Digital Commons Network^™

Antisense Oligonucleotides Targeting Angiotensinogen: Insights From Animal Studies, Chia-Hua Wu, Ya Wang, Murong Ma, Adam E. Mullick, Rosanne M. Crooke, Mark J. Graham, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

Angiotensinogen (AGT) is the unique substrate of all angiotensin peptides. We review the recent preclinical research of AGT antisense oligonucleotides (ASOs), a rapidly evolving therapeutic approach. The scope of the research findings not only opens doors for potentially new therapeutics of hypertension and many other diseases, but also provides insights into understanding critical physiological and pathophysiological roles mediated by AGT.

Apo-Opsin Exists In Equilibrium Between A Predominant Inactive And A Rare Highly Active State, Shinya Sato, Beata Jastrzebska, Andreas Engel, Krzysztof Palczewski, Vladimir J. Kefalov

Open Access Publications

Bleaching adaptation in rod photoreceptors is mediated by apo-opsin, which activates phototransduction with effective activity 10

Disruption Of The Hippocampal And Hypothalamic Blood-Brain Barrier In A Diet-Induced Obese Model Of Type Ii Diabetes: Prevention And Treatment By The Mitochondrial Carbonic Anhydrase Inhibitor, Topiramate, Therese S. Salameh, William G. Mortell, Aric F. Logsdon, D. Allan Butterfield, William A. Banks

Chemistry Faculty Publications

Background: Type II diabetes is a vascular risk factor for cognitive impairment and increased risk of dementia. Disruption of the blood–retinal barrier (BRB) and blood–brain barrier (BBB) are hallmarks of subsequent retinal edema and central nervous system dysfunction. However, the mechanisms by which diet or metabolic syndrome induces dysfunction are not understood. A proposed mechanism is an increase in reactive oxygen species (ROS) and oxidative stress. Inhibition of mitochondrial carbonic anhydrase (mCA) decreases ROS and oxidative stress. In this study, topiramate, a mCA inhibitor, was examined for its ability to protect the BRB and BBB in diet-induced obese type II …

Star-Related Lipid Transfer Protein 10 (Stard10): A Novel Key Player In Alcohol-Induced Breast Cancer Progression, Andrea Floris, Jia Luo, Jacqueline A. Frank, Jennifer Zhou, Sandro Orrù, Michela Biancolella, Sabina Pucci, Augusto Orlandi, Paolo Campagna, Antonella Balzano, Komal Ramani, Maria Lauda Tomasi

Pharmacology and Nutritional Sciences Faculty Publications

Background: Ethanol abuse promotes breast cancer development, metastasis and recurrence stimulating mammary tumorigenesis by mechanisms that remain unclear. Normally, 35% of breast cancer is Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2)-positive that predisposes to poor prognosis and relapse, while ethanol drinking leads to invasion of their ERBB2 positive cells triggering the phosphorylation status of mitogen-activated protein kinase. StAR-related lipid transfer protein 10 (STARD10) is a lipid transporter of phosphatidylcholine (PC) and phosphatidylethanolamine (PE); changes on membrane composition of PC and PE occur before the morphological tumorigenic events. Interestingly, STARD10 has been described to be highly expressed in 35–40% of ERBB2-positive breast …

Ctcf Governs The Identity And Migration Of Mge-Derived Cortical Interneurons., Adrienne Elbert, Daniel Vogt, Ashley Watson, Michael Levy, Yan Jiang, Emilie Brûlé, Megan E Rowland, John Rubenstein, Nathalie G Bérubé

Paediatrics Publications

The CCCTC-binding factor (CTCF) is a central regulator of chromatin topology recently linked to neurodevelopmental disorders such as intellectual disability, autism, and schizophrenia. The aim of this study was to identify novel roles of CTCF in the developing mouse brain. We provide evidence that CTCF is required for the expression of the LIM homeodomain factor LHX6 involved in fate determination of cortical interneurons (CINs) that originate in the medial ganglionic eminence (MGE). Conditional

The Transcriptional Regulator Snon Promotes The Proliferation Of Cerebellar Granule Neuron Precursors In The Postnatal Mouse Brain, Xiaoying Chen, Ayan Chanda, Yoshiho Ikeuchi, Xiaoqing Zhang, Jared V. Goodman, Naveen C. Reddy, Shahriyar P. Majidi, Dennis Y. Wu, Sarah E. Smith, Abigail Godec, Anna Oldenborg, Harrison W. Gabel, Guoyan Zhao, Shirin Bonni, Azad Bonni

Open Access Publications

Control of neuronal precursor cell proliferation is essential for normal brain development, and deregulation of this fundamental developmental event contributes to brain diseases. Typically, neuronal precursor cell proliferation extends over long periods of time during brain development. However, how neuronal precursor proliferation is regulated in a temporally specific manner remains to be elucidated. Here, we report that conditional KO of the transcriptional regulator SnoN in cerebellar granule neuron precursors robustly inhibits the proliferation of these cells and promotes their cell cycle exit at later stages of cerebellar development in the postnatal male and female mouse brain. In laser capture microdissection …

Voltage-Independent Sk-Channel Dysfunction Causes Neuronal Hyperexcitability In The Hippocampus Of Fmr1 Knock-Out Mice, Pan-Yue Deng, Dan Carlin, Young Mi Oh, Leila K. Myrick, Stephen T. Warren, Valeria Cavalli, Vitaly A. Klyachko

Open Access Publications

Neuronal hyperexcitability is one of the major characteristics of fragile X syndrome (FXS), yet the molecular mechanisms of this critical dysfunction remain poorly understood. Here we report a major role of voltage-independent potassium (K

The Loss Of Atrx Increases Susceptibility To Pancreatic Injury And Oncogenic Kras In Female But Not Male Mice., Claire C Young, Ryan M Baker, Christopher J Howlett, Todd Hryciw, Joshua E Herman, Douglas Higgs, Richard Gibbons, Howard Crawford, Arthur Brown, Christopher L Pin

Paediatrics Publications

Background

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in North America, accounting for >30,000 deaths annually. Although somatic activating mutations in KRAS appear in 97% of PDAC patients, additional factors are required to initiate PDAC. Because mutations in genes encoding chromatin remodelling proteins have been implicated in KRAS-mediated PDAC, we investigated whether loss of chromatin remodeler ɑ-thalassemia, mental-retardation, X-linked (ATRX) affects oncogenic KRAS’s ability to promote PDAC. ATRX affects DNA replication, repair, and gene expression and is implicated in other cancers including glioblastomas and pancreatic neuroendocrine tumors. The hypothesis was that deletion of Atrx …

Mapping Of Lymphatic Filariasis In Loiasis Areas: A New Strategy Shows No Evidence For Wuchereria Bancrofti Endemicity In Cameroon, Samuel Wanji, Mathias Eyong Esum, Abdel Jelil Njouendou, Amuam Andrew Mbeng, Patrick W Chounna Ndongmo, Raphael Awah Abong, Jerome Fru, Fanny F. Fombad, Gordon Takop Nchanji, Glory Ngongeh, Narcisse V. Ngandjui, Peter Ivo Enyong, Helen Storey, Kurt C. Curtis, Kerstin Fischer, Joseph R. Fauver, Daphne Lew, Charles W. Goss, Peter U. Fischer

Journal Articles: Epidemiology

BACKGROUND: Mapping of lymphatic filariasis (LF) caused by Wuchereria bancrofti largely relies on the detection of circulating antigen using ICT cards. Several studies have recently shown that this test can be cross-reactive with sera of subjects heavily infected with Loa loa and thus mapping results in loiasis endemic areas may be inaccurate.

METHODOLOGY/PRINCIPAL FINDINGS: In order to develop an LF mapping strategy for areas with high loiasis prevalence, we collected day blood samples from 5,001 subjects residing in 50 villages that make up 6 health districts throughout Cameroon. Antigen testing using Filarial Test Strip (FTS, a novel platform that uses …

The Political Animal: The Animal Rights Movement And Public Policy, Dorothy Jean Simnett

Department of Conflict Resolution Studies Theses and Dissertations

Social movements are consequences of social conflict. This project examines the conflicting and contentious efforts of animal rights activists at changing public policy and it evaluates the successes and failures of the animal rights movement. Animal rights activists’ challenges concerning animal rights, animal welfare and animal protection, combined with divergences from the special interest consortiums compounded by societal norms will all be addressed here. Furthermore, none of this has been previously addressed in the field of Conflict Resolution. This project highlights the challenges that animal rights advocates encounter when attempting to safeguard animal protective measures. The power struggle between animal …

Lipid-Polymer Hybrid Nanoparticles As A Next-Generation Drug Delivery Platform: State Of The Art, Emerging Technologies, And Perspectives., Anubhab Mukherjee, Ariana K Waters, Pranav Kalyan, Achal Singh Achrol, Santosh Kesari, Venkata Yenugonda

Articles, Abstracts, and Reports

Lipid-polymer hybrid nanoparticles (LPHNPs) are next-generation core-shell nanostructures, conceptually derived from both liposome and polymeric nanoparticles (NPs), where a polymer core remains enveloped by a lipid layer. Although they have garnered significant interest, they remain not yet widely exploited or ubiquitous. Recently, a fundamental transformation has occurred in the preparation of LPHNPs, characterized by a transition from a two-step to a one-step strategy, involving synchronous self-assembly of polymers and lipids. Owing to its two-in-one structure, this approach is of particular interest as a combinatorial drug delivery platform in oncology. In particular, the outer surface can be decorated in multifarious ways …

De Novo Assembly Of The Brugia Malayi Genome Using Long Reads From A Single Minion Flowcell, Joseph R. Fauver, John Martin, Gary J. Weil, Makedonka Mitreva, Peter U. Fischer

Journal Articles: Epidemiology

Filarial nematode infections cause a substantial global disease burden. Genomic studies of filarial worms can improve our understanding of their biology and epidemiology. However, genomic information from field isolates is limited and available reference genomes are often discontinuous. Single molecule sequencing technologies can reduce the cost of genome sequencing and long reads produced from these devices can improve the contiguity and completeness of genome assemblies. In addition, these new technologies can make generation and analysis of large numbers of field isolates feasible. In this study, we assessed the performance of the Oxford Nanopore Technologies MinION for sequencing and assembling the …

Methods To Quantify Nanomaterial Association With, And Distribution Across, The Blood-Brain Barrier In Vivo, Robert A. Yokel

Pharmaceutical Sciences Faculty Publications

The role and functional anatomy of the blood-brain barrier (BBB) is summarized to enable the investigator to appropriately address evaluation of nanomaterial interaction with, and distribution across, it into brain tissue (parenchyma). Transport mechanisms across the BBB are presented, in relation to nanomaterial physicochemical properties. Measures and test substances to assess BBB integrity/disruption/permeation are introduced, along with how they are used to interpret the results obtained with the presented methods. Experimental pitfalls and misinterpretation of results of studies of brain nanomaterial uptake are briefly summarized, that can be avoided with the methods presented in this chapter. Two methods are presented. …

Don't Touch Me Like That: Masculinity, Touch, And The Role Of Affect In Media Representations Of Animal Attacks, Carolyn Grace Block

Electronic Theses and Dissertations Archive

This dissertation analyzes masculinity and touch in three highly publicized cases where men intentionally interacted with wild animals and were harmed in the process. I focus predominately on the first week of media coverage following Steve The Crocodile Hunter Irwin who was killed by a massive stingray while filming for a television series off the Great Barrier Reef, Roy Horn of the famed Las Vegas magician duo Siegfried and Roy who was mauled by one of his performing tigers in front of a live audience, and Antoine Yates, an African American man bitten by the pet tiger he kept in …

Diagnosis Of Schistosoma Mansoni Infections: What Are The Choices In Brazilian Low-Endemic Areas?, Vanessa Silva-Moraes, Lisa M. Shollenberger, Liliane Maria Vidal Siqueira, William Castro-Borges, Donald A. Harn, Rafaella Fortini Queiroz E. Grenfell, Ana Lucia Teles Rabello, Paulo Marcos Zech Coelho

