Digital Commons Network^™

Sickle Cell Disease Induces Chromatin Introversion And Ferroptosis In Cd8+ T Cells To Suppress Anti-Tumor Immunity, Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Jun Yao, Lanxin Bei, Yaohua Zhang, Pengju Gong, Lisa A Huang, Zhou Jiang, Jian Gao, Shuang Peng, Tina K Nguyen, Menuka Karki, Bora Lim, Cassian Yee, Jared K Burks, Qing Zhang, Li Ma, Jianjun Gao, Nizar M Tannir, Leng Han, Dihua Yu, Linghua Wang, Michael A Curran, Maria A Gubbiotti, Giannicola Genovese, Boyi Gan, Wenbo Li, Pavlos Msaouel, Liuqing Yang, Chunru Lin

Faculty, Staff and Student Publications

Understanding how genetic disorders affect CD8+ T cells in the tumor microenvironment is key to improving cancer immunotherapy. Individuals with sickle cell disease (SCD), the most prevalent inherited blood disorder, have a higher risk of developing certain cancers than the general population, but the mechanisms driving this increased risk remain unclear. Our study revealed that SCD altered CD8+ T cell 3D genome architecture, triggering ferroptosis and weakening anti-tumor immunity, thereby promoting tumor growth. Using murine and humanized SCD models, we found that disrupted chromosomal interactions in CD8+ T cells reduced the expression of anti-ferroptotic genes, including SLC7A11 and hydrogen sulfide …

Application Of Claims-Based Frailty Index To A Structured Electronic Health Record Data, Min Ji Kwak, Caroline Schaefer, Youngran Kim, Sunyang Fu, Chan Mi Park, Abhijeet Dhoble, Nahid Rianon, Holly M Holmes, Dae Hyun Kim

Faculty, Staff and Student Publications

Background: The Claims-based Frailty Index (CFI) has been developed and validated using Medicare claims data. However, whether CFI can be applied to structured electronic health record data has not been studied.

Methods: We applied the CFI to a structured electronic health record dataset (Explorys dataset) and a Medicare fee-for-service 5% sample data and compared the prevalence of frailty from each dataset, using the cohort of older adults. Then, we assessed the odds ratio and area under the curve of the frailty predicting adverse clinical outcomes, any hospital or emergency room visit, or any adverse drug events related encounter within 1 …

Arid4b: An Orchestrator From Stem Cell Fate To Carcinogenesis, Rakhee Rathnam Kalari Kandy, Madan Kumar Arumugam, Mukesh Pratap Yadav, Bibhuti Bhusan Mishra, Jyotika Sharma

Faculty, Staff and Student Publications

All biological processes, from embryonic development to cancer, are tightly controlled by the interactions between genetics and epigenetics. An array of epigenetic modifications, such as DNA methylation, histone/chromatin modifications, and noncoding RNA-mediated targeting, are essential to regulate the heritable changes that occur during multiple cellular processes. A failure in proper regulation results in inappropriate gene expression that ultimately leads to pathological states. Groundbreaking advances in genomics and transcriptomics have revealed the potential involvement of epigenetics in various physiological and pathological states. The promising clinical and preclinical results shown by epigenetics drugs further underscore the central role of epigenetics in multiple …

Sickle Cell Disease Induces Chromatin Introversion And Ferroptosis In Cd8+ T Cells To Suppress Anti-Tumor Immunity, Zilong Zhao, Benxia Hu, Yalan Deng, Melinda Soeung, Jun Yao, Lanxin Bei, Yaohua Zhang, Pengju Gong, Lisa A Huang, Zhou Jiang, Jian Gao, Shuang Peng, Tina K Nguyen, Menuka Karki, Bora Lim, Cassian Yee, Jared K Burks, Qing Zhang, Li Ma, Jianjun Gao, Nizar M Tannir, Leng Han, Dihua Yu, Linghua Wang, Michael A Curran, Maria A Gubbiotti, Giannicola Genovese, Boyi Gan, Wenbo Li, Pavlos Msaouel, Liuqing Yang, Chunru Lin

Faculty, Staff and Student Publications

Understanding how genetic disorders affect CD8

Exposure-Response Relationship Of Household Air Pollution On Body Mass Index Among Women In Rural Areas Of Guatemala, India, Peru And Rwanda: Household Air Pollution Intervention Network Trial, Adolphe Ndikubwimana, Lisa De Las Fuentes, Victor G Dávila-Román, Et Al.

2020-Current year OA Pubs

BACKGROUND: Household air pollution from burning biomass materials, the main cooking fuel in low- and middle-income countries, may be linked to metabolic dysfunction. We assessed cross-sectional associations between household air pollution and body mass index (BMI), expecting to see increased BMI with higher pollution concentrations.

METHODS: We analyzed data from 414 women aged 40 to 79 years who resided in the households using biomass fuel and were enrolled in the multi-country Household Air Pollution Intervention Network (HAPIN) Trial. We explored associations of 24-h average personal exposure to fine particulate matter (PM

RESULTS: We observed mixed evidence of associations between household …

High Prevalence Of Co-Infections With Latent Tuberculosis, Syphilis And Hepatitis B And C Among People With Hiv In Ghana: A Call For Integrating Screening Into Routine Care, Helena Lamptey, James Odame Aboagye, Christopher Zaab-Yen Abana, Anthony Twumasi Boateng, Ephraim Mawufemor Kofi Kanda, Dzidzor Aku Attoh, Araba Abaidoo-Myles, Charlotte Borteley Bortey, Jonathan Klutse, Peter Puplampu, Gloria Ansa, Vincent Jessey Ganu, Joseph Oliver-Commey, Evelyn Yayra Bonney, George Boateng Kyei

2020-Current year OA Pubs

BACKGROUND: People with HIV (PWH) are at risk of co-infections, such as latent tuberculosis (LTBI), hepatitis B (HBV), hepatitis C (HCV), and syphilis; hence, routine screening is critical. However, evaluation of routine screening is not being fully implemented in Ghana. This study assessed the prevalence of these co-infections among PWH in Accra, Ghana.

METHODS: The HIV Cure Research Infrastructure Study (H-CRIS) followed 390 PWH from three HIV treatment centres in Accra. A cross-sectional study was conducted within this cohort, and participants were screened for LTBI, hepatitis B, hepatitis C, and syphilis using standardized assays. LTBI was detected using the QuantiFERON-TB …

Structure-Function Coupling In The First Month Of Life: Associations With Age And Attention, Ursula A Tooley, Jeanette K Kenley, M Catalina Camacho, Aidan Latham, Dimitrios Alexopoulos, Ashley N Nielsen, Tara A Smyser, Barbara B Warner, Joshua S Shimony, Jeffrey J Neil, Joan L Luby, Deanna M Barch, Cynthia E Rogers, Christopher D Smyser

2020-Current year OA Pubs

How brain structure relates to function is a critical and open question in neuroscience. Here, we characterize regional variation in structure-function coupling, capturing the degree to which a cortical region's structural connections relate to patterns of coordinated neural activity in healthy, term-born neonates (

Impact Of Vein-To-Vein Time In Patients With R/R Lbcl Treated With Axicabtagene Ciloleucel, Frederick L Locke, Armin Ghobadi, Et Al.

2020-Current year OA Pubs

Chimeric antigen receptor (CAR) T-cell products axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel) are approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Emerging evidence indicates that delayed CAR T-cell infusion, including prolonged time from leukapheresis to infusion, known as vein-to-vein time (V2Vt), may adversely impact clinical outcomes. We conducted a systematic literature review (SLR) and meta-analysis to identify differences in V2Vt in patients with R/R LBCL treated with axi-cel, tisa-cel, or liso-cel. The impact of V2Vt (< 28 days vs ≥28 to < 40 days vs ≥40 days) on effectiveness and safety outcomes was evaluated in patients treated with axi-cel enrolled in a post-authorization safety study using the Center for International Blood and Marrow Transplant Research data. SLR and meta-analysis showed that patients treated with axi-cel had the shortest median V2Vt (30.6 days) compared with tisa-cel (48.4 days) or liso-cel (35.9 days). Real-world analysis of patients treated with axi-cel demonstrated that V2Vt ≥40 days was associated with significantly lower complete response rate than V2Vt < 28 days (odds ratio [OR], 0.61) or ≥28 to < 40 days (OR, 0.66) and significantly worse overall survival than V2Vt < 28 days (hazard ratio [HR], 1.33) or ≥28 to < 40 days (HR, 1.36). Higher prolonged thrombocytopenia rates were observed in patients with axi-cel V2Vt ≥28 to < 40 days or ≥40 days compared with < 28 days (OR, 1.44 or 1.95, respectively). Together, these results show the impact of V2Vt on patient outcomes with axi-cel therapy and that earlier infusion with CD19-CAR therapies may be beneficial.

