Digital Commons Network^™

Early Treatment With Vigabatrin Does Not Decrease Focal Seizures Or Improve Cognition In Tuberous Sclerosis Complex: The Prevent Trial, Elizabeth Martina Bebin, Jurriaan M Peters, Brenda E Porter, Tarrant O Mcpherson, Sarah O'Kelley, Mustafa Sahin, Katherine S Taub, Rajsekar Rajaraman, Stephanie C Randle, William M Mcclintock, Mary Kay Koenig, Mike D Frost, Hope A Northrup, Klaus Werner, Danielle A Nolan, Michael Wong, Jessica L Krefting, Fred Biasini, Kalyani Peri, Gary Cutter, Darcy A Krueger

Faculty, Staff and Student Publications

Objective: This study was undertaken to test the hypothesis that early vigabatrin treatment in tuberous sclerosis complex (TSC) infants improves neurocognitive outcome at 24 months of age.

Methods: A phase IIb multicenter randomized double-blind placebo-controlled trial was conducted of vigabatrin at first epileptiform electroencephalogram (EEG) versus vigabatrin at seizure onset in infants with TSC. Primary outcome was Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) cognitive assessment score at 24 months. Secondary outcomes were prevalence of drug-resistant epilepsy, additional developmental outcomes, and safety of vigabatrin.

Results: Of 84 infants enrolled, 12 were screen failures, 4 went straight to …

Environmental Bacteriophage Presence In Drainage Ponds At Coastal Carolina University, Hailey Oldfield, Alexei E. Chesnutwood, Gabriella A. Caldwell, Shiraz C. Cohen, Paul E. Richardson

Journal of the South Carolina Academy of Science

No abstract provided.

Non-Coding Rnas: Foes Or Friends For Targeting Tumor Microenvironment, Anna Szymanowska, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Paola Amero

Faculty, Staff and Student Publications

Non-coding RNAs (ncRNAs) are a group of molecules critical for cell development and growth regulation. They are key regulators of important cellular pathways in the tumor microenvironment. To analyze ncRNAs in the tumor microenvironment, the use of RNA sequencing technology has revolutionized the field. The advancement of this technique has broadened our understanding of the molecular biology of cancer, presenting abundant possibilities for the exploration of novel biomarkers for cancer treatment. In this review, we will summarize recent achievements in understanding the complex role of ncRNA in the tumor microenvironment, we will report the latest studies on the tumor microenvironment …

Flavonoids Quercetin And Kaempferol Are Nr4a1 Antagonists And Suppress Endometriosis In Female Mice, Lei Zhang, Kumaravel Mohankumar, Gregory Martin, Fuada Mariyam, Yuri Park, Sang Jun Han, Stephen Safe

Faculty, Staff and Students Publications

Nuclear receptor 4A1 (NR4A1) plays an important role in endometriosis progression; levels of NR4A1 in endometriotic lesions are higher than in normal endometrium, and substituted bis-indole analogs (NR4A1) antagonists suppress endometriosis progression in mice with endometriosis. In addition, the flavonoids kaempferol and quercetin are natural products that directly bind NR4A1 and significantly repress the intrinsic NR4A1-dependent transcriptional activity in human endometriotic epithelial and stromal cells and Ishikawa endometrial cancer cells. NR4A1 knockdown and inhibition of NR4A1 by kaempferol and quercetin suppressed proliferation of human endometriotic epithelial cells and Ishikawa cells by inhibiting epidermal growth factor receptor/c-Myc/survivin-mediated growth-promoting and survival pathways, …

The Histone Chaperone Function Of Daxx Is Dispensable For Embryonic Development, Chang Sun, Yuan Qi, Natalie Fowlkes, Nina Lazic, Xiaoping Su, Guillermina Lozano, Amanda R Wasylishen

Faculty, Staff and Student Publications

Daxx functions as a histone chaperone for the histone H3 variant, H3.3, and is essential for embryonic development. Daxx interacts with Atrx to form a protein complex that deposits H3.3 into heterochromatic regions of the genome, including centromeres, telomeres, and repeat loci. To advance our understanding of histone chaperone activity in vivo, we developed two Daxx mutant alleles in the mouse germline, which abolish the interactions between Daxx and Atrx (DaxxY130A), and Daxx and H3.3 (DaxxS226A). We found that the interaction between Daxx and Atrx is dispensable for viability; mice are born at the …

A Non-Coding Insertional Mutation Of Grhl2 Causes Gene Over-Expression And Multiple Structural Anomalies Including Cleft Palate, Spina Bifida And Encephalocele, Zoe Crane-Smith, Sandra C P De Castro, Evanthia Nikolopoulou, Paul Wolujewicz, Damian Smedley, Yunping Lei, Emma Mather, Chloe Santos, Mark Hopkinson, Andrew A Pitsillides, Richard H Finnell, M Elisabeth Ross, Andrew J Copp, Nicholas D E Greene

Faculty, Staff and Students Publications

Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple …

Ant-Dependent Mptp Underlies Necrotic Myofiber Death In Muscular Dystrophy, Michael J Bround, Julian R Havens, Allen J York, Michelle A Sargent, Jason Karch, Jeffery D Molkentin

Faculty, Staff and Students Publications

Mitochondrial permeability transition pore (MPTP) formation contributes to ischemia-reperfusion injury in the heart and several degenerative diseases, including muscular dystrophy (MD). MD is a family of genetic disorders characterized by progressive muscle necrosis and premature death. It has been proposed that the MPTP has two molecular components, the adenine nucleotide translocase (ANT) family of proteins and an unknown component that requires the chaperone cyclophilin D (CypD) to activate. This model was examined in vivo by deleting the gene encoding ANT1 (Slc25a4) or CypD (Ppif) in a δ-sarcoglycan (Sgcd) gene–deleted mouse model of MD, revealing …

Immunotherapy Targeting Different Immune Compartments In Combination With Radiation Therapy Induces Regression Of Resistant Tumors, Nils-Petter Rudqvist, Maud Charpentier, Claire Lhuillier, Erik Wennerberg, Sheila Spada, Caroline Sheridan, Xi Kathy Zhou, Tuo Zhang, Silvia C Formenti, Jennifer S Sims, Alicia Alonso, Sandra Demaria

Faculty, Staff and Student Publications

Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ …

Effect Of Various Types Of Extracellular Dna On V Hyugaensis Biofilm Formation, Carmen Gu Liu, Anthony W Maresso

Faculty, Staff and Students Publications

Marine bacteria face a constant influx of new extracellular DNA (exDNA) due to the massive viral lysis that occurs in the ocean on a daily basis. Generally, biofilms have shown to be induced by self-secreted exDNA. However, the effect of various types of exDNA with varying lengths, self vs non-self, as well as guanine-cytosine content (GC) content on biofilm formation has not been explored, despite being a critical component of the extracellular polymeric substance. To test the effect of such exDNA on biofilms, a marine bioluminescent bacterium (Vibrio hyugaensis) was isolated from the Sippewissett Salt Marsh, USA, and …

Development Of Chimeric Protein As A Multivalent Vaccine For Human Kinetoplastid Infections: Chagas Disease And Leishmaniasis, Marianna De Carvalho Clímaco, Luiza Almeida De Figueiredo, Rayane Cristina Lucas, Guilherme Rafael Gomide Pinheiro, Luísa Mourão Dias Magalhães, Ana Laura Grossi De Oliveira, Raquel Martins Almeida, Fernando Sérgio Barbosa, Daniella Castanheira Bartholomeu, Lilian Lacerda Bueno, Tiago Antonio Mendes, Bin Zhan, Kathryn Marie Jones, Peter Hotez, Maria Elena Bottazzi, Fabrício Marcus Silva Oliveira, Ricardo Toshio Fujiwara

Faculty, Staff and Students Publications

Leishmania spp. and Trypanosoma cruzi are parasitic kinetoplastids of great medical and epidemiological importance since they are responsible for thousands of deaths and disability-adjusted life-years annually, especially in low- and middle-income countries. Despite efforts to minimize their impact, current prevention measures have failed to fully control their spread. There are still no vaccines available. Taking into account the genetic similarity within the Class Kinetoplastida, we selected CD8+ T cell epitopes preserved among Leishmania spp. and T. cruzi to construct a multivalent and broad-spectrum chimeric polyprotein vaccine. In addition to inducing specific IgG production, immunization with the vaccine was able to …

Utilization Of Wellness Practices For Burnout And Stress During Covid-19 Among An Interdisciplinary Cohort Of Emergency Healthcare Workers, Michael J. Zdradzinski, Sheri-Ann O. Kaltiso, Roslyn Seitz, Timothy P. Moran, Jennifer Clements, Sheryl L. Heron, Michelle D. Lall

Journal of Wellness

Introduction: The Coronavirus Disease (COVID-19) introduced additional stress to the baseline occupational stressors of emergency care workers. The objectives of this study were to evaluate perceived stress and burnout and the utilization and perceived benefit of wellness practices among emergency healthcare workers (EHCWs), including: emergency physicians, advanced practice providers (APPs), nurses, and departmental administrative staff during the COVID-19 pandemic.

