Digital Commons Network^™

Dna Methylation Patterns In Umbilical Cord Blood From Infants Of Methadone Maintained Opioid Dependent Mothers, Oluwatobi Adegboyega, Suhita Gayen Nee' Betal, Pedro Urday, Rachel Huang, Katherine Bodycot, Huda Al-Kouatly, Kolawole Solarin, Joanna Chan, Sankar Addya, Rupsa Boelig, Zubair Aghai

Department of Pediatrics Faculty Papers

Methadone maintenance treatment for opioid dependent mothers is standard of care. Infants of methadone maintained opioid dependent (MMOD) mothers have better outcomes compared to infants of opioid dependent mothers without treatment. However, when compared to non-exposed infants, infants of MMOD mothers are associated with worse outcomes. We conducted a pilot study to examine genome wide differential DNA methylation using cord blood samples from sixteen term and near-term infants of MMOD and opioid naïve mothers, excluding Infants with chorioamnionitis. A total of 152 differentially methylated loci were identified at a difference >  + 2, < - 2 and p-value < 0.05. There were 90 hypermethylated loci (59 annotated genes) and 62 hypomethylated loci (38 annotated genes) observed. The hypermethylated and hypomethylated DNA changes involved multiple genes, pathways and networks that may explain some of the changes seen in infants of MMOD mothers. Top hypermethylated and hypomethylated genes involved areas of cell growth, neurodevelopment, vision and xenobiotic metabolism functions. Our data may explain the role of key pathways and genes relevant to neonatal outcomes seen from methadone exposure in pregnancy. Functional studies on the identified pathways and genes could lead to improved understanding of the mechanisms and identify areas for intervention.

Global Burden Of Five Major Types Of Gastrointestinal Cancer, Arjun Singh

Division of Gastroenterology and Hepatology Faculty Papers

Gastrointestinal (GI) cancers cause major global morbidity and mortality, with over 5 million new cases and 3.5 million deaths in 2020. The most prevalent GI malignancies are colorectal, gastric, liver, oesophageal, and pancreatic cancers. Marked geographic variations exist, with high incidence in developed regions contrasting with high mortality in developing areas. These patterns reflect disparities in risk factors and cancer control capacities. However, GI cancer incidence is rising with economic growth and lifestyle changes. Poor prognosis and increasing burden underscore the critical need for expanded prevention and research. This review examines global epidemiology, risks, prevention, detection, treatment, and priorities for …

In Silico Analysis Of The Rop29 Protein As A Vaccine Candidate Against Toxoplasma Gondii, Amir Karimipour-Saryazdi, Fatemeh Ghaffarifar, Abdolhossein Dalimi, Masoud Foroutan, John Horton, Javid Sadraei

Faculty, Staff and Student Publications

The progression of Toxoplasma gondii (T. gondii) invasion is aided by rhoptry proteins (ROPs), which are also crucial for the parasite's survival in host cells. In this study, in silico analysis was performed to examine the various aspects of the ROP29 protein, such as physicochemical properties, potential T- and B-cell epitopes, and other significant features. The research revealed that there were 55 possible sites for posttranslational modification in the ROP29 protein. The secondary structure of the ROP29 protein consists of a random coil, an alpha-helix, and an extended strand, which account for 49.69%, 36.81%, and 13.50%, respectively. Moreover, …

Detection Of Diffusely Abnormal White Matter In Multiple Sclerosis On Multiparametric Brain Mri Using Semi-Supervised Deep Learning, Benjamin C Musall, Refaat E Gabr, Yanyu Yang, Arash Kamali, John A Lincoln, Michael A Jacobs, Vi Ly, Xi Luo, Jerry S Wolinsky, Ponnada A Narayana, Khader M Hasan

Faculty, Staff and Student Publications

In addition to focal lesions, diffusely abnormal white matter (DAWM) is seen on brain MRI of multiple sclerosis (MS) patients and may represent early or distinct disease processes. The role of MRI-observed DAWM is understudied due to a lack of automated assessment methods. Supervised deep learning (DL) methods are highly capable in this domain, but require large sets of labeled data. To overcome this challenge, a DL-based network (DAWM-Net) was trained using semi-supervised learning on a limited set of labeled data for segmentation of DAWM, focal lesions, and normal-appearing brain tissues on multiparametric MRI. DAWM-Net segmentation performance was compared to …