Biological Sciences Faculty Publications

The population of Brazil is currently characterised by many individuals harbouring low-intensity Schistosoma mansoni infections. The Kato-Katz technique is the diagnostic method recommended by the World Health Organization (WHO) to assess these infections, but this method is not sensitive enough in the context of low egg excretion. In this regard, potential alternatives are being employed to overcome the limits of the Kato-Katz technique. In the present review, we evaluated the performance of parasitological and immunological approaches adopted in Brazilian areas. Currently, the diagnostic choices involve a combination of strategies, including the utilisation of antibody methods to screen individuals and then …

Field Testing Integrated Interventions For Schistosomiasis Elimination In The People's Republic Of China: Outcomes Of A Multifactorial Cluster-Randomized Controlled Trial, Gail M. Williams, Yue-Sheng Li, Darren J. Gray, Zheng-Yuan Zhao, Donald A. Harn, Lisa M. Shollenberger, Sheng-Ming Li, Xinglin Yu, Zeng Feng, Jia-Gang Guo, Jie Zhou, Yu-Lan Dong, Yuan Li, Biao Guo, Patrick Driguez, Marina Harvie, Hong You, Allen G. Ross, Donald P. Mcmanus

Biological Sciences Faculty Publications

Despite significant progress, China faces the challenge of re-emerging schistosomiasis transmission in currently controlled areas due, in part, to the presence of a range of animal reservoirs, notably water buffalo and cattle, which can harbor Schistosoma japonicum infections. Environmental, ecological and social-demographic changes in China, shown to affect the distribution of oncomelanid snails, can also impact future schistosomiasis transmission. In light of their importance in the S. japonicum, lifecycle, vaccination has been proposed as a means to reduce the excretion of egg from cattle and buffalo, thereby interrupting transmission from these reservoir hosts to snails. A DNA-based vaccine (SjCTPI) …

Castration-Resistant Prostate Cancer: Androgen Receptor Inactivation Induces Telomere Dna Damage, And Damage Response Inhibition Leads To Cell Death, Vidyavathi Reddy, Asm Iskander, Clara Hwang, George Divine, Mani Menon, Evelyn R. Barrack, Prem-Veer Reddy, Sahn-Ho Kim

Urology Articles

Telomere stability is important for cell viability, as cells with telomere DNA damage that is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR antagonist. Treatment with AR antagonist enzalutamide (ENZ) …

Do Teachers Participating In A Therapy Dog Program Perceive An Impact On Students’ Attitudes And Behaviors Toward Reading?, Jenna M. Dragani-Reagan

PCOM Psychology Dissertations

No abstract provided.

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 …

Hope For Paws New York: Rescue, Rehabilitation And Veterinary Hospital, Jasmine Arndt

Architecture Theses and Projects

Hope for Paws has made it their mission to rescue any and all animals, no matter the size, shape, breed or species. Their goal is to rehabilitate them, foster them out, and get them adopted into loving forever homes, where they will never know the abuse and neglect that they had previously known. But is there a better system? Hope for Paws runs the rescue missions, pays for the vet bills, find the fosters, and works with the fosters to find them their forever homes. They accomplish this while they still care for all they rescue and check in on …

Developmental Expression Of Monocarboxylate Transporter 1 And 4 In Rat Liver, Michael Ng, Justin Louie, Jieyun Cao, Melanie A. Felmlee

School of Pharmacy Faculty Articles

PURPOSE: Monocarboxylate transporters (MCT) are proton-coupled integral membrane proteins that control the influx and efflux of endogenous monocarboxylates such as lactate, acetate and pyruvate. They also transport and mediate the clearance of drugs such as valproate and gamma-hydroxybutyrate. CD147 functions as ancillary protein that chaperones MCT1 and MCT4 to the cell membrane. There is limited data on the maturation of MCT and CD147 expression in tissues related to drug distribution and clearance. The objective of the present study was to quantify hepatic MCT1, MCT4, and CD147 mRNA, whole cell and membrane protein expression from birth to sexual maturity.