Methods: A cross-sectional 28-item electronic survey of EHCWs at three hospitals in a major United States city was used to measure participants’ utilization and perceived benefit of wellness practices, burnout (2-item measure), overall stress (perceived stress scale), and stress …

Triple-Negative Breast Tumors Are Dependent On Mutant P53 For Growth And Survival, Denada Dibra, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in the majority of patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. We developed an autochthonous somatic K14-Cre driven TNBC mouse model with p53R172H and p53R245W mutations in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53. These mice develop TNBCs with a median latency of 1 y. Deletion of mutant p53R172H or p53R245W in vivo in these tumors blunts their tumor growth and significantly extends survival of mice. Downstream …

Identifying The Reactive Metabolites Of Tyrosine Kinase Inhibitor Pexidartinib In Vitro Using Lc-Ms-Based Metabolomic Approaches, Xuan Qin, Yong Wang, Kevin R Mackenzie, John M Hakenjos, Si Chen, Saleh M Khalil, Sung Yun Jung, Damian W Young, Lei Guo, Feng Li

Faculty, Staff and Students Publications

Pexidartinib (PEX, TURALIO), a selective and potent inhibitor of the macrophage colony-stimulating factor-1 receptor, has been approved for the treatment of tenosynovial giant cell tumor. However, frequent and severe adverse effects have been reported in the clinic, resulting in a boxed warning on PEX for its risk of liver injury. The mechanisms underlying PEX-related hepatotoxicity, particularly metabolism-related toxicity, remain unknown. In the current study, the metabolic activation of PEX was investigated in human/mouse liver microsomes (HLM/MLM) and primary human hepatocytes (PHH) using glutathione (GSH) and methoxyamine (NH2OMe) as trapping reagents. A total of 11 PEX-GSH and 7 PEX-NH2OMe adducts were …

Multiomic Investigations Into Lung Health And Disease, Sarah E Blutt, Cristian Coarfa, Josef Neu, Mohan Pammi

Faculty, Staff and Students Publications

Diseases of the lung account for more than 5 million deaths worldwide and are a healthcare burden. Improving clinical outcomes, including mortality and quality of life, involves a holistic understanding of the disease, which can be provided by the integration of lung multi-omics data. An enhanced understanding of comprehensive multiomic datasets provides opportunities to leverage those datasets to inform the treatment and prevention of lung diseases by classifying severity, prognostication, and discovery of biomarkers. The main objective of this review is to summarize the use of multiomics investigations in lung disease, including multiomics integration and the use of machine learning …

The Importance Of Skin Prick Test In Differentiating Cat Sensitivities And Allergies In Children, Mehmet Şi̇ri̇n Kaya, Özge Atay, İdi̇l Akay Haci, İlke Taşkirdi, Seli̇me Özen Bölük, Fi̇gen Çelebi̇ Çeli̇k, Özgen Soyöz, Canan Şule Ünsal Karkiner, Demet Can

Turkish Journal of Medical Sciences

Background/aim: The incidence of cat allergies in children has increased over the years. Children with cat allergies have mostly reported respiratory symptoms. The skin prick test (SPT) is the most preferred method to demonstrate sensitization to allergens. However, not all children who develop cat sensitization due to environmental exposure become allergic to cats. In our study, we aimed to determine the frequency of sensitization to cat and cat allergy, cat-related symptoms, and the cut-off value for the SPT that may indicate cat allergy. Materials and methods: Patients aged 2-18 years, who applied to the Health Sciences University İzmir Dr Behçet …

Effects Of Thymoquinone And Memantine Alone And In Combination On Memory And Hippocampal Morphology In Rats With Streptozotocin-Induced Alzheimer's Disease, Şeyma Özsoy, Zi̇ya Çakir, Eli̇f Akçay, Fi̇kret Gevrek

Turkish Journal of Medical Sciences

Background/aim: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Thymoquinone (TQ) has broad biological functions, including antiinflammatory, antioxidant, neuroprotective properties. Memantine (MEM) is indicated for the symptomatic treatment of moderate to severe AD. We aimed to evaluate the effect of TQ alone or in combination with MEM on memory and hippocampal morphology in an STZ-induced rat AD model. Materials and methods: Thirty male rats were included in this study. The AD model was created by giving ICV STZ. The rats were divided into 5 groups (n = 6 each). Group 1 (control group): The rats received only ICV-STZ 3 mg/kg …