Characterizing A Complex Ct-Rich Haplotype In Intron 4 Of Snca Using Large-Scale Targeted Amplicon Long-Read Sequencing, Pilar Alvarez Jerez, Kensuke Daida, Francis P Grenn, Laksh Malik, Abigail Miano-Burkhardt, Mary B Makarious, Jinhui Ding, J Raphael Gibbs, Anni Moore, Xylena Reed, Mike A Nalls, Syed Shah, Medhat Mahmoud, Fritz J Sedlazeck, Egor Dolzhenko, Morgan Park, Hirotaka Iwaki, Bradford Casey, Mina Ryten, Cornelis Blauwendraat, Andrew B Singleton, Kimberley J Billingsley

Faculty, Staff and Students Publications

Parkinson's disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has …

N-Myc And Stat Interactor Is An Endometriosis Suppressor, Yuri Park, Xiaoming Guan, Sang Jun Han

Faculty, Staff and Students Publications

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI …

Risk Factors Associated With Pyogenic Spinal Infections Among Intravenous Drug Users And Nonusers, Vivek Biololikar, Brendan Gleason, Lee Kripke, Robert Merrill, Colin Whitaker, Jon Handal

Einstein Health Papers

PURPOSE: To identify the differences in patient factors, presentation, treatment course, and outcomes of intravenous drug users (IVDA) vs. nonusers (non-IVDA) presenting with pyogenic spinal infections.

METHODS: We identified all cases involving spinal infections at our institution between May 2017 and January 2023. Postsurgical infections were excluded, and patients were separated into IVDA and non-IVDA groups. The patient charts were reviewed and analyzed for statistical or clinically significant differences using RStudio (2019 version 3.6.2). Our institutional review board approved this study, IRB# 2020-277, iRISID-2023-1384.

RESULTS: Fifty patients (29 males and 21 females) with primary pyogenic spinal infections were included in …

Exposure To Light At Night And Risk Of Cancer: A Systematic Review, Meta-Analysis, And Data Synthesis, Samuel Ma, Yossef Alsabawi, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

BACKGROUND: Emerging interest surrounds the role of environmental factors, notably exposure to light at night (LAN), as a potential cause of cancer. The aim of this study was to conduct a systematic review and, if possible, meta-analysis of observational studies on LAN and cancer risk of multiple types.

METHODS: A systematic literature search in PubMed, Web of Science, and Embase, spanning from inception to May 2023, was conducted. Studies focusing on the association between LAN exposure and cancer risk in adult populations were included. We used random effects models to calculate pooled risk estimates (RR) and 95% confidence intervals (CI). …

Exposure To Light At Night And Risk Of Cancer: A Systematic Review, Meta-Analysis, And Data Synthesis, Samuel Ma, Yossef Alsabawi, Hashem B. El-Serag, Aaron P. Thrift

School of Medicine Publications

Simple Summary

Cancer is the second leading cause of death globally, and the causes of cancer are numerous and multifactorial, including genetic and environmental factors. There is a developing interest in the role of sleep and light at night (LAN) exposure in cancer development. The aim of our study is to further understand the relationship between LAN exposure and the risk of cancer by systematically reviewing existing literature assessing LAN exposure and the risk of various cancer types. We found a positive association between LAN exposure and breast cancer risk, but there was insufficient data to convincingly draw a conclusion …

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, …

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 …

Randomized, Double-Blind, Placebo-Controlled Study Of Anti-Mycobacterial Therapy (Rhb-104) In Active Crohn's Disease, David Y Graham, Saleh A Naser, Thomas Borody, Zbigniew Hebzda, Harry Sarles, Scott Levenson, Robert Hardi, Tomasz Arłukowicz, Petar Svorcan, Reza Fathi, Aida Bibliowicz, Patricia Anderson, Patrick Mclean, Clara Fehrmann, M Scott Harris, Shuhong Zhao, Ira N Kalfus

Faculty, Staff and Students Publications

This study, conducted between 4 October 2013, and 30 November 2018, tested the hypothesis that triple antimicrobial therapy, targeting Mycobacterium avium subspecies paratuberculosis (MAP), long considered a putative cause, would favorably affect Crohn’s disease. A double-blind multicenter study of adults with active Crohn’s disease, (i.e., Crohn’s Disease Activity Index [CDAI] 220–450 plus C-reactive protein ≥ 1.0 mg/dL, fecal calprotectin (FCP) >162.9 µg/g stool, or recent endoscopic or radiographic confirmation of active disease) receiving concomitant standard-of-care Crohn’s disease treatment (Clinicaltrials.gov: NCT01951326) were stratified by anti-tumor necrosis factor use and randomized (1:1) to anti-MAP RHB-104 (clarithromycin 95 mg, rifabutin 45 mg, …