Parallel Use Of Low-Complexity Automated Nucleic Acid Amplification Tests And Lateral Flow Urine Lipoarabinomannan Assays To Detect Tuberculosis Disease In Adults And Adolescents Living With Hiv, Stephanie Bjerrum, Bada Yang, Johanna Åhsberg, Laura Olbrich, Mathias Weis Damkjær, Ruvandhi R Nathavitharana, Tobias Broger, Ioana Diana Olaru, Brittney Sweetser, Hayley Poore, Alia Razid, Alexander W Kay, Claudia M Denkinger, Ian Schiller, Nandini Dendukuri, Devan Jaganath, Andreas Lundh, Maunank Shah

Faculty, Staff and Students Publications

Background: Low-complexity automated nucleic acid amplification tests (LC-aNAATs) are molecular World Health Organization (WHO)-recommended rapid diagnostic tests (also known as mWRDs) widely used to diagnose tuberculosis disease. The lateral flow urine lipoarabinomannan assay (LF-LAM) is recommended by the WHO to assist in diagnosing tuberculosis disease amongst people with HIV. Previous systematic reviews have assessed the diagnostic accuracy of LC-aNAATs and LF-LAM used in isolation for the detection of tuberculosis, but in clinical practice the tests may be used in parallel (i.e. LC-aNAAT in combination with LF-LAM).

Objectives: To compare the diagnostic accuracy of the parallel use of LC-aNAAT on respiratory …

Current Cutting-Edge Omics Techniques On Musculoskeletal Tissues And Diseases, Xiaofei Li, Liang Fang, Sade W Clayton, Dakota R Kamm, Cuicui Wang, Farshid Guilak, Simon Y Tang, Gretchen A Meyer, Jie Shen, Et Al.

2020-Current year OA Pubs

Musculoskeletal disorders, including osteoarthritis, rheumatoid arthritis, osteoporosis, bone fracture, intervertebral disc degeneration, tendinopathy, and myopathy, are prevalent conditions that profoundly impact quality of life and place substantial economic burdens on healthcare systems. Traditional bulk transcriptomics, genomics, proteomics, and metabolomics have played a pivotal role in uncovering disease-associated alterations at the population level. However, these approaches are inherently limited in their ability to resolve cellular heterogeneity or to capture the spatial organization of cells within tissues, thus hindering a comprehensive understanding of the complex cellular and molecular mechanisms underlying these diseases. To address these limitations, advanced single-cell and spatial omics techniques …

Radiotherapy Promotes Cuproptosis And Synergizes With Cuproptosis Inducers To Overcome Tumor Radioresistance, Guang Lei, Mingchuang Sun, Jun Cheng, Rui Ye, Zhengze Lu, Amber Horbath, David Huo, Shengrong Wu, Anagha Alapati, Sadhna Aggarwal, Zhihao Xu, Chao Mao, Yuelong Yan, Jun Yao, Qidong Li, Xiong Chen, Hyemin Lee, Li Zhuang, Dadi Jiang, Apar Pataer, Jack A Roth, Nicholas Navin, Albert C Koong, Mingjian James You, Steven H Lin, Boyi Gan

Faculty, Staff and Student Publications

Cuproptosis is a recently identified form of copper-dependent cell death. Here, we reveal that radiotherapy (RT) induces cuproptosis in cancer cells, independent of apoptosis and ferroptosis, and depletes lipoylated proteins and iron-sulfur (Fe-S) cluster proteins-both hallmarks of cuproptosis-in patient tumors. Mechanistically, RT elevates mitochondrial copper levels by upregulating copper transporter 1 (CTR1) and depleting mitochondrial glutathione, a copper chelator, thereby triggering cuproptosis. Integrated analyses of RNA sequencing (RNA-seq) from radioresistant esophageal cancer cells and single-cell RNA-seq from esophageal tumors of patients unresponsive to RT link radioresistance to the downregulation of BTB and CNC homology 1 (BACH1). This downregulation de-represses the …

Longitudinal Plasma Amino Acids During Pregnancy And Neonatal Anthropometry: Findings From The Nichd Fetal Growth Studies-Singleton Cohort, Claire Guivarch, Jing Wu, Ruijin Lu, Jagteshwar Grewal, Guoqi Yu, Ling-Jun Li, Jiaxi Yang, Wei Wei Pang, Dong D Wang, Natalie L Weir, Zhen Chen, Michael Y Tsai, Cuilin Zhang

2020-Current year OA Pubs

BACKGROUND: Amino acids (AAs) during pregnancy are crucial for fetal growth. Prior studies measured AA concentrations at single time points in pregnancy, despite their fluctuations throughout pregnancy. We measured plasma AA profiles in blood samples longitudinally collected from early through late pregnancy and evaluated their associations with neonatal anthropometry.

METHODS: Concentrations of plasma aromatic AAs, branched-chain AAs, and AAs involved in one-carbon metabolism were assessed at 10-14, 15-26, 23-31, and 33-39 gestational weeks (GW) among 321 women from a case-control study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort. Associations …

A Forward Genetic Screen Identifies Potassium Channel Essentiality In Shh Medulloblastoma Maintenance, Jerry J Fan, Anders W Erickson, Julia Carrillo-Garcia, Xin Wang, Patryk Skowron, Xian Wang, Xin Chen, Guanqiao Shan, Wenkun Dou, Shahrzad Bahrampour, Yi Xiong, Weifan Dong, Namal Abeysundara, Michelle A Francisco, Ronwell J Pusong, Wei Wang, Miranda Li, Elliot Ying, Raúl A Suárez, Hamza Farooq, Borja L Holgado, Xiaochong Wu, Craig Daniels, Adam J Dupuy, Juan Cadiñanos, Allan Bradley, Anindya Bagchi, Branden S Moriarity, David A Largaespada, A Sorana Morrissy, Vijay Ramaswamy, Stephen C Mack, Livia Garzia, Peter B Dirks, Xuejun Li, Siyi Wanggou, Sean Egan, Yu Sun, Michael D Taylor, Xi Huang

Faculty, Staff and Students Publications

Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo, and applied this to SHH medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells, with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of EGFR, thereby mitigating proliferation of MB-propagating cells to ultimately impair MB growth. …

What Happens To Conservatively Managed Chronic Subdural Haematoma., J Read, E Edlmann

Peninsula Medical School

Background: Chronic subdural haematoma (CSDH) is a common neurosurgical problem, increasingly prevalent due to an ageing population. Conservative management is an option for asymptomatic or mild cases, though data on outcomes is limited. Aim/Objective: This study aims to address critical gaps in understanding around conservatively managedCSDH and whether there are features that can predict progression and the longer-term prognosis of these patients. Methods: A retrospective cohort study was performed at a major trauma centre in the UK. All patients with chronic subdural haematoma referred from March 2019 to March 2021 were included and grouped into surgical or conservative management. Demographic, …

Translation Suppresses Exogenous Target Rna-Mediated Microrna Decay, Tianqi Li, Lu Li, Nicholas M Hiers, Peike Sheng, Yuzhi Wang, Conner M Traugot, Jessi F Effinger-Morris, Pitchaporn Akaphan, Yanyan Liu, Jiang Bian, Kotaro Fujii, Mingyi Xie

Faculty, Staff and Student Publications

MicroRNAs (miRNAs) interact with the target mRNAs to induce translational repression and mRNA degradation. Interestingly, miRNAs themselves can turnover rapidly when binding to a target RNA with extensive complementarity, a phenomenon called target-directed miRNA degradation (TDMD). To date, all validated TDMD "triggers" can induce miRNA degradation reside in non-coding regions of the RNA. We found that TDMD triggers placed in the 3' untranslated region (UTR) of a reporter degraded miRNAs more effectively than those in the coding sequence (CDS). Inhibiting translation of the reporter enhanced miRNA degradation by the CDS trigger, indicating that ribosome-free CDS triggers are more accessible to …

Rewired M6a Of Promoter Antisense Rnas In Alzheimer’S Disease Regulates Neuronal Genes In 3d Nucleome, Benxia Hu, Yuqiang Shi, Feng Xiong, Yi-Ting Chen, Xiaoyu Zhu, Elisa Carrillo, Xingzhao Wen, Nathan Drolet, Chetan Singh Rajpurohit, Xiangmin Xu, Dung-Fang Lee, Claudio Soto, Sheng Zhong, Vasanthi Jayaraman, Hui Zheng, Wenbo Li

Faculty, Staff and Student Publications

N6-methyladenosine (m6A) is an abundant internal RNA modification that can impact gene expression at both post-transcriptional and transcriptional levels. However, the landscapes and functions of m6A in human brains and neurodegenerative diseases, including Alzheimer's disease (AD), are under-explored. Here, we examined RNA m6A methylome using total RNA-seq and meRIP-seq in middle frontal cortex of post-mortem brains from individuals with or without AD, which revealed m6A alteration on both mRNAs and various noncoding RNAs. Notably, many promoter-antisense RNAs (paRNAs) displayed cell-type-specific expression and changes in AD, including one produced adjacent to MAPT that encodes the Tau protein. MAPT-paRNA is highly expressed …

The Effect Of Birthweight And Gestational Age On Cognitive Function In Midlife: The Bogalusa Heart Study, Eunsun Gill, David J Libon, Soo Jung Kang, Ileana De Anda-Duran, Lydia A Bazzano, Wei Chen, Camilo Fernandez-Alonso, Emily W Harville

Rowan-Virtua School of Osteopathic Medicine Departmental Research

BACKGROUND: Although the relationships between birthweight, gestational age (GA), and cognitive function (CF) before midlife have been demonstrated, the relationships after midlife and potential racial disparities remain inconclusive. This study examined the association between birthweight, GA, and midlife CF stratified by race.

METHOD: 1,032 subjects from the Bogalusa Heart Study (67% Whites, 33% Blacks, mean age 48.1 ± 5.3 years) were studied. Cognition was assessed with tests measuring verbal episodic memory, working memory, attention, graphomotor information processing speed, and global CF. Each test was standardized by sex and age, then averaged. The global CF was computed by averaging all cognitive …

Swi/Snf Atpase Silenced Hlf Potentiates Lung Metastasis In Solid Cancers, Jin Zhou, Austin Hepperla, Jeremy M Simon, Kangsan Kim, Qing Hu, Chuanhai Zhang, Lei Dong, Lianxin Hu, Cheng Zhang, Chengheng Liao, Alice Fang, Yayoi Adachi, Haoyong Fu, Tao Wang, Qian Liang, Fangzhou Zhao, Hongyi Liu, Masashi Takeda, Jun Fang, Hua Zhong, Peter Ly, Lu Wang, Payal Kapur, Lin Xu, Liwei Jia, Srinivas Malladi, James Brugarolas, M Celeste Simon, Bo Li, Qing Zhang

Faculty, Staff and Student Publications

Metastasis is the main cause of cancer-related deaths, yet the underlying mechanisms remain elusive. Here, using clear cell renal cell carcinoma (ccRCC), a tumor type with frequent lung metastases, we conduct an in vivo genome-wide CRISPR-Cas9 screen and identify HLF as a potent suppressor of lung metastasis. HLF depletion enhances ccRCC cell migration and lung metastasis, whereas HLF overexpression abrogates these effects. In ccRCC patients, HLF expression is reduced at metastatic sites and associates with epigenetic silencing mediated by the SWI/SNF ATPase subunit BRG1. HLF levels negatively correlate with migration potential in collagen. Mechanistically, HLF regulates LPXN expression, modulating the …

Omitting Regional Nodal Irradiation After Response To Neoadjuvant Chemotherapy, Eleftherios P Mamounas, Hanna Bandos, Julia R White, Thomas B Julian, Atif J Khan, Simona F Shaitelman, Mylin A Torres, Frank A Vicini, Patricia A Ganz, Susan A Mccloskey, Peter C Lucas, Nilendu Gupta, X Allen Li, Beryl Mccormick, Benjamin Smith, Rahul D Tendulkar, Vivek S Kavadi, Koji Matsumoto, Samantha Andrews Seaward, William J Irvin, Jolinta Y Lin, Robert W Mutter, Thierry M Muanza, Jannifer Stromberg, Reshma Jagsi, Anna C Weiss, Walter J Curran, Norman Wolmark

Faculty, Staff and Student Publications

Background: The benefit of regional nodal irradiation in the treatment of breast cancer is well established for patients with pathologically positive axillary nodes, but whether it is also beneficial for patients whose nodes become pathologically tumor free (ypN0) after neoadjuvant chemotherapy remains unclear.

Methods: We evaluated whether regional nodal irradiation improves outcomes in patients with biopsy-proven, node-positive breast cancer who reach ypN0 status after neoadjuvant chemotherapy. Patients with breast cancer with a clinical stage of T1 to T3 (tumor size, ≤2 cm to >5 cm), N1, and M0 (indicating spread to one to three axillary lymph nodes but no distant …

Psilocybin's Acute And Persistent Brain Effects: A Precision Imaging Drug Trial, Subha Subramanian, Travis Rick Reneau, Demetrius Perry, Ravi Chacko, Timothy O Laumann, Karin Flavin, Christine Horan, Julie Schweiger, Nicholas Metcalf, Eric J Lenze, Abraham Z Snyder, Nico U F Dosenbach, Ginger Nicol, Joshua S Siegel

2020-Current year OA Pubs

Psilocybin (PSIL) is a psychedelic drug and a promising experimental therapeutic for many psychiatric conditions. Precision functional mapping (PFM) combines densely repeated resting state fMRI sampling and individual-specific network mapping to improve signal-to-noise ratio (SNR) and effect size in brain imaging research. We present a randomized cross-over study in which PFM was used to characterize acute and persistent effects of psilocybin or methylphenidate (MTP) on brain networks. Seven healthy volunteers (mean age 34.1 years, SD = 9.8; n = 3 females, n = 6 Caucasians) underwent (1) extensive baseline imaging, (2) imaging beginning 60-90 minutes after drug exposure, and (3) …

Cognition And Behavior In Neurofibromatosis Type 1: Report And Perspective From The Cognition And Behavior In Nf1 (Cabin) Task Force, David H Gutmann, Corina Anastasaki, Aditi Gupta, Yang Hou, Stephanie M Morris, Jonathan M Payne, Jacob Raber, Seth M Tomchik, Linda Van Aelst, James A Walker, Kaleb H Yohay

2020-Current year OA Pubs

Individuals with neurofibromatosis type 1 (NF1) are prone to the evolution of neurodevelopmental symptomatology including motor delays, learning disabilities, autism, and attention deficits. Caused by heterozygous germline mutations in the

Importance Of Outbreak Response Research In Bridging Knowledge Gaps On Emerging Infectious Diseases, Robert F Breiman, David Wang, Michael Diamond, Adrianus C M Boon, Et Al.

2020-Current year OA Pubs

An important outcome of the devastating 2014 West African Ebola virus disease outbreak and the 2020 COVID-19 pandemic has been the growing promotion of conducting research during outbreaks of emerging infectious diseases (EIDs) as a valuable and acceptable process of acquiring knowledge to enhance our ability to better prevent and control these diseases in the future. Recognising the unique opportunity during outbreaks to leverage increases in cases over a short time interval and in a circumscribed area, we articulate a systematic process of conducting EID outbreak response research, highlighting knowledge gaps that should be prioritised, and measures that can be …

Prediction Of Methotrexate Neurotoxicity Using Clinical, Sociodemographic, And Area-Based Information In Children With Acute Lymphoblastic Leukemia, Rachel D Harris, Olga A Taylor, Maria Monica Gramatges, Amy E Hughes, Mark Zobeck, Sandi Pruitt, M Brooke Bernhardt, Ashley Chavana, Van Huynh, Kathleen Ludwig, Laura Klesse, Kenneth Heym, Timothy Griffin, Rodrigo Erana, Juan Carlos Bernini, Ashley Choi, Yuu Ohno, Melissa A Richard, Alanna C Morrison, Han Chen, Bing Yu, Philip J Lupo, Karen R Rabin, Michael E Scheurer, Austin L Brown

Center for Medical Ethics and Health Policy Staff Publications

Background: Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine learning to develop a neurotoxicity risk prediction model in a diverse cohort of children with ALL.

Methods: We included children (age 2-20 years) diagnosed with ALL (2005-2019) and treated in Texas without pre-existing neurologic disease. Clinical information was obtained by medical record review. Neurotoxicity occurring post-induction and prior to maintenance therapy was defined as neurologic episodes occurring within 21 days of methotrexate. Suspected cases were independently confirmed by 2 …

177lu-Labeled Antibody-Drug Conjugate: A Dual-Mechanistic Treatment Modality In Solid Tumors, Aiko Yamaguchi, Chisato M Yamazaki, Yasuaki Anami, Summer Y Y Ha, Wei Xiong, Robert T Ta, Ningyan Zhang, H Charles Manning, Zhiqiang An, Kyoji Tsuchikama

The Brown Foundation: Institute of Molecular Medicine

To explore the potential of site-selectively radiolabeled antibody-drug conjugates (ADC) against solid tumors, we constructed and evaluated radiolabeled ADCs equipped with lutetium-177 (177Lu) and a membrane-permeable antimitotic agent. Site-selective 177Lu-labeled ADCs [anti-trophoblast cell-surface antigen 2 (TROP2) 177Lu-DTPA ADCs or anti-HER2 177Lu-DO3A ADCs], a 177Lu-labeled homogeneous radioimmunoconjugate (homogeneous RIC), and 177Lu-labeled conventional RIC (heterogeneous RIC) were constructed. We confirmed that 177Lu-labeled ADCs and the homogeneous RIC were obtained with high homogeneity and defined chelator/payload-to-antibody ratios. Next, we performed biodistribution studies and treatment efficacy studies in xenograft mouse models bearing orthotopic breast tumors. Compared with the heterogeneous RIC, the 177Lu-DTPA TROP2 ADC …

Eph Receptors Activate Myeloid Checkpoint Receptor Lilrb5 To Support Tumor Development, Yubo He, Chengcheng Zhang, Lingxiao Tan, Mi Deng, Xiaoye Liu, Ryan Huang, Xing Yang, Jingjing Xie, Qi Lou, Meng Fang, Caroline Smith, Samuel John, Wei Xiong, Xin Li, Cheryl Lewis, Jade Homsi, Ankit Gupta, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid …

Olaparib And Radiotherapy Induce Type I Interferon- And Cd8+ T Cell-Dependent Sensitization To Immunotherapy In Pancreatic Cancer, Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan

Faculty, Staff and Student Publications

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN) mediated anti-tumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote anti-tumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). We found that olaparib enhanced T1IFN production following radiation and …

Refine: A Database Of Linked Clinical Data And Genomic Biomarkers In Renal Cell Carcinoma Patients Receiving Immunotherapy-Based Treatment Regimens, Jeffrey Zhong, Albert Jang, Bashar Abuqayas, Arnab Basu, David Benjamin, Vineel Bhatlapenumarthi, Mehmet Asim Bilen, Dhvani Buch, Mark Chang, Erica Chin, Sourat Darabi, Nagendra Dhanikonda, Pooja Ghatalia, Claud Grigg, Abby Grier, Tanya Jindal, Joannah Jung, Deepak Kilari, Hamsa Kumar, Suzanna Lee, Brittany Neelands, Chinmayi Pandya, Jeff Pawalek, Jaimee Staggers, Ahmet Yildirim, Yousef Zakharia, Kevin Zarrabi, Michael Zimmerman, George Sledge, David Spetzler, Andrew Elliott, Rana Mckay, Pedro Barata

Department of Medical Oncology Faculty Papers

The REnal cancer consortium for Focused Investigation of Novel biomarkers and Expression (REFINE) consortium represents an important initiative in integrating clinical data with molecular sequencing in patients with advanced renal cell carcinoma (RCC) treated with immunotherapy-based approaches. By leveraging real-world evidence and genomic analysis, this consortium aims to explore putative predictive biomarkers with the potential to inform personalized treatment strategies. Findings from the REFINE database may further contribute to our understanding of disease courses of immunotherapy-based approaches for various molecular subtypes of RCC, associations of race and ethnicity with RCC treatment and outcomes with representation of patient populations underrepresented in …

Mesenchymal Stem Cells And Fibroblasts Contribute To Microvascular Proliferation In Glioblastoma And Are Correlated With Immunosuppression And Poor Outcome, Candice C Poon, Shelley M Herbrich, Yulong Chen, Anwar Hossain, Gregory N Fuller, Sonali Jindal, Sreyashi Basu, Daniel Ledbetter, Marc Macaluso, Lynnette M Phillips, Joy Gumin, Zhong He, Brittany C Parker Kerrigan, Sanjay K Singh, Pratishtha Singh, Mohammed Fayyad Zaman, Derek Ng Tang, Sangeeta Goswami, Frederick F Lang, Padmanee Sharma

Faculty, Staff and Student Publications

Microvascular proliferation (MVP) is a disease-defining hallmark of glioblastoma and other World Health Organization grade 4 gliomas. MVP also serves as a poor prognostic marker in various solid tumors. Despite its clinical significance, the mechanisms and biological consequences of MVP are controversial and remain unclear. In this study, we performed single-cell RNA sequencing on paired CD45-CD105+ vascular/perivascular stromal cells (PVSC) and CD45+CD105± immune cells from 16 primary glioma patient samples, both with and without MVP. This analysis revealed the presence of developmentally related mesenchymal stem cells alongside cancer-associated fibroblasts, pericytes, fibromyocytes, and smooth muscle cells within the CD45-CD105+ compartment. RNA …

The Present And Future Of Precision Oncology And Tumor-Agnostic Therapeutic Approaches, Nakul M Shah, Funda Meric-Bernstam

Faculty, Staff and Student Publications

Precision oncology has transformed the treatment landscape for patients with advanced solid tumors. Tumor-agnostic therapies, those that have been approved based on genetic mutations or biomarkers across tumor histology types, are important examples of how the implementation of precision oncology can expand therapeutic options for patients, especially those with rare cancer types and treatment-refractory disease. In this review, we first discuss how advances in next-generation sequencing and molecular profiling have enabled the identification of shared actionable alterations. Subsequently, we explore the current landscape of tumor-agnostic therapies that have received approval from the Food and Drug Administration. We discuss the strengths …

Linking Dna Methylation In Brain Regions To Alzheimer’S Disease Risk: A Mendelian Randomization Study, Hua Zhong, Jingjing Zhu, Shuai Liu, Dan Zhou, Quan Long, Chong Wu, Bingxin Zhao, Chao Cheng, Yaohua Yang, Qing Wu, Yong Wu, Changwei Li, Zhaoming Wang, Jianyong Wu, Xingyi Guo, Degui Zhi, Youping Deng, Lang Wu

Faculty, Staff and Students Publications

Aim: DNA methylation in brain regions represents a potential mechanism linking genetic variation to Alzheimer's disease (ad) risk, yet most studies have focused on blood-derived methylation markers. In this study, we conducted a systematic Mendelian randomization (MR) study to evaluate associations between predicted brain region-specific DNA methylation levels and ad risk, using methylation quantitative trait loci (mQTL) as genetic instruments.

Methods: We analyzed mQTLs from five human brain regions: cerebellum (CRBLM), frontal cortex (FCTX), causal pons (PONS), and temporal cortex (TCTX) from 600 individuals in Gibbs et al's study, as well as mQTLs from dorsolateral prefrontal cortex (DLPFC) of 543 …