Medicine and Health Sciences Commons^™

Conducting Comparative Effectiveness, Multisite Palliative Care And Advance Care Planning Trials: Lessons Learned And Future Directions From Pcori-Funded Studies, Areej El-Jawahri, Brittany Waterman, Susan Enguidanos, Lisa Gibbs, Victor Navarro, Maren Olsen, Jennifer Temel, Annette Totten, Corita R. Grudzen

Department of Medicine Faculty Papers

The Patient-Centered Outcomes Research Institute (PCORI) funded multiple large-scale comparative effectiveness clinical trials evaluating palliative care (PC) and advance care planning (ACP) healthcare delivery models. This article provides an overview of the most common barriers our investigative teams encountered while implementing these trials and the strategies we utilized to overcome these challenges, with particular attention to identifying research partners for multisite trials; addressing contracting and regulatory issues; creating a team governance structure; training and engaging study staff across sites; recruiting, consenting, and enrolling study participants; collecting PC and ACP data and study outcomes; and managing multisite collaborations. The goal of …

Treatment Of Acute Myeloid Leukemia In The Community Setting, Taha Al-Juhaishi, Servillano Dela Cruz, Rohan Gupta, Gina Keiffer, Vicki Morrison, Iuliana Shapira, Ashley Woods, Kelly Norsworthy, Romeo Angelo De Claro, Marc Theoret, Ravin Garg, Elizabeth Dianne Pulte

Kimmel Cancer Center Faculty Papers

The treatment landscape for acute myeloid leukemia (AML) is rapidly changing. Many new agents and lower-intensity regimens have been approved and can be safely used by hematologists and oncologists in both academic and community settings. The US Food and Drug Administration (FDA) held a virtual symposium on AML treatment in the community in November 2022. Several members of the FDA, along with practicing hematologists and oncologists in both academic and community settings, participated in the symposium. The goal of the symposium was to discuss challenges and opportunities in the treatment of patients with AML in community oncology settings. A summary …

Single-Cell Chromatin Accessibility Reveals Malignant Regulatory Programs In Primary Human Cancers, Laksshman Sundaram, Arvind Kumar, Matthew Zatzman, Adriana Salcedo, Neal Ravindra, Shadi Shams, Bryan H Louie, S Tansu Bagdatli, Matthew A Myers, Shahab Sarmashghi, Hyo Young Choi, Won-Young Choi, Kathryn E Yost, Yanding Zhao, Jeffrey M Granja, Toshinori Hinoue, D Neil Hayes, Andrew Cherniack, Ina Felau, Hani Choudhry, Jean C Zenklusen, Kyle Kai-How Farh, Andrew Mcpherson, Christina Curtis, Peter W Laird, Cancer Genome Atlas Analysis Network, John A Demchok, Liming Yang, Roy Tarnuzzer, Samantha J Caesar-Johnson, Zhining Wang, Ashley S Doane, Ekta Khurana, Mauro A A Castro, Alexander J Lazar, Bradley M Broom, John N Weinstein, Rehan Akbani, Shwetha V Kumar, Benjamin J Raphael, Christopher K Wong, Joshua M Stuart, Rojin Safavi, Christopher C Benz, Benjamin K Johnson, Cindy Kyi, Hui Shen, M Ryan Corces, Howard Y Chang, William J Greenleaf

Faculty, Staff and Student Publications

To identify cancer-associated gene regulatory changes, we generated single-cell chromatin accessibility landscapes across eight tumor types as part of The Cancer Genome Atlas. Tumor chromatin accessibility is strongly influenced by copy number alterations that can be used to identify subclones, yet underlying cis-regulatory landscapes retain cancer type-specific features. Using organ-matched healthy tissues, we identified the "nearest healthy" cell types in diverse cancers, demonstrating that the chromatin signature of basal-like-subtype breast cancer is most similar to secretory-type luminal epithelial cells. Neural network models trained to learn regulatory programs in cancer revealed enrichment of model-prioritized somatic noncoding mutations near cancer-associated genes, suggesting …

Menopausal Hormone Therapy Use Among Postmenopausal Women, Lin Yang, Adetunji T Toriola

2020-Current year OA Pubs

IMPORTANCE: Menopausal hormone therapy (MHT) is the treatment of choice for symptoms of menopause. However, its adoption is hindered by the risk-benefit trade-off in relation to acute and chronic diseases.

OBJECTIVE: To evaluate trends in and correlates of MHT use among postmenopausal women in the US from 1999 to March 2020.

DESIGN, SETTING, AND PARTICIPANTS: This serial cross-sectional analysis of MHT use used data from the nationally representative National Health and Nutrition Examination Survey (NHANES). Participants included noninstitutionalized US postmenopausal women from 10 NHANES study cycles (1999-2000 to 2017-March 2020 [pre-COVID-19 pandemic]). Data were analyzed from December 2023 to April …

Novel Cyclic Homogeneous Oscillation Detection Method For High Accuracy And Specific Characterization Of Neural Dynamics, Hohyun Cho, Markus Adamek, Jon T Willie, Peter Brunner

2020-Current year OA Pubs

Determining the presence and frequency of neural oscillations is essential to understanding dynamic brain function. Traditional methods that detect peaks over 1/

Identification Of A Clade-Specific Hla-C*03:02 Ctl Epitope Gy9 Derived From The Hiv-1 P17 Matrix Protein, Samuel Kyobe, Savannah Mwesigwa, Gyaviira Nkurunungi, Gaone Retshabile, Moses Egesa, Eric Katagirya, Marion Amujal, Busisiwe C Mlotshwa, Lesedi Williams, Hakim Sendagire, On Behalf Of The Cafgen Consortium, Dithan Kiragga, Graeme Mardon, Mogomotsi Matshaba, Neil A Hanchard, Jacqueline Kyosiimire-Lugemwa, David Robinson

Faculty, Staff and Students Publications

Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02 CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope potentially restricted to HLA-C*03:02. Residues …

Substitution Of A Single Non-Coding Nucleotide Upstream Of Tmem216 Causes Non-Syndromic Retinitis Pigmentosa And Is Associated With Reduced Tmem216 Expression, Samantha Malka, Pooja Biswas, Anne-Marie Berry, Riccardo Sangermano, Mukhtar Ullah, Siying Lin, Matteo D'Antonio, Aleksandr Jestin, Xiaodong Jiao, Mathieu Quinodoz, Lori Sullivan, Jessica C Gardner, Emily M Place, Michel Michaelides, Karolina Kaminska, Omar A Mahroo, Elena Schiff, Genevieve Wright, Francesca Cancellieri, Veronika Vaclavik, Cristina Santos, Atta Ur Rehman, Sudeep Mehrotra, Hafiz Muhammad Azhar Baig, Muhammad Iqbal, Muhammad Ansar, Luisa Coutinho Santos, Ana Berta Sousa, Viet H Tran, Hiroko Matsui, Anjana Bhatia, Muhammad Asif Naeem, Shehla J Akram, Javed Akram, Sheikh Riazuddin, Carmen Ayuso, Eric A Pierce, Alison J Hardcastle, S Amer Riazuddin, Kelly A Frazer, J Fielding Hejtmancik, Carlo Rivolta, Kinga M Bujakowska, Gavin Arno, Andrew R Webster, Radha Ayyagari

Faculty, Staff and Student Publications

Genome analysis of individuals affected by retinitis pigmentosa (RP) identified two rare nucleotide substitutions at the same genomic location on chromosome 11 (g.61392563 [GRCh38]), 69 base pairs upstream of the start codon of the ciliopathy gene TMEM216 (c.-69G>A, c.-69G>T [GenBank: NM_001173991.3]), in individuals of South Asian and African ancestry, respectively. Genotypes included 71 homozygotes and 3 mixed heterozygotes in trans with a predicted loss-of-function allele. Haplotype analysis showed single-nucleotide variants (SNVs) common across families, suggesting ancestral alleles within the two distinct ethnic populations. Clinical phenotype analysis of 62 available individuals from 49 families indicated a similar clinical presentation …

Current Diagnostic And Quantitative Techniques In The Field Of Lymphedema Management: A Critical Review, Mary Vargo, Melissa Aldrich, Paula Donahue, Emily Iker, Louise Koelmeyer, Rachelle Crescenzi, Andrea Cheville

The Brown Foundation: Institute of Molecular Medicine

Lymphedema evaluation entails multifaceted considerations for which options continue to evolve and emerge. This paper provides a critical review of the current status of diagnostic and quantitative measures for lymphedema, from traditional and novel bedside assessment tools for volumetric and fluid assessment, to advanced imaging modalities. Modalities are contrasted with regard to empirical support and feasibility of clinical implementation. The manuscript proposes a grid framework for comparing the ability of each modality to quantify specific lymphedema characteristics, including distribution, dysmorphism, tissue composition and fluid content, lymphatic anatomy and function, metaplasia, clinical symptoms, and quality of life and function. This review …

Targeting Igf2 To Reprogram The Tumor Microenvironment For Enhanced Viro-Immunotherapy, Min Hye Noh, Jin Muk Kang, Alexandra A Miller, Grace Nguyen, Minxin Huang, Ji Seon Shim, Alberto J Bueso-Perez, Sara A Murphy, Kimberly A Rivera-Caraballo, Yoshihiro Otani, Eunju Kim, Seung-Hee Yoo, Yuanqing Yan, Yeshavanth Banasavadi-Siddegowda, Hiroshi Nakashima, E Antonio Chiocca, Balveen Kaur, Zhongming Zhao, Tae Jin Lee, Ji Young Yoo

Faculty, Staff and Student Publications

BACKGROUND: The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).

METHODS: RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.

RESULTS: Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. …

A Systematic Review Of The Timing Of Therapeutic Anticoagulation In Adult Patients With Acute Traumatic Brain Injury: Narrative Synthesis Of Observational Studies, Sophie Samuel, Jennifer Cortes, Eugene Uh, Huimahn Alex Choi

Library Staff Publications

Traumatic brain injury (TBI) presents complex management scenarios, particularly in patients requiring anticoagulation for concurrent conditions such as venous thromboembolism (VTE) or atrial fibrillation (AF). A systematic search of PubMed/MEDLINE, Embase, and the Cochrane Library databases was conducted to identify relevant studies. Inclusion criteria encompassed studies assessing the effects of anticoagulation therapy on outcomes such as re-hemorrhage, hematoma expansion, thrombotic events, and hemorrhagic events in TBI patients with subdural hematomas (SDH). This systematic review critically addresses two key questions: the optimal timing for initiating anticoagulation therapy and the differential impact of this timing based on the type of intracranial bleed, …

Regional Desynchronization Of Microglial Activity Is Associated With Cognitive Decline In Alzheimer's Disease, Artem Zatcepin, Samira Parhizkar, Et Al.

2020-Current year OA Pubs

BACKGROUND: Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker.

METHODS: To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia …

Stat3-Mediated Atg7 Expression Regulates Anti-Tumor Immunity In Mouse Melanoma, Sarah M Zimmerman, Erin Suh, Sofia R Smith, George P Souroullas

2020-Current year OA Pubs

Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2

Adjunctive Intravenous Argatroban Or Eptifibatide For Ischemic Stroke, Opeolu Adeoye, Peter Panagos, Stephanie Pizzella, Et Al.

2020-Current year OA Pubs

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear.

METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with …

Tulips Decorate The Three-Dimensional Genome Of Pfa Ependymoma, Michael J Johnston, John J Y Lee, Bo Hu, Ana Nikolic, Elham Hasheminasabgorji, Audrey Baguette, Seungil Paik, Haifen Chen, Sachin Kumar, Carol C L Chen, Selin Jessa, Polina Balin, Vernon Fong, Melissa Zwaig, Kulandaimanuvel Antony Michealraj, Xun Chen, Yanlin Zhang, Srinidhi Varadharajan, Pierre Billon, Nikoleta Juretic, Craig Daniels, Amulya Nageswara Rao, Caterina Giannini, Eric M Thompson, Miklos Garami, Peter Hauser, Timea Pocza, Young Shin Ra, Byung-Kyu Cho, Seung-Ki Kim, Kyu-Chang Wang, Ji Yeoun Lee, Wieslawa Grajkowska, Marta Perek-Polnik, Sameer Agnihotri, Stephen Mack, Benjamin Ellezam, Alex Weil, Jeremy Rich, Guillaume Bourque, Jennifer A Chan, V Wee Yong, Mathieu Lupien, Jiannis Ragoussis, Claudia Kleinman, Jacek Majewski, Mathieu Blanchette, Nada Jabado, Michael D Taylor, Marco Gallo

Faculty, Staff and Students Publications

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in …

Cyp3a-Mediated Carbon-Carbon Bond Cleavages In Drug Metabolism, Junhui Zhou, Xuan Qin, Shenzhi Zhou, Kevin R Mackenzie, Feng Li

Faculty, Staff and Students Publications

Cytochrome P450 enzymes (P450s) play a critical role in drug metabolism, with the CYP3A subfamily being responsible for the biotransformation of over 50% of marked drugs. While CYP3A enzymes are known for their extensive catalytic versatility, one intriguing and less understood function is the ability to mediate carbon-carbon (C-C) bond cleavage. These uncommon reactions can lead to unusual metabolites and potentially influence drug safety and efficacy. This review focuses on examining examples of C-C bond cleavage catalyzed by CYP3A, exploring the mechanisms, physiological significance, and implications for drug metabolism. Additionally, examples of CYP3A-mediated ring expansion via C-C bond cleavages are …

Rna Interacts With Topoisomerase I To Adjust Dna Topology, Mannan Bhola, Kouki Abe, Paola Orozco, Homa Rahnamoun, Pedro Avila-Lopez, Elijah Taylor, Nefertiti Muhammad, Bei Liu, Prachi Patel, John F Marko, Anne C Starner, Chuan He, Eric L Van Nostrand, Alfonso Mondragón, Shannon M Lauberth

Faculty, Staff and Students Publications

Topoisomerase I (TOP1) is an essential enzyme that relaxes DNA to prevent and dissipate torsional stress during transcription. However, the mechanisms underlying the regulation of TOP1 activity remain elusive. Using enhanced cross-linking and immunoprecipitation (eCLIP) and ultraviolet-cross-linked RNA immunoprecipitation followed by total RNA sequencing (UV-RIP-seq) in human colon cancer cells along with RNA electrophoretic mobility shift assays (EMSAs), biolayer interferometry (BLI), and in vitro RNA-binding assays, we identify TOP1 as an RNA-binding protein (RBP). We show that TOP1 directly binds RNA in vitro and in cells and that most RNAs bound by TOP1 are mRNAs. Using a TOP1 RNA-binding mutant …

Neoadjuvant Parpi Or Chemotherapy In Ovarian Cancer Informs Targeting Effector Treg Cells For Homologous-Recombination-Deficient Tumors, Yikai Luo, Yu Xia, Dan Liu, Xiong Li, Huayi Li, Jiahao Liu, Dongchen Zhou, Yu Dong, Xin Li, Yiyu Qian, Cheng Xu, Kangjia Tao, Guannan Li, Wen Pan, Qing Zhong, Xingzhe Liu, Sen Xu, Zhi Wang, Ronghua Liu, Wei Zhang, Wanying Shan, Tian Fang, Siyuan Wang, Zikun Peng, Ping Jin, Ning Jin, Shennan Shi, Yuxin Chen, Mengjie Wang, Xiaofei Jiao, Mengshi Luo, Wenjian Gong, Ya Wang, Yue Yao, Yi Zhao, Xinlin Huang, Xuwo Ji, Zhaoren He, Guangnian Zhao, Rong Liu, Mingfu Wu, Gang Chen, Li Hong, Cocpo Consortium, Ding Ma, Yong Fang, Han Liang, Qinglei Gao

Faculty, Staff and Student Publications

Homologous recombination deficiency (HRD) is prevalent in cancer, sensitizing tumor cells to poly (ADP-ribose) polymerase (PARP) inhibition. However, the impact of HRD and related therapies on the tumor microenvironment (TME) remains elusive. Our study generates single-cell gene expression and T cell receptor profiles, along with validatory multimodal datasets from >100 high-grade serous ovarian cancer (HGSOC) samples, primarily from a phase II clinical trial (NCT04507841). Neoadjuvant monotherapy with the PARP inhibitor (PARPi) niraparib achieves impressive 62.5% and 73.6% response rates per RECIST v.1.1 and GCIG CA125, respectively. We identify effector regulatory T cells (eTregs) as key responders to HRD …

Implementation Of A Dyadic Nomenclature For Monogenic Diseases, Courtney Thaxton, Leslie G Biesecker, Marina Distefano, Melissa Haendel, Ada Hamosh, Emma Owens, Sharon E Plon, Heidi L Rehm, Jonathan S Berg

Center for Medical Ethics and Health Policy Staff Publications

A core task when establishing the strength of evidence for a gene's role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a process of lumping and splitting, disease reorganization, and updates to disease nomenclature. Reappraisal of the names that are used as labels for disease entities is therefore a necessary and perpetual process. The Clinical Genome Resource (ClinGen), in collaboration with representatives from Monarch Disease …

Physiological And Communicative Emotional Disconcordance In Children On The Autism Spectrum, Emma Finkel, Eric Sah, Mckenna Spaulding, John Herrington, Liza Tomczuk, Aaron Masino, Xueqin Pang, Anushua Bhattacharya, Darren Hedley, Yelena Kushleyeva, Phoebe Thomson, Natalie Doppelt, Jessica Tan, Jeffrey Pennington, Cheryl Dissanayake, Christopher Bonafide, Heather Nuske

SKMC Student Presentations and Publications

BACKGROUND: Individuals on the autism spectrum commonly have differences from non-autistic people in expressing their emotions using communicative behaviors, such as facial expressions. However, it is not yet clear if this reduced expressivity stems from reduced physiological reactivity in emotional contexts or if individuals react internally, but do not show these reactions externally to others. We hypothesized that autism is characterized by a discordance between in-the-moment internal psychophysiological arousal and external communicative expressions of emotion.

METHODS: Forty-one children on the autism spectrum and 39 non-autistic, typically developing (TD) children of two age groups (2-4 and 8-12 years) participated in a …

Different Sensory Information Is Used For State Estimation When Stationary Or Moving., Aaron Wong, Alyssa Eyssalenne, Luke Carter, Amanda S Therrien

Moss-Magee Rehabilitation Papers

The accurