol, Agatha Schluter, Gregory A. Graf, Henry N. Ginsberg, Hetal S. Shah, He Gao, Mario-Luca Morieri, Alessandro Doria, Josyf C. Mychaleckyi, Howard L. Mcleod, John B. Buse, Michael J. Wagner, Alison A. Motsinger-Reif, Accord/Accordion Investigators

Pharmaceutical Sciences Faculty Publications

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10^‐6). Rare variant and gene expression changes …

Early Relapse After Autologous Hematopoietic Cell Transplantation Remains A Poor Prognostic Factor In Multiple Myeloma But Outcomes Have Improved Over Time, Shaji K. Kumar, Angela Dispenzieri, Raphael Fraser, Fei Mingwei, Gorgun Akpek, Robert Cornell, Mohamed Kharfan-Dabaja, Cesar Freytes, Shahrukh Hashmi, Gerhard C. Hildebrandt, Leona Holmberg, Robert Kyle, Hillard Lazarus, Cindy Lee, Jospeh Mikhael, Taiga Nishihori, Jason Tay, Saad Usmani, David Vesole, Ravi Vij, Baldeep Wirk, Amrita Krishnan, Cristina Gasparetto, Tomer Mark, Yago Nieto, Parameswaran Hari, Anita D'Souza

Internal Medicine Faculty Publications

Duration of initial disease response remains a strong prognostic factor in multiple myeloma (MM) particularly for upfront autologous hematopoietic cell transplant (AHCT) recipients. We hypothesized that new drug classes and combinations employed prior to AHCT as well as after post-AHCT relapse may have changed the natural history of MM in this population. We analyzed the Center for International Blood and Marrow Transplant Research database to track overall survival (OS) of MM patients receiving single AHCT within 12 months after diagnosis (N=3256) and relapsing early post-AHCT (< 24 months), and to identify factors predicting for early vs late relapses (24−48 months post-AHCT). Over three periods (2001–2004, 2005–2008, 2009–2013), patient characteristics were balanced except for lower proportion of Stage III, higher likelihood of one induction therapy with novel triplets and higher rates of planned post-AHCT maintenance over time. The proportion of patients relapsing early was stable over time at 35–38%. Factors reducing risk of early relapse included lower stage, chemosensitivity, transplant after 2008 and post-AHCT maintenance. Shorter post-relapse OS was associated with early relapse, IgA MM, Karnofsky < 90, stage III, > 1 line of induction and lack of maintenance. Post-AHCT early relapse remains …

A Model-Based Approach For Estimation Of Changes In Lumbar Segmental Kinematics Associated With Alterations In Trunk Muscle Forces, Iman Shojaei, Navid Arjmand, Judith R. Meakin, Babak Bazrgari

Biomedical Engineering Faculty Publications

The kinematics information from imaging, if combined with optimization-based biomechanical models, may provide a unique platform for personalized assessment of trunk muscle forces (TMFs). Such a method, however, is feasible only if differences in lumbar spine kinematics due to differences in TMFs can be captured by the current imaging techniques. A finite element model of the spine within an optimization procedure was used to estimate segmental kinematics of lumbar spine associated with five different sets of TMFs. Each set of TMFs was associated with a hypothetical trunk neuromuscular strategy that optimized one aspect of lower back biomechanics. For each set …

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 …

Morphogenetic Defects Underlie Superior Coloboma, A Newly Identified Closure Disorder Of The Dorsal Eye, Jennifer C. Hocking, Jakub K. Famulski, Kevin H. Yoon, Sonya A. Widen, Cassidy S. Bernstein, Sophie Koch, Omri Weiss, Forge Canada Consortium, Canada, Seema Agarwala, Adi Inbal, Ordan J. Lehmann, Andrew J. Waskiewicz

Biology Faculty Publications

The eye primordium arises as a lateral outgrowth of the forebrain, with a transient fissure on the inferior side of the optic cup providing an entry point for developing blood vessels. Incomplete closure of the inferior ocular fissure results in coloboma, a disease characterized by gaps in the inferior eye and recognized as a significant cause of pediatric blindness. Here, we identify eight patients with defects in tissues of the superior eye, a congenital disorder that we term superior coloboma. The embryonic origin of superior coloboma could not be explained by conventional models of eye development, leading us to …

Structure Of Full-Length Human Trpm4, Jingjing Duan, Zongli Li, Jian Li, Ana Santa-Cruz, Silvia Sanchez-Martinez, Jin Zhang, David E. Clapham

Molecular and Cellular Biochemistry Faculty Publications

Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na⁺-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist …

Comparative Analysis Of Microbial Sensing Molecules In Mucosal Tissues With Aging, Octavio A. Gonzalez, Sreenatha S. Kirakodu, Michael John Novak, A. J. Stromberg, L. Orraca, J. Gonzalez-Martinez, A. Burgos, Jeffrey L. Ebersole

Center for Oral Health Research Faculty Publications

Host-bacterial interactions at mucosal surfaces require recognition of the bacteria by host cells enabling targeted responses to maintain tissue homeostasis. It is now well recognized that an array of host-derived pattern recognition receptors (PRRs), both cell-bound and soluble, are critical to innate immune engagement of microbes via microbial-associated molecular patterns (MAMP). This report describes the use of a nonhuman primate model to evaluate changes in the expression of these sensing molecules related to aging in healthy gingival tissues. Macaca mulatta aged 3-24 years were evaluated clinically and gingival tissues obtained, RNA isolated and microarray analysis conducted for gene expression of …