METHODS: Liver …

Mesenchymal Stromal Cell Therapeutic Delivery: Translational Challenges To Clinical Application, Henry Caplan, Scott D Olson, Akshita Kumar, Mitchell George, Karthik S Prabhakara, Pamela Wenzel, Supinder Bedi, Naama E Toledano-Furman, Fabio Triolo, Julian Kamhieh-Milz, Guido Moll, Charles S Cox

Faculty, Staff and Student Publications

For several decades, multipotent mesenchymal stromal cells (MSCs) have been extensively studied for their therapeutic potential across a wide range of diseases. In the preclinical setting, MSCs demonstrate consistent ability to promote tissue healing, down-regulate excessive inflammation and improve outcomes in animal models. Several proposed mechanisms of action have been posited and demonstrated across an array of in vitro models. However, translation into clinical practice has proven considerably more difficult. A number of prominent well-funded late-phase clinical trials have failed, thus calling out for new efforts to optimize product delivery in the clinical setting. In this review, we discuss novel …

Melatonin Enhances Sorafenib-Induced Cytotoxicity In Flt3-Itd Acute Myeloid Leukemia Cells By Redox Modification, Tian Tian, Jiajun Li, Yizhuo Li, Yun-Xin Lu, Yan-Lai Tang, Hua Wang, Fufu Zheng, Dingbo Shi, Qian Long, Miao Chen, Guillermo Garcia-Manero, Yumin Hu, Lijun Qin, Wuguo Deng

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with an internal tandem duplication in Fms-related tyrosine kinase 3 (FLT3-ITD) is identified as a subgroup with poor outcome and intrinsic resistance to chemotherapy and therefore urgent need for development of novel therapeutic strategies.

Methods: The antitumor effects of melatonin alone or combined with sorafenib were evaluated via flow cytometry and immunoblotting assays in FLT-ITD AML cells. Also, the ex vivo and in vivo models were used to test the synergistic effects of melatonin and sorafenib against leukemia with FLT3/ITD mutation.

Results: Our study shows for the first time that melatonin inhibits proliferation and induces apoptosis …

Mitochondrial Superoxide Disrupts The Metabolic And Epigenetic Landscape Of Cd4, Cassandra M. Moshfegh, Christopher W. Collins, Venugopal Gunda, A. Vasanthakumar, J. Z. Cao, Pankaj K. Singh, L. A. Godley, Adam J. Case

Journal Articles: Eppley Institute

While the role of mitochondrial metabolism in controlling T-lymphocyte activation and function is becoming more clear, the specifics of how mitochondrial redox signaling contributes to T-lymphocyte regulation remains elusive. Here, we examined the global effects of elevated mitochondrial superoxide (O₂^-) on T-lymphocyte activation using a novel model of inducible manganese superoxide dismutase (MnSOD) knock-out. Loss of MnSOD led to specific increases in mitochondrial O₂^- with no evident changes in hydrogen peroxide (H₂O₂), peroxynitrite (ONOO^-), or copper/zinc superoxide dismutase (CuZnSOD) levels. Unexpectedly, both mitochondrial and glycolytic metabolism showed significant reductions …

Inhibition Of Geranylgeranyl Diphosphate Synthase Is A Novel Therapeutic Strategy For Pancreatic Ductal Adenocarcinoma, Staci L. Haney, Michelle L. Varney, Yashpal S. Chhonker, Simon Shin, Kamiya Mehla, Ayrianne J. Crawford, Heather Jensen Smith, Lynette M. Smith, Daryl J. Murry, Michael A. Hollingsworth, Sarah A. Holstein

Journal Articles: Eppley Institute

Rab proteins play an essential role in regulating intracellular membrane trafficking processes. Rab activity is dependent upon geranylgeranylation, a post-translational modification that involves the addition of 20-carbon isoprenoid chains via the enzyme geranylgeranyl transferase (GGTase) II. We have focused on the development of inhibitors against geranylgeranyl diphosphate synthase (GGDPS), which generates the isoprenoid donor (GGPP), as anti-Rab agents. Pancreatic ductal adenocarcinoma (PDAC) is characterized by abnormal mucin production and these mucins play important roles in tumor development, metastasis and chemo-resistance. We hypothesized that GGDPS inhibitor (GGDPSi) treatment would induce PDAC cell death by disrupting mucin trafficking, thereby inducing the unfolded …