Radioprotective Effects Of Melatonin And Thymoquinone On Liver, Parotid Gland, Brain, And Testis Of Rats Exposed To Total Body Irradiation, Mehmet Koç, Çi̇ğdem Damla Deni̇z, Mehmet Aki̇f Eryilmaz, Yilmaz Tezcan, Mehmet Gürbi̇lek

Turkish Journal of Medical Sciences

Background/aim: This study aimed to investigate thymoquinone (TQ), and melatonin's radioprotective effects on liver, parotid gland, brain, and testis of rats which were exposed to total body irradiation (IR). Materials and methods: Thirty adult Wistar rats were randomly divided into four groups that are Group 1 (control group): total body IR only, Group 2: IR-Melatonin (10 mg/kg), Group 3: IR-TQ (10 mg/kg), and Group 4 (sham group): nothing. Total body IR dose was 6 Gy. Tissue samples were taken 90 min after IR. The measurements of malondialdehyde (MDA), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were performed in all groups. …

Evaluation Of Local And Systemic Side Effects Of Turkovac Vaccine In Adults, Bülent Nuri̇ Kalayci, Doğu Karahan

Turkish Journal of Medical Sciences

Background/aim: COVID-19 is a respiratory disease that caused a pandemic after reportedly emerging from Wuhan, China, in December 2019. Different types of COVID-19 vaccines such as viral vectors, mRNA, and inactivated vaccines have been produced since the beginning of the pandemic. Turkovac is an inactive COVID-19 vaccine developed and produced in Türkiye. We conducted our study to investigate the local and systemic side effects of the Turkovac vaccine. Materials and methods: A cross-sectional survey-based study was conducted to collect data on the postvaccine side effects in people aged over 18 who were vaccinated with Turkovac, between March and June 2022, …

Early-Adulthood Spike In Protein Translation Drives Aging Via Juvenile Hormone/Germline Signaling, Harper S Kim, Danitra J Parker, Madison M Hardiman, Erin Munkácsy, Nisi Jiang, Aric N Rogers, Yidong Bai, Colin Brent, James A Mobley, Steven N Austad, Andrew M Pickering

Faculty, Staff and Student Publications

Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related …

Advances In The Radiological Evaluation Of And Theranostics For Glioblastoma, Grayson W Hooper, Shehbaz Ansari, Jason M Johnson, Daniel T Ginat

Faculty, Staff and Student Publications

Imaging is essential for evaluating patients with glioblastoma. Traditionally a multimodality undertaking, CT, including CT cerebral blood profusion, PET/CT with traditional fluorine-18 fluorodeoxyglucose (18F-FDG), and MRI have been the mainstays for diagnosis and post-therapeutic assessment. However, recent advances in these modalities, in league with the emerging fields of radiomics and theranostics, may prove helpful in improving diagnostic accuracy and treating the disease.

In Vitro Hepatotoxicity Evaluation Of Methotrexate-Loaded Niosome Formulation: Fabrication, Characterization And Cell Culture Studies, Ahmet Doğan Ergi̇n, Çağatay Oltulu, Nebi̇ye Peli̇n Türker, Gülen Meli̇ke Demi̇rbolat

Turkish Journal of Medical Sciences

Background/aim: Methotrexate (MTX) is a folic acid antagonist that is widely used to treat osteosarcoma, leukemia, breast cancer, and autoimmune and inflammatory diseases. The most important concerns with MTX are its poor solubility and high toxicity, particularly in liver cells. To enhance its solubility and to minimize its toxicity, we encapsulated MTX in niosomes and investigated its hepatotoxicity mechanisms using genetic biomarkers. Materials and methods: Niosomes were successfully prepared using a modified thin film method, and the prepared monodisperse smallsized formulation was subsequently characterized. In vitro cytotoxicity studies were performed both in hepatocarcinoma (HEP3G) and healthy liver (AML12) cell lines. …

Neuroanatomical And Neurochemical Effects Of Prolonged Social Isolation In Adult Mice, Vibol Heng, Michael Zigmond, Richard Jay Smeyne

Department of Neuroscience Faculty Papers

INTRODUCTION: As social animals, our health depends in part on interactions with other human beings. Yet millions suffer from chronic social isolation, including those in nursing/assisted living facilities, people experiencing chronic loneliness as well as those in enforced isolation within our criminal justice system. While many historical studies have examined the effects of early isolation on the brain, few have examined its effects when this condition begins in adulthood. Here, we developed a model of adult isolation using mice (C57BL/6J) born and raised in an enriched environment.

