Digital Commons Network^™

Systematic Transcriptome Profiling Of Hpsc-Derived Osteoblasts Unveils Corin’S Mastery In Governing Osteogenesis Through Cebpd Modulation, Dandan Zhu, Mo-Fan Huang, An Xu, Xueqin Gao, Yu-Wen Huang, Trinh T T Phan, Linchao Lu, Ting-Yen Chi, Yulin Dai, Lon Kai Pang, Julian A Gingold, Jian Tu, Zijun Huo, Danielle A Bazer, Rachel Shoemaker, Jun Wang, Catherine G Ambrose, Jingnan Shen, Jun Kameoka, Zhongming Zhao, Lisa L Wang, Yang Zhang, Ruiying Zhao, Dung-Fang Lee

Faculty, Staff and Student Publications

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin …

Bigh3 Mediates Apoptosis And Gap Junction Failure In Osteocytes During Renal Cell Carcinoma Bone Metastasis Progression, Tianhong Pan, Fengshuo Liu, Xiaoxin Hao, Shubo Wang, Murtaza Wasi, Jian H Song, Valerae O Lewis, Patrick P Lin, Bryan Moon, Justin E Bird, Theocharis Panaretakis, Sue-Hwa Lin, Danielle Wu, Mary C Farach-Carson, Liyun Wang, Ningyan Zhang, Zhiqiang An, Xiang H-F Zhang, Robert L Satcher

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens …

The F Plasmid Conjutome: The Repertoire Of E Coli Proteins Translocated Through An F-Encoded Type Iv Secretion System, Abu Amar M Al Mamun, Kimberley Kissoon, Yang Grace Li, Erin Hancock, Peter J Christie

Faculty, Staff and Student Publications

Bacterial conjugation systems pose a major threat to human health through their widespread dissemination of mobile genetic elements (MGEs) carrying cargoes of antibiotic resistance genes. Using the Cre Recombinase Assay for Translocation (CRAfT), we recently reported that the IncFV pED208 conjugation system also translocates at least 16 plasmid-encoded proteins to recipient bacteria. Here, we deployed a high-throughput CRAfT screen to identify the repertoire of chromosomally encoded protein substrates of the pED208 system. We identified 32 substrates encoded by the Escherichia coli W3110 genome with functions associated with (i) DNA/nucleotide metabolism, (ii) stress tolerance/physiology, (iii) transcriptional regulation, or (iv) toxin inhibition. …

Exploring The Pdz, Duf, And Lim Domains Of Pdlim5 In Dendrite Branching, Yogesh Srivastava, Maxsam Donta, Lydia L Mireles, Adriana Paulucci-Holthauzen, Leilei Shi, Mark T Bedford, M Neal Waxham, Pierre D Mccrea

Faculty, Staff and Student Publications

The branched architecture of neuronal dendrites is a key factor in how neurons form ordered networks and discoveries continue to be made identifying proteins and protein-protein interactions that direct or execute the branching and extension of dendrites. Our prior work showed that the molecular scaffold Pdlim5 and delta-catenin, in conjunction, are two proteins that help regulate the branching and elongation of dendrites in cultured hippocampal neurons and do so through a phosphorylation-dependent mechanism triggered by upstream glutamate signaling. In this report we have focused on Pdlim5's multiple scaffolding domains and how each contributes to dendrite branching. The three identified regions …

Cerebellar Nuclei Cells Produce Distinct Pathogenic Spike Signatures In Mouse Models Of Ataxia, Dystonia, And Tremor, Meike E Van Der Heijden, Amanda M Brown, Dominic J Kizek, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

The cerebellum contributes to a diverse array of motor conditions, including ataxia, dystonia, and tremor. The neural substrates that encode this diversity are unclear. Here, we tested whether the neural spike activity of cerebellar output neurons is distinct between movement disorders with different impairments, generalizable across movement disorders with similar impairments, and capable of causing distinct movement impairments. Using in vivo awake recordings as input data, we trained a supervised classifier model to differentiate the spike parameters between mouse models for ataxia, dystonia, and tremor. The classifier model correctly assigned mouse phenotypes based on single-neuron signatures. Spike signatures were shared …

Social Marketing And The Challenges Of Participant Recruitment, Tom Baranowski, Teresia M O'Connor, John A Jimenez-Garcia, Kavita Radhakrishnan, Elva M Arrendondo, Debbe Thompson

Children’s Nutrition Research Center Staff Publications

Recruitment of research participants often has not obtained a desired sample size, thereby becoming a major problem inhibiting investigators' ability to adequately test the specified hypotheses. Social marketing with its four Ps, originally developed by the business world to sell products and adapted for public health initiatives, is proposed as a dynamic comprehensive conceptual framework to apply marketing principles and practices to enhance participant recruitment. Applying a social marketing approach to research recruitment would require initial investigation to understand the motivations of the target audience in regard to research participation, and continued research throughout the main project to adapt the …

Selection For Robust Metabolism In Domesticated Yeasts Is Driven By Adaptation To Hsp90 Stress, Natalia Condic, Hatim Amiji, Dipak Patel, William Charles Shropshire, Nejla Ozirmak Lermi, Youssef Sabha, Beryl John, Blake Hanson, Georgios Ioannis Karras

Faculty, Staff and Student Publications

Protein folding both promotes and constrains adaptive evolution. We uncover this surprising duality in the role of the protein-folding chaperone heat shock protein 90 (Hsp90) in maintaining the integrity of yeast metabolism amid proteotoxic stressors within industrial domestication niches. Ethanol disrupts critical Hsp90-dependent metabolic pathways and exerts strong selective pressure for redundant duplications of key genes within these pathways, yielding the classical genomic signatures of beer and bread domestication. This work demonstrates a mechanism of adaptive canalization in an ecology of major economic importance and highlights Hsp90-dependent variation as an important source of phantom heritability in complex traits.

Trends Of Methicillin-Resistant Staphylococcus Aureus Infections Among Thai Pediatric Patients, Pintip Suchartlikitwong, Nopphon Wuthinantiwong, Watsamon Jantarabenjakul, Noppadol Wacharachaisurapol, Jiratchaya Sophonphan, Tanittha Chatsuwan, Thanyawee Puthanakit

Chulalongkorn Medical Journal

Background While reductions in methicillin-resistant Staphylococcus aureus (MRSA) infections have been reported, vancomycin prescription rates have remained high.

Objectives We aimed to update trends in pediatric prevalence and antibiotic susceptibilities of MRSA infections.

Methods We conducted a retrospective study in patients aged S. aureus infections during 2016-2022 at a Thai tertiary-care hospital. MRSA was defined when resistant to cefoxitin or oxacillin MIC of >4 µg/mL. Patients with MRSA infections and their first isolates were classified into HA-MRSA or CA-MRSA based on surveillance definitions. Antibiotic susceptibilities were tested using the VITEK 2XL automated system and disk diffusion. The annual prevalence of …

Csf1r Inhibition Depletes Brain Macrophages And Reduces Brain Virus Burden In Siv-Infected Macaques, Diana G. Bohannon, Laurent D. Zablocki-Thomas, Evan S. Leung, Jinbum K. Dupont, Julian B. Hattler, Jolanta Kowalewska, Miaoyun Zhao, Jiangtao Luo, Marco Salemi, Angela M. Amedee, Qingsheng Li, Marcelo J. Kuroda, Woong-Ki Kim

School of Graduate Studies Faculty Publications

Perivascular macrophages (PVMs) and, to a lesser degree, microglia are targets and reservoirs of HIV and simian immunodeficiency virus (SIV) in the brain. Previously, we demonstrated that colony-stimulating factor 1 receptor (CSF1R) in PVMs was upregulated and activated in chronically SIV-infected rhesus macaques with encephalitis, correlating with SIV infection of PVMs. Herein, we investigated the role of CSF1R in the brain during acute SIV infection using BLZ945, a brain-penetrant CSF1R kinase inhibitor. Apart from three uninfected historic controls, nine Indian rhesus macaques were infected acutely with SIVmac251 and divided into three groups (n = 3 each): an untreated control and …

Vaccine Value Profile For Hookworm, Karl Philipp Puchner, Maria Elena Bottazzi, Victoria Periago, Martin Grobusch, Rick Maizels, James Mccarthy, Bruce Lee, Erika Gaspari, David Diemert, Peter Hotez

Faculty, Staff and Students Publications

Hookworm, a parasitic infection, retains a considerable burden of disease, affecting the most underprivileged segments of the general population in endemic countries and remains one of the leading causes of mild to severe anemia in Low and Middle Income Countries (LMICs), particularly in pregnancy and children under 5. Despite repeated large scale Preventive Chemotherapy (PC) interventions since more than 3 decades, there is broad consensus among scholars that elimination targets set in the newly launched NTD roadmap will require additional tools and interventions. Development of a vaccine could constitute a promising expansion of the existing arsenal against hookworm. Therefore, we …

Tert Activation Targets Dna Methylation And Multiple Aging Hallmarks, Hong Seok Shim, Jonathan Iaconelli, Xiaoying Shang, Jiexi Li, Zheng D Lan, Shan Jiang, Kayla Nutsch, Brittney A Beyer, Luke L Lairson, Adam T Boutin, Michael J Bollong, Peter G Schultz, Ronald A Depinho

Faculty, Staff and Student Publications

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, …

Antibody-Activation Of Connexin Hemichannels In Bone Osteocytes With Atp Release Suppresses Breast Cancer And Osteosarcoma Malignancy, Manuel A Riquelme, Xuewei Wang, Francisca M Acosta, Jingruo Zhang, Jeffery Chavez, Sumin Gu, Peng Zhao, Wei Xiong, Ningyan Zhang, Guo Li, Saranya Srinivasan, Chaoyu Ma, Manjeet K Rao, Lu-Zhe Sun, Nu Zhang, Zhiqiang An, Jean X Jiang

The Brown Foundation: Institute of Molecular Medicine

Bone tissue represents the most frequent site of cancer metastasis. We developed a hemichannel-activating antibody, Cx43-M2. Cx43-M2, directly targeting osteocytes in situ, activates osteocytic hemichannels and elevates extracellular ATP, thereby inhibiting the growth and migration of cultured breast and osteosarcoma cancer cells. Cx43-M2 significantly decreases breast cancer metastasis, osteosarcoma growth, and osteolytic activity, while improving survival rates in mice. The antibody's inhibition of breast cancer and osteosarcoma is dose dependent in both mouse and human cancer metastatic models. Furthermore, Cx43-M2 enhances anti-tumor immunity by increasing the population and activation of tumor-infiltrating immune-promoting effector T lymphocytes, while reducing immune-suppressive regulatory T …

Sart3 Reads Methylarginine-Marked Glycine- And Arginine-Rich Motifs, Yalong Wang, Jujun Zhou, Wei He, Rongjie Fu, Leilei Shi, Ngoc Khoi Dang, Bin Liu, Han Xu, Xiaodong Cheng, Mark T Bedford

Faculty, Staff and Student Publications

Glycine- and arginine-rich (GAR) motifs, commonly found in RNA-binding and -processing proteins, can be symmetrically (SDMA) or asymmetrically (ADMA) dimethylated at the arginine residue by protein arginine methyltransferases. Arginine-methylated protein motifs are usually read by Tudor domain-containing proteins. Here, using a GFP-Trap, we identify a non-Tudor domain protein, squamous cell carcinoma antigen recognized by T cells 3 (SART3), as a reader for SDMA-marked GAR motifs. Structural analysis and mutagenesis of SART3 show that aromatic residues lining a groove between two adjacent aromatic-rich half-a-tetratricopeptide (HAT) repeat domains are essential for SART3 to recognize and bind to SDMA-marked GAR motif peptides, as …