The Interplay Between Gender And Duration Of Hospitalization Modulates Psychiatric Symptom Severity In Subjects With Long Covid-19, Alessio Simonetti, Antonio Restaino, Claudia Calderoni, Emanuela De Chiara, Antonio Maria D'Onofrio, Salvatore Lioniello, Giovanni Camardese, Delfina Janiri, Matteo Tosato, Francesco Landi, Gabriele Sani

Faculty, Staff and Students Publications

Long COVID-19 is characterized by ongoing symptoms or prolonged or long-term complications of SARS-CoV-2 contraction which persist beyond 4 weeks from the initial onset of symptoms. Gender and duration of hospitalization (DH) are key risk factors for developing long COVID-19 syndrome, but their impact and interplay need further study. This research involved 996 long COVID-19 patients, and we compared the levels of general psychopathology, depression, agitated depression, anxiety, and medication use between hospitalized and non-hospitalized males and females. In the hospitalized patients, multivariate regressions assessed the impact of gender, DH, and the interaction of these variables. The females had higher …

Adult Zymosan Re-Exposure Exacerbates The Molecular Alterations In The Brainstem Rostral Ventromedial Medulla Of Rats With Early Life Zymosan-Induced Cystitis, Bhavana Talluri, Sankar Addya, Maia Terashvili, Bidyut K. Medda, Anjishnu Banerjee, Reza Shaker, Jyoti N. Sengupta, Banani Banerjee

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. …

Differential Lipid Binding Specificities Of Rap1a And Rap1b Are Encoded By The Amino Acid Sequence Of The Membrane Anchors, Mussie K Araya, Wei Chen, Yuepeng Ke, Yubin Zhou, Alemayehu A Gorfe, John F Hancock, Junchen Liu

Faculty, Staff and Student Publications

RAP1 proteins belong to the RAS family of small GTPases that operate as molecular switches by cycling between GDP-bound inactive and GTP-bound active states. The C-terminal anchors of RAP1 proteins are known to direct membrane localization, but how these anchors organize RAP1 on the plasma membrane (PM) has not been investigated. Using high-resolution imaging, we show that RAP1A and RAP1B form spatially segregated nanoclusters on the inner leaflet of the PM, with further lateral segregation between GDP-bound and GTP-bound proteins. The C-terminal polybasic anchors of RAP1A and RAP1B differ in their amino acid sequences and exhibit different lipid binding specificities, …

A Light-Responsive Neural Circuit Suppresses Feeding, Hailan Liu, Na Qu, Natalia Valdez Gonzalez, Marco A Palma, Huamin Chen, Jiani Xiong, Abhinav Choubey, Yongxiang Li, Xin Li, Meng Yu, Hesong Liu, Longlong Tu, Nan Zhang, Na Yin, Kristine Marie Conde, Mengjie Wang, Jonathan Carter Bean, Junying Han, Nikolas Anthony Scarcelli, Yongjie Yang, Kenji Saito, Huxing Cui, Qingchun Tong, Zheng Sun, Chunmei Wang, Xing Cai, Li Lu, Yang He, Yong Xu

Faculty, Staff and Students Publications

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb→5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition …

Multi-Antigen Intranasal Vaccine Protects Against Challenge With Sarbecoviruses And Prevents Transmission In Hamsters, Ankita Leekha, Arash Saeedi, K M Samiur Rahman Sefat, Monish Kumar, Melisa Martinez-Paniagua, Adrian Damian, Rohan Kulkarni, Kate Reichel, Ali Rezvan, Shalaleh Masoumi, Xinli Liu, Laurence J N Cooper, Manu Sebastian, Courtney M Sands, Vallabh E Das, Nimesh B Patel, Brett Hurst, Navin Varadarajan