METHODS: From birth until 4 months of age C57BL/6J mice were raised in …

Defining The Roles Of Pyruvate Oxidation, Tca Cycle, And Mannitol Metabolism In Methicillin-Resistant Staphylococcus Aureus Catheter-Associated Urinary Tract Infection, Santosh Paudel, Sarah Guedry, Chloe L P Obernuefemann, Scott J Hultgren, Jennifer N Walker, Ritwij Kulkarni

Faculty, Staff and Student Publications

Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of complicated urinary tract infection (UTI) associated with the use of indwelling urinary catheters. Previous reports have revealed host and pathogen effectors critical for MRSA uropathogenesis. Here, we sought to determine the significance of specific metabolic pathways during MRSA UTI. First, we identified four mutants from the Nebraska transposon mutant library in the MRSA JE2 background that grew normally in rich medium but displayed significantly reduced growth in pooled human urine (HU). This prompted us to transduce the uropathogenic MRSA 1369 strain with the transposon mutants in sucD and fumC (tricarboxylic acid …

Pyruvate Anaplerosis Is A Targetable Vulnerability In Persistent Leukaemic Stem Cells, Kevin M Rattigan, Zuzana Brabcova, Daniele Sarnello, Martha M Zarou, Kiron Roy, Ryan Kwan, Lucie De Beauchamp, Amy Dawson, Angela Ianniciello, Ahmed Khalaf, Eric R Kalkman, Mary T Scott, Karen Dunn, David Sumpton, Alison M Michie, Mhairi Copland, Saverio Tardito, Eyal Gottlieb, G Vignir Helgason

Faculty, Staff and Student Publications

Deregulated oxidative metabolism is a hallmark of leukaemia. While tyrosine kinase inhibitors (TKIs) such as imatinib have increased survival of chronic myeloid leukaemia (CML) patients, they fail to eradicate disease-initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays, we generate multi-omics datasets that offer unique insight into metabolic adaptation and nutrient fate in patient-derived CML LSCs. We demonstrate that LSCs have increased pyruvate anaplerosis, mediated by increased mitochondrial pyruvate carrier 1/2 (MPC1/2) levels and pyruvate carboxylase (PC) activity, in comparison to normal counterparts. While imatinib reverses BCR::ABL1-mediated LSC metabolic …

Genetic Dissection Of Crossover Mutants Defines Discrete Intermediates In Mouse Meiosis, Tolkappiyan Premkumar, Lakshmi Paniker, Rhea Kang, Mathilde Biot, Ericka Humphrey, Honorine Destain, Isabella Ferranti, Iyinyeoluwa Okulate, Holly Nguyen, Vindhya Kilaru, Melissa Frasca, Parijat Chakraborty, Francesca Cole

Faculty, Staff and Student Publications

Crossovers (COs), the exchange of homolog arms, are required for accurate chromosome segregation during meiosis. Studies in yeast have described the single-end invasion (SEI) intermediate: a stabilized 3' end annealed with the homolog as the first detectible CO precursor. SEIs are thought to differentiate into double Holliday junctions (dHJs) that are resolved by MutLgamma (MLH1/MLH3) into COs. Currently, we lack knowledge of early steps of mammalian CO recombination or how intermediates are differentiated in any organism. Using comprehensive analysis of recombination in thirteen different genetic conditions with varying levels of compromised CO resolution, we infer CO precursors include asymmetric SEI-like …

Enhanced Cerebroprotection Of Xenon-Loaded Liposomes In Combination With Rtpa Thrombolysis For Embolic Ischemic Stroke, Tao Peng, Keith Booher, Melanie R Moody, Xing Yin, Jaroslaw Aronowski, David D Mcpherson, Sean I Savitz, Hyunggun Kim, Shao-Ling Huang

Faculty, Staff and Student Publications

Xenon (Xe) has shown great potential as a stroke treatment due to its exceptional ability to protect brain tissue without inducing side effects. We have previously developed Xe-loaded liposomes for the ultrasound-activated delivery of Xe into the cerebral region and demonstrated their therapeutic efficacy. At present, the sole FDA-approved thrombolytic agent for stroke treatment is recombinant tissue plasminogen activator (rtPA). In this study, we aimed to investigate the potential of combining Xe-liposomes with an intravenous rtPA treatment in a clinically relevant embolic rat stroke model. We evaluated the combinational effect using an in vitro clot lysis model and an in …

Labeling Piezo2 Activity In The Peripheral Nervous System, Nicholas W Villarino, Yasmeen M F Hamed, Britya Ghosh, Adrienne E Dubin, Amanda H Lewis, Max A Odem, Meaghan C Loud, Yu Wang, M Rocio Servin-Vences, Ardem Patapoutian, Kara L Marshall

Duncan NRI Faculty and Staff Publications

Sensory neurons detect mechanical forces from both the environment and internal organs to regulate physiology. PIEZO2 is a mechanosensory ion channel critical for touch, proprioception, and bladder stretch sensation, yet its broad expression in sensory neurons suggests it has undiscovered physiological roles. To fully understand mechanosensory physiology, we must know where and when PIEZO2-expressing neurons detect force. The fluorescent styryl dye FM 1-43 was previously shown to label sensory neurons. Surprisingly, we find that the vast majority of FM 1-43 somatosensory neuron labeling in mice in vivo is dependent on PIEZO2 activity within the peripheral nerve endings. We illustrate the …

Genome-Wide Association Studies And Fine-Mapping Identify Genomic Loci For N-3 And N-6 Polyunsaturated Fatty Acids In Hispanic American And African American Cohorts, Chaojie Yang, Jenna Veenstra, Traci M Bartz, Matthew C Pahl, Brian Hallmark, Yii-Der Ida Chen, Jason Westra, Lyn M Steffen, Christopher D Brown, David Siscovick, Michael Y Tsai, Alexis C Wood, Stephen S Rich, Caren E Smith, Timothy D O'Connor, Dariush Mozaffarian, Struan F A Grant, Floyd H Chilton, Nathan L Tintle, Rozenn N Lemaitre, Ani Manichaikul

Faculty, Staff and Students Publications

Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) play critical roles in human health. Prior genome-wide association studies (GWAS) of n-3 and n-6 PUFAs in European Americans from the CHARGE Consortium have documented strong genetic signals in/near the FADS locus on chromosome 11. We performed a GWAS of four n-3 and four n-6 PUFAs in Hispanic American (n = 1454) and African American (n = 2278) participants from three CHARGE cohorts. Applying a genome-wide significance threshold of P < 5 × 10

Targeting Bcl2 Overcomes Resistance And Augments Response To Aurora Kinase B Inhibition By Azd2811 In Small Cell Lung Cancer, Kavya Ramkumar, Azusa Tanimoto, Carminia M Della Corte, C Allison Stewart, Qi Wang, Li Shen, Robert J Cardnell, Jing Wang, Urszula M Polanska, Courtney Andersen, Jamal Saeh, J Elizabeth Pease, Jon Travers, Giulia Fabbri, Carl M Gay, Jelena Urosevic, Lauren A Byers

Faculty, Staff and Student Publications

PURPOSE: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy.

EXPERIMENTAL DESIGN: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. …

Prolonged Cytopenia Following Cd19 Car T Cell Therapy Is Linked With Bone Marrow Infiltration Of Clonally Expanded Ifnγ-Expressing Cd8 T Cells, Paolo Strati, Xubin Li, Qing Deng, Mario L Marques-Piubelli, Jared Henderson, Grace Watson, Laurel Deaton, Taylor Cain, Haopeng Yang, Vida Ravanmehr, Luis E Fayad, Swaminathan P Iyer, Loretta J Nastoupil, Frederick B Hagemeister, Edwin R Parra, Neeraj Saini, Koichi Takahashi, Nathan H Fowler, Jason R Westin, Raphael E Steiner, Ranjit Nair, Christopher R Flowers, Linghua Wang, Sairah Ahmed, Gheath Al-Atrash, Francisco Vega, Sattva S Neelapu, Michael R Green

Faculty, Staff and Student Publications

Autologous anti-CD19 chimeric antigen receptor T cell (CAR T) therapy is highly effective in relapsed/refractory large B cell lymphoma (rrLBCL) but is associated with toxicities that delay recovery. While the biological mechanisms of cytokine release syndrome and neurotoxicity have been investigated, the pathophysiology is poorly understood for prolonged cytopenia, defined as grade ≥3 cytopenia lasting beyond 30 days after CAR T infusion. We performed single-cell RNA sequencing of bone marrow samples from healthy donors and rrLBCL patients with or without prolonged cytopenia and identified significantly increased frequencies of clonally expanded CX3CR1hi cytotoxic T cells, expressing high interferon (IFN)-γ and cytokine …