Cell-Specific Regulation Of The Circadian Clock By Bmal1 In The Paraventricular Nucleus: Implications For Regulation Of Systemic Biological Rhythms, Rachel Van Drunen, Yulin Dai, Haichao Wei, Baharan Fekry, Sina Noori, Samay Shivshankar, Rafael Bravo, Zhongming Zhao, Seung-Hee Yoo, Nicholas Justice, Jia Qian Wu, Qingchun Tong, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Circadian rhythms are internal biological rhythms driving temporal tissue-specific, metabolic programs. Loss of the circadian transcription factor BMAL1 in the paraventricular nucleus (PVN) of the hypothalamus reveals its importance in metabolic rhythms, but its functions in individual PVN cells are poorly understood. Here, loss of BMAL1 in the PVN results in arrhythmicity of processes controlling energy balance and alters peripheral diurnal gene expression. BMAL1 chromatin immunoprecipitation sequencing (ChIP-seq) and single-nucleus RNA sequencing (snRNA-seq) reveal its temporal regulation of target genes, including oxytocin (OXT), and restoring circulating OXT peaks in BMAL1-PVN knockout (KO) mice rescues absent activity rhythms. While glutamatergic neurons …

Global Burden Of Cardiovascular Disease Attributable To Smoking, 1990–2019: An Analysis Of The 2019 Global Burden Of Disease Study, Abdul Mannan Khan Minhas, Ramy Sedhom, Estelle D Jean, Michael D Shapiro, Julio A Panza, Mahboob Alam, Salim S Virani, Christie M Ballantyne, Dmitry Abramov

Faculty, Staff and Students Publications

Aims: This study aims to investigate the trends in the global cardiovascular disease (CVD) burden attributable to smoking from 1990 to 2019.

Methods and results: Global Burden of Disease Study 2019 was used to analyse the burden of CVD attributable to smoking (i.e. ischaemic heart disease, peripheral artery disease, stroke, atrial fibrillation and flutter, and aortic aneurysm). Age-standardized mortality rates (ASMRs) per 100 000 and age-standardized disability-adjusted life year rates (ASDRs) per 100 000, as well as an estimated annual percentage change (EAPC) in ASMR and ASDR, were determined by age, sex, year, socio-demographic index (SDI), regions, and countries or …

Bile Acid-Sensitive Human Norovirus Strains Are Susceptible To Sphingosine-1-Phosphate Receptor 2 Inhibition, Victoria Tenge, B Vijayalakshmi Ayyar, Khalil Ettayebi, Sue E Crawford, Nicole M Hayes, Yi-Ting Shen, Frederick H Neill, Robert L Atmar, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are a diverse group of RNA viruses that cause endemic and pandemic acute viral gastroenteritis. Previously, we reported that many HuNoV strains require bile or bile acid (BA) to infect human jejunal intestinal enteroid cultures. BA was not essential for the replication of a pandemic-causing GII.4 HuNoV strain. We found the hydrophobic BA glycochenodeoxycholic acid (GCDCA) promotes the replication of the BA-dependent strain GII.3 in jejunal enteroids. Furthermore, we found that inhibition of the G-protein-coupled BA receptor, sphingosine-1-phosphate receptor 2 (S1PR2), by JTE-013, reduced GII.3 infection dose-dependently and inhibited GII.3 cellular uptake in enteroids. Herein, we sought …

Molecular Mechanism Of Bitter Taste Receptor Agonist-Mediated Relaxation Of Airway Smooth Muscle, Stanley Conaway, Weiliang Huang, Miguel A. Hernandez-Lara, Maureen A. Kane, Raymond B. Penn, Deepak A. Deshpande

Center for Translational Medicine Faculty Papers

G-protein-coupled receptors (GPCRs) belonging to the type 2 taste receptors (TAS2Rs) family are predominantly present in taste cells to allow the perception of bitter-tasting compounds. TAS2Rs have also been shown to be expressed in human airway smooth muscle (ASM), and TAS2R agonists relax ASM cells and bronchodilate airways despite elevating intracellular calcium. This calcium “paradox” (calcium mediates contraction by pro-contractile Gq-coupled GPCRs) and the mechanisms by which TAS2R agonists relax ASM remain poorly understood. To gain insight into pro-relaxant mechanisms effected by TAS2Rs, we employed an unbiased phosphoproteomic approach involving dual-mass spectrometry to determine differences in the phosphorylation of contractile-related …