Genome-Wide Interactions With Dairy Intake For Body Mass Index In Adults Of European Descent, Caren E. Smith, Jack L. Follis, Hassan S. Dashti, Toshiko Tanaka, Mariaelisa Graff, Amanda M. Fretts, Tuomas O. Kilpeläinen, Mary K. Wojczynski, Kris Richardson, Mike A. Nalls, Christina-Alexandra Schulz, Yongmei Liu, Alexis C. Frazier-Wood, Esther Van Eekelen, Carol Wang, Paul S. De Vries, Vera Mikkilä, Rebecca Rohde, Bruce M. Psaty, Torben Hansen, Mary F. Feitosa, Chao-Qiang Lai, Denise K. Houston, Luigi Ferruci, Ulrika Ericson, Zhe Wang, Renée De Mutsert, Wendy H. Oddy, Ester A. L. De Jonge, Ilkka Seppälä, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Scope: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter‐individual variability in associations between body weight and dairy consumption.

Methods and results: A genome‐wide interaction study to discover genetic variants that account for variation in BMI in the context of low‐fat, high‐fat and total dairy intake in cross‐sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta‐analyzed. Twenty‐six genetic variants reached the selected significance threshold (p‐interaction <10⁻⁷⁾, and six independent variants (LINC01512‐rs7751666, PALM2/AKAP2‐rs914359, ACTA2‐rs1388, PPP1R12A‐rs7961195, LINC00333‐rs9635058, …

Auditing Snomed Ct Hierarchical Relations Based On Lexical Features Of Concepts In Non-Lattice Subgraphs, Licong Cui, Olivier Bodenreider, Jay Shi, Guo-Qiang Zhang

Computer Science Faculty Publications

Objective—We introduce a structural-lexical approach for auditing SNOMED CT using a combination of non-lattice subgraphs of the underlying hierarchical relations and enriched lexical attributes of fully specified concept names. Our goal is to develop a scalable and effective approach that automatically identifies missing hierarchical IS-A relations.

Methods—Our approach involves 3 stages. In stage 1, all non-lattice subgraphs of SNOMED CT’s IS-A hierarchical relations are extracted. In stage 2, lexical attributes of fully-specified concept names in such non-lattice subgraphs are extracted. For each concept in a non-lattice subgraph, we enrich its set of attributes with attributes from its ancestor …

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). …

Kruppel-Like Factor 4-Dependent Staufen1-Mediated Mrna Decay Regulates Cortical Neurogenesis, Byoung-San Moon, Jinlun Bai, Mingyang Cai, Chunming Liu, Jiandang Shi, Wange Lu

Molecular and Cellular Biochemistry Faculty Publications

Kruppel-like factor 4 (Klf4) is a zinc-finger-containing protein that plays a critical role in diverse cellular physiology. While most of these functions attribute to its role as a transcription factor, it is postulated that Klf4 may play a role other than transcriptional regulation. Here we demonstrate that Klf4 loss in neural progenitor cells (NPCs) leads to increased neurogenesis and reduced self-renewal in mice. In addition, Klf4 interacts with RNA-binding protein Staufen1 (Stau1) and RNA helicase Ddx5/17. They function together as a complex to maintain NPC self-renewal. We report that Klf4 promotes Stau1 recruitment to the 3′-untranslated region of neurogenesis-associated mRNAs, …

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 …

Selective Inhibition Of Ctcf Binding By Ias Directs Tet-Mediated Reprogramming Of 5-Hydroxymethylation Patterns In Ias-Transformed Cells, Matthew Rea, Tyler Gripshover, Yvonne N. Fondufe-Mittendorf

Molecular and Cellular Biochemistry Faculty Publications

Methylation at cytosine (5mC) is a fundamental epigenetic DNA modification recently associated with iAs-mediated carcinogenesis. In contrast, the role of 5-hydroxymethylcytosine (5hmC), the oxidation product of 5mC in iAs-mediated carcinogenesis is unknown. Here we assess the hydroxymethylome in iAs-transformed cells, showing that dynamic modulation of hydroxymethylated DNA is associated with specific transcriptional networks. Moreover, this pathologic iAs-mediated carcinogenesis is characterized by a shift toward a higher hydroxymethylation pattern genome-wide. At specific promoters, hydroxymethylation correlated with increased gene expression. Furthermore, this increase in hydroxymethylation occurs concurrently with an upregulation of ten-eleven translocation (TET) enzymes that oxidize 5-methylcytosine (5mC) in DNA. To …

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 …

Autonomic Dysreflexia After Spinal Cord Injury: Systemic Pathophysiology And Methods Of Management, Khalid C. Eldahan, Alexander G. Rabchevsky

Physiology Faculty Publications

Traumatic spinal cord injury (SCI) has widespread physiological effects beyond the disruption of sensory and motor function, notably the loss of normal autonomic and cardiovascular control. Injury at or above the sixth thoracic spinal cord segment segregates critical spinal sympathetic neurons from supraspinal modulation which can result in a syndrome known as autonomic dysreflexia (AD). AD is defined as episodic hypertension and concomitant baroreflex-mediated bradycardia initiated by unmodulated sympathetic reflexes in the decentralized cord. This condition is often triggered by noxious yet unperceived visceral or somatic stimuli below the injury level and if severe enough can require immediate medical attention. …