Serological Proteomic Screening And Evaluation Of A Recombinant Egg Antigen For The Diagnosis Of Low-Intensity Schistosoma Mansoni Infections In Endemic Area In Brazil, Vanessa Silva-Moraes, Lisa Marie Shollenberger, William Castro-Borges, Ana Lucia Teles Rabello, Donald A. Harn, Lia Carolina Soares Medeiros, Wander De Jesus Jeremias, Liliane Maria Vidal Siqueira, Caroline Stephane Salviano Pereira, Maria Luysa Camargos Pedrosa, Nathalie Bonatti Franco Almeida, Aureo Almeida, Jose Roberto Lambertucci, Nidia Francisca De Figueiredo Carneiro, Paulo Marcos Zech Coelho, Refaella Fortini Queiroz Grenfell

Biological Sciences Faculty Publications

Background

Despite decades of use of control programs, schistosomiasis remains a global public health problem. To further reduce prevalence and intensity of infection, or to achieve the goal of elimination in low-endemic areas, there needs to be better diagnostic tools to detect low-intensity infections in low-endemic areas in Brazil. The rationale for development of new diagnostic tools is that the current standard test Kato-Katz (KK) is not sensitive enough to detect low-intensity infections in low-endemic areas. In order to develop new diagnostic tools, we employed a proteomics approach to identify biomarkers associated with schistosome-specific immune responses in hopes of developing …

Resveratrol Attenuates Allergic Asthma And Associated Inflammation In The Lungs Through Regulation Of Mirna-34a That Targets Foxp3 In Mice, Esraah Alharris, Hasan Alghetaa, Ratanesh K. Seth, Saurabh Chatterjee, Narendra P. Singh, Mitzi Nagarkatti, Prakash Nagarkatti

Faculty Publications

Asthma is a chronic inflammatory disease of airways mediated by T-helper 2 (Th2) cells involving complex signaling pathways. Although resveratrol has previously been shown to attenuate allergic asthma, the role of miRNA in this process has not been studied. We investigated the effect of resveratrol on ovalbumin-induced experimental allergic asthma in mice. To that end, BALB/c mice were immunized with ovalbumin (OVA) intraperitoneally followed by oral gavage of vehicle (OVA-veh) or resveratrol (100 mg/kg body) (OVA-res). On day 7, the experimental groups received intranasal challenge of OVA followed by 7 days of additional oral gavage of vehicle or resveratrol. At …

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 …

Rare But Recurrent Ros1 Fusions Resulting From Chromosome 6q22 Microdeletions Are Targetable Oncogenes In Glioma., Monika A Davare, Jacob J Henderson, Anupriya Agarwal, Jacob P Wagner, Sudarshan R Iyer, Nameeta Shah, Randy Woltjer, Romel Somwar, Stephen W Gilheeney, Ana Decarvalo, Tom Mikkelson, Erwin G Van Meir, Marc Ladanyi, Brian J Druker

Articles, Abstracts, and Reports

PURPOSE: Gliomas, a genetically heterogeneous group of primary central nervous system tumors, continue to pose a significant clinical challenge. Discovery of chromosomal rearrangements involving kinase genes has enabled precision therapy, and improved outcomes in several malignancies.

EXPERIMENTAL DESIGN: Positing that similar benefit could be accomplished for patients with brain cancer, we evaluated The Cancer Genome Atlas (TCGA) glioblastoma dataset. Functional validation of the oncogenic potential and inhibitory sensitivity of discovered ROS1 fusions was performed using three independent cell-based model systems, and an

RESULTS:

CONCLUSIONS: Our findings highlight that CNS tumors should be specifically interrogated for these rare intrachromosomal 6q22 microdeletion …

Clinical Pharmacology Of Tisagenlecleucel In B-Cell Acute Lymphoblastic Leukemia., Karen Thudium Mueller, Edward Waldron, Stephan A. Grupp, John E. Levine, Theodore W. Laetsch, Michael A. Pulsipher, Michael W. Boyer, Keith August, Jason Hamilton, Rakesh Awasthi, Andrew M. Stein, Denise Sickert, Abhijit Chakraborty, Bruce L. Levine, Carl H. June, Lori Tomassian, Sweta S. Shah, Mimi Leung, Tetiana Taran, Patricia A. Wood, Shannon L. Maude

Manuscripts, Articles, Book Chapters and Other Papers

PURPOSE: Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).

PATIENTS AND METHODS: We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN).

RESULTS: Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders ( …