Intouch Week Of July 22, 2024, New York Medical College

InTouch

• Funding Will Bolster Medical School Success for Historically Disadvantaged Students
• NYMC and Lovelace Forge Powerful Ties in Health Research
• College Enhances MEC Roadway with Improved Parking
• NYMC and TU Presents “Ninety Minutes: The Medical Magazine of the Web”
• TCDM Welcomes Class of 2028
• Student Spotlight: SOM Student David Zuckerman Awarded AMA Physicians of Tomorrow Scholarship
• Alumni Spotlight: Disparities in Femoral Fractures in Children and Adolescents

First-In-Human Dose Escalation Trial To Evaluate The Clinical Safety And Efficacy Of An Anti-Magea1 Autologous Tcr-Transgenic T Cell Therapy In Relapsed And Refractory Solid Tumors, Martin Wermke, Tobias A W Holderried, Jason John Luke, Van K Morris, Winfried H Alsdorf, Katrin Wetzko, Borje S Andersson, Ignacio I Wistuba, Edwin R Parra, Mohammad B Hossain, Sandra Grund-Gröschke, Katrin Aslan, Arun Satelli, Anantha Marisetty, Swapna Satam, Mamta Kalra, Jens Hukelmann, M Alper Kursunel, Karine Pozo, Andreas Acs, Linus Backert, Melissa Baumeister, Sebastian Bunk, Claudia Wagner, Oliver Schoor, Ali S Mohamed, Andrea Mayer-Mokler, Norbert Hilf, Delfi Krishna, Steffen Walter, Apostolia M Tsimberidou, Cedrik M Britten

Faculty, Staff and Student Publications

RATIONALE OF THE TRIAL: Although the use of engineered T cells in cancer immunotherapy has greatly advanced the treatment of hematological malignancies, reaching meaningful clinical responses in the treatment of solid tumors is still challenging. We investigated the safety and tolerability of IMA202 in a first-in-human, dose escalation basket trial in human leucocyte antigen A*02:01 positive patients with melanoma-associated antigen A1 (MAGEA1)-positive advanced solid tumors.

TRIAL DESIGN: The 2+2 trial design was an algorithmic design based on a maximally acceptable dose-limiting toxicity (DLT) rate of 25% and the sample size was driven by the algorithmic design with a maximum of …

Exploration Of A Potential Door Endpoint For Hospital-Acquired Bacterial Pneumonia And Ventilator-Associated Bacterial Pneumonia Using Six Registrational Trials For Antibacterial Drugs, Tori Kinamon, Ursula Waack, Mark Needles, Daniel Rubin, Deborah Collyar, Sarah B Doernberg, Scott R Evans, Toshimitsu Hamasaki, Thomas L Holland, Jessica Howard-Anderson, Henry Chambers, Vance G Fowler, Sumati Nambiar, Peter Kim, Helen W Boucher, Ramya Gopinath

Faculty, Staff and Student Publications

BACKGROUND: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP).

METHODS: Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that …

In Vitro Data Suggest A Role For Pms2 Kozak Sequence Mutations In Lynch Syndrome Risk, Evanjalina J Matoy, Jocelyn N Plowman, Cynthia J Watson, Michael A Belshan, Elizabeth E Blue, Chad D Huff, Holly A F Stessman

Faculty, Staff and Student Publications

This study investigates the role of 5′ UTR PMS2 Kozak sequence genetic variation in cancer risk. It accomplishes this through the development of a mid-throughput reporter assay where variants can be tested for protein translation efficiency. The results highlight the importance of continued study of the Kozak sequence related to human disease.

Targeted Sequencing For Hereditary Breast And Ovarian Cancer In Brca1/2-Negative Families Reveals Complex Genetic Architecture And Phenocopies, Jocelyn N Plowman, Evanjalina J Matoy, Lavanya V Uppala, Samantha B Draves, Cynthia J Watson, Bridget A Sefranek, Mark L Stacey, Samuel P Anderson, Michael A Belshan, Elizabeth E Blue, Chad D Huff, Yusi Fu, Holly A F Stessman

Faculty, Staff and Student Publications

Approximately 20% of breast cancer cases are attributed to increased family risk, yet variation in BRCA1/2 can only explain 20%-25% of cases. Historically, only single gene or single variant testing were common in at-risk family members, and further sequencing studies were rarely offered after negative results. In this study, we applied an efficient and inexpensive targeted sequencing approach to provide molecular diagnoses in 245 human samples representing 134 BRCA mutation-negative (BRCAX) hereditary breast and ovarian cancer (HBOC) families recruited from 1973 to 2019 by Dr. Henry Lynch. Sequencing identified 391 variants, which were functionally annotated and ranked based on their …

Crispr-Cas9 And Cas12a Target Site Richness Reflects Genomic Diversity In Natural Populations Of Anopheles Gambiae And Aedes Aegypti Mosquitoes, Travis C Collier, Yoosook Lee, Derrick K Mathias, Víctor López Del Amo

Faculty, Staff and Student Publications

Due to limitations in conventional disease vector control strategies including the rise of insecticide resistance in natural populations of mosquitoes, genetic control strategies using CRISPR gene drive systems have been under serious consideration. The identification of CRISPR target sites in mosquito populations is a key aspect for developing efficient genetic vector control strategies. While genome-wide Cas9 target sites have been explored in mosquitoes, a precise evaluation of target sites focused on coding sequence (CDS) is lacking. Additionally, target site polymorphisms have not been characterized for other nucleases such as Cas12a, which require a different DNA recognition site (PAM) and would …

Effect Of Transcranial Direct Current Stimulation And Narrow-Band Auditory Stimulation On The Intraoperative Electroencephalogram: An Exploratoratory Feasibility Study, Oliver G. Isik, Tuan Z. Cassim, Meah T. Ahmed, Matthias Kreuzer, Alice M. Daramola, Paul S. Garcia

SKMC Student Presentations and Publications

INTRODUCTION: During general anesthesia, frontal electroencephalogram (EEG) activity in the alpha frequency band (8-12 Hz) correlates with the adequacy of analgesia. Transcranial direct current stimulation (tDCS) and auditory stimulation, two noninvasive neuromodulation techniques, can entrain alpha activity in awake or sleeping patients. This study evaluates their effects on alpha oscillations in patients under general anesthesia.

METHODS: 30 patients receiving general anesthesia for surgery were enrolled in this two-by-two randomized clinical trial. Each participant received active or sham tDCS followed by auditory stimulation or silence according to assigned group (TDCS/AUD, TDCS/SIL, SHAM/AUD, SHAM/SIL). Frontal EEG was recorded before and after neuromodulation. …

Mutant Androgen Receptor Induces Neurite Loss And Senescence Independently Of Are Binding In A Neuronal Model Of Sbma, Jordyn Karliner, Y Liu, Diane Merry

Department of Biochemistry and Molecular Biology Faculty Papers

Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing neuromuscular disease caused by a polyglutamine (polyQ)-encoding CAG trinucleotide repeat expansion in the androgen receptor (AR) gene, leading to AR aggregation, lower motor neuron death, and muscle atrophy. AR is a ligand-activated transcription factor that regulates neuronal architecture and promotes axon regeneration; however, whether AR transcriptional functions contribute to disease pathogenesis is not fully understood. Using a differentiated PC12 cell model of SBMA, we identified dysfunction of polyQ-expanded AR in its regulation of neurite growth and maintenance. Specifically, we found that in the presence of androgens, polyQ-expanded AR inhibited neurite …

Setd3 Is A Mechanosensitive Enzyme That Methylates Actin On His73 To Regulate Mitochondrial Dynamics And Function, Vaibhav Deshmukh, James F Martin

Faculty, Staff and Students Publications

Mitochondria, which act as sensors of metabolic homeostasis and metabolite signaling, form a dynamic intracellular network that continuously changes shape, size and localization to respond to localized cellular energy demands. Mitochondrial dynamics and function depend on interactions with the F-actin cytoskeleton that are poorly understood. Here, we show that SET domain protein 3 (SETD3), a recently described actin histidine methyltransferase, directly methylates actin at histidine-73 and enhances F-actin polymerization on mitochondria. SETD3 is a mechano-sensitive enzyme that is localized on the outer mitochondrial membrane and promotes actin polymerization around mitochondria. SETD3 loss of function leads to diminished F-actin around mitochondria …

Transcriptomic Analysis Reveals The Anti-Cancer Effect Of Gestational Mesenchymal Stem Cell Secretome, Salvatore Vaiasicca, Gianmarco Melone, David W James, Marcos Quintela, Jing Xiao, Seydou Yao, Richard H Finnell, Robert S Conlan, Lewis W Francis, Bruna Corradetti

Faculty, Staff and Students Publications

The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer effect of mesenchymal stem cells (MSCs) derived from 2 different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with emphasis on their secretome. Transcriptomic analysis was performed on patient-derived AF- and CV-MSCs collected during prenatal diagnosis and identified both mRNAs and lncRNAs, involved in tissue homeostasis and inhibiting biological processes associated with the etiology of aggressive cancers while regulating immune pathways shown to be important in chronic disorders. Secretome enrichment analysis also identified soluble moieties …

Nrg Oncology And Particle Therapy Co-Operative Group Patterns Of Practice Survey And Consensus Recommendations On Pencil-Beam Scanning Proton Stereotactic Body Radiation Therapy And Hypofractionated Radiation Therapy For Thoracic Malignancies, Wei Liu, Hongying Feng, Paige A Taylor, Minglei Kang, Jiajian Shen, Jatinder Saini, Jun Zhou, Huan B Giap, Nathan Y Yu, Terence S Sio, Pranshu Mohindra, Joe Y Chang, Jeffrey D Bradley, Ying Xiao, Charles B Simone, Liyong Lin

Faculty, Staff and Student Publications

Stereotactic body radiation therapy (SBRT) and hypofractionation using pencil-beam scanning (PBS) proton therapy (PBSPT) is an attractive option for thoracic malignancies. Combining the advantages of target coverage conformity and critical organ sparing from both PBSPT and SBRT, this new delivery technique has great potential to improve the therapeutic ratio, particularly for tumors near critical organs. Safe and effective implementation of PBSPT SBRT/hypofractionation to treat thoracic malignancies is more challenging than the conventionally fractionated PBSPT because of concerns of amplified uncertainties at the larger dose per fraction. The NRG Oncology and Particle Therapy Cooperative Group Thoracic Subcommittee surveyed proton centers in …

Antitumor Activity Of A Pyrrolobenzodiazepine Antibody-Drug Conjugate Targeting Lgr5 In Preclinical Models Of Neuroblastoma, Jianghua Tu, Yukimatsu Toh, Adela M Aldana, Jake J Wen, Ling Wu, Joan Jacob, Li Li, Sheng Pan, Kendra S Carmon, Qingyun J Liu

Faculty, Staff and Student Publications

Neuroblastoma (NB) is a cancer of the peripheral nervous system found in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all cancer-related deaths in children. Leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5) is a membrane receptor that is associated with the primary tumor formation and metastasis of cancers in the gastrointestinal system. Remarkably, high levels of LGR5 are found in NB tumor cells, and high LGR5 expression is strongly correlated with poor survival. Antibody-drug conjugates (ADCs) are monoclonal antibodies that are covalently linked to cell-killing cytotoxins to deliver the payloads …

Challenges Of Spatially Resolved Metabolism In Cancer Research, Andrew N. Lane, Richard M. Higashi, Teresa W-M Fan

Markey Cancer Center Faculty Publications

Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further …