Faculty, Staff and Student Publications

Immunization programs against SARS-CoV-2 with commercial intramuscular vaccines prevent disease but are less efficient in preventing infections. Mucosal vaccines can provide improved protection against transmission, ideally for different variants of concern (VOCs) and related sarbecoviruses. Here, we report a multi-antigen, intranasal vaccine, NanoSTING-SN (NanoSTING-Spike-Nucleocapsid), eliminates virus replication in both the lungs and the nostrils upon challenge with the pathogenic SARS-CoV-2 Delta VOC. We further demonstrate that NanoSTING-SN prevents transmission of the SARS-CoV-2 Omicron VOC (BA.5) to vaccine-naïve hamsters. To evaluate protection against other sarbecoviruses, we immunized mice with NanoSTING-SN. We showed that immunization affords protection against SARS-CoV, leading to protection …

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 …

Hyaluronan Mediates Cold-Induced Adipose Tissue Beiging, Xi Chen, Yifan Wang, Huiqiao Li, Yanru Deng, Charlise Giang, Anying Song, Yu'e Liu, Qiong A Wang, Yi Zhu

Faculty, Staff and Students Publications

Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear …

Elevating Plk1 Overcomes Beti Resistance In Prostate Cancer Via Triggering Brd4 Phosphorylation-Dependent Degradation In Mitosis, Yanquan Zhang, Ka-Wing Fong, Fengyi Mao, Ruixin Wang, Derek B. Allison, Dana Napier, Daheng He, Jinpeng Liu, Yeqing Zhang, Jing Chen, Yifan Kong, Chaohao Li, Guangbing Li, Jinghui Liu, Zhiguo Li, Haining Zhu, Chi Wang, Xiaoqi Liu

Markey Cancer Center Faculty Publications

Bromodomain-containing protein 4 (BRD4) has emerged as a promising therapeutic target in prostate cancer (PCa). Understanding the mechanisms of BRD4 stability could enhance the clinical response to BRD4-tar- geted therapy. In this study, we report that BRD4 protein levels are significantly decreased during mitosis in a PLK1-dependent manner. Mechanistically, we show that BRD4 is primarily phosphorylated at T1186 by the CDK1/cyclin B complex, recruiting PLK1 to phosphorylate BRD4 at S24/S1100, which are recognized by the APC/CCdh1 complex for proteasome pathway degradation. We find that PLK1 overexpression lowers SPOP mutation-stabilized BRD4, consequently rendering PCa cells re-sensitized to BRD4 inhibitors. Intrigu-ingly, we …

Dna Fork Remodeling Proteins, Zranb3 And Smarcal1, Are Uniquely Essential For Aging Hematopoiesis, Saul Kushinsky, Matthew V. Puccetti, Clare M. Adams, Irina Shkundina, Nikkole James, Brittany M. Mahon, Peter Michener, Christine M. Eischen

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Over a lifetime, hematopoietic stem and progenitor cells (HSPCs) are forced to repeatedly proliferate to maintain hematopoiesis, increasing their susceptibility to DNA damaging replication stress. However, the proteins that mitigate this stress, protect HSPC replication, and prevent aging-driven dysregulation are unknown. We report two evolutionarily conserved, ubiquitously expressed chromatin remodeling enzymes with similar DNA replication fork reversal biochemical functions, Zranb3 and Smarcal1, have surprisingly specialized roles in distinct HSPC populations. While both proteins actively mitigate replication stress and prevent DNA damage and breaks during lifelong hematopoiesis, the loss of either resulted in distinct biochemical and biological consequences. Notably, defective long-term …

Neighborhood Socioeconomic Context Predicts Pediatric Asthma Exacerbation, Ashley W. Kranjac, Zeev N. Kain, Louis Ehwerhemuepha, Michael Weiss, Brooke N. Jenkins

Sociology Faculty Articles and Research

Causes of asthma exacerbation in children have been studied extensively at the individual level, but contributions of neighborhood-level factors are less explored. We test which distinctive residential characteristics produce variation in uncontrolled asthma among pediatric patients. We extracted electronic medical record data from pediatric patients living in Southern California and used multilevel modeling techniques to isolate which neighborhood characteristics drive inequitable asthma control. Above and beyond the individual-level factors known to predict inadequate disease control, neighborhoods with greater concentration of non-Hispanic black residents (odds ratios [OR] = 1.02; 95% confidence interval [CI]: 0.99-1.03; P < .05), higher proportions of female-headed households (OR = 1.01; 95% CI: 0.99-1.01; P < .05), and higher levels of ambient air pollution (OR = 1.05; 95% CI: 1.01-1.10; P < .001) associate with greater odds of asthma exacerbation. The interplay between community characteristics and asthma management during childhood is complex, and place-based initiatives are needed to narrow the gap in asthma exacerbation.

A Scaled Proteomic Discovery Study For Prostate Cancer Diagnostic Markers Using Proteograph, Matthew E K Chang, Jane Lange, Jessie May Cartier, Travis W Moore, Sophia M Soriano, Brenna Albracht, Michael Krawitzky, Harendra Guturu, Amir Alavi, Alexey Stukalov, Xiaoyuan Zhou, Eltaher M Elgierari, Jessica Chu, Ryan Benz, Juan C Cuevas, Shadi Ferdosi, Daniel Hornburg, Omid Farokhzad, Asim Siddiqui, Serafim Batzoglou, Robin J Leach, Michael A Liss, Ryan P Kopp, Mark R Flory

Faculty, Staff and Student Publications

There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate …

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 …

Do Apoe4, Malnutrition, And Long Covid-19 Compound The Risk Factors For Stroke In Adverse Environments?, Alexander Vasconcelos Buzaglo, Carlos Meton De Alencar Gadelha Vieira, Gabriella Cunha Vieira Ciurleo, Ludmila Belayev, Reinaldo B. Oriá

School of Medicine Faculty Publications

No abstract provided.

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 …

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 …

A Trivalent Protein-Based Pan-Betacoronavirus Vaccine Elicits Cross-Neutralizing Antibodies Against A Panel Of Coronavirus Pseudoviruses, Syamala Rani Thimmiraju, Rakesh Adhikari, Jeanna R Redd, Maria Jose Villar, Jungsoon Lee, Zhuyun Liu, Yi-Lin Chen, Suman Sharma, Amandeep Kaur, Nestor L Uzcategui, Shannon E Ronca, Wen-Hsiang Chen, Jason T Kimata, Bin Zhan, Ulrich Strych, Maria Elena Bottazzi, Peter J Hotez, Jeroen Pollet

Faculty, Staff and Students Publications

The development of broad-spectrum coronavirus vaccines is essential to prepare for future respiratory virus pandemics. We demonstrated broad neutralization by a trivalent subunit vaccine, formulating the receptor-binding domains of SARS-CoV, MERS-CoV, and SARS-CoV-2 XBB.1.5 with Alum and CpG55.2. Vaccinated mice produced cross-neutralizing antibodies against all three human Betacoronaviruses and others currently exclusive to bats, indicating the epitope preservation of the individual antigens during co-formulation and the potential for epitope broadening.

The Utility Of Sentinel Lymph Node Biopsy In Elderly Patients With Melanoma, Carmen A. Jung, Kathleen M. Mulligan, Iris Sheng, John B. Ammori, Ankit Mangla, Richard S. Hoehn, Luke D. Rothermel

Faculty Scholarship

Background: Sentinel lymph node biopsy (SLNB) is performed less often for older patients with melanoma. We investigated the association of SLNB and melanoma-specific survival (MSS) in the elderly. Methods: We retrospectively reviewed the Surveillance, Epidemiology, and End Results (SEER: 2010–2019) for patients ≥ 70 years with cT2-4N0M0 melanoma. We used multivariable Cox proportional hazard models to evaluate the impact of SLNB performance and SLN status on MSS at increasing age cutoffs. In addition, we evaluated the association of different factors with SLNB performance using multivariable logistic regression. Results: We identified 11,548 patients. Sentinel lymph node biopsy occurred in 6754 (58.5%) …

Refining The Optimal Caf Cluster Marker For Predicting Tme-Dependent Survival Expectancy And Treatment Benefits In Nsclc Patients, Kai Li, Rui Wang, Guo-Wei Liu, Zi-Yang Peng, Ji-Chang Wang, Guo-Dong Xiao, Shou-Ching Tang, Ning Du, Jia Zhang, Jing Zhang, Hong Ren, Xin Sun, Yi-Ping Yang, Da-Peng Liu

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The tumor microenvironment (TME) plays a pivotal role in the onset, progression, and treatment response of cancer. Among the various components of the TME, cancer-associated fibroblasts (CAFs) are key regulators of both immune and non-immune cellular functions. Leveraging single-cell RNA sequencing (scRNA) data, we have uncovered previously hidden and promising roles within this specific CAF subgroup, paving the way for its clinical application. However, several critical questions persist, primarily stemming from the heterogeneous nature of CAFs and the use of different fibroblast markers in various sample analyses, causing confusion and hindrance in their clinical implementation. In this groundbreaking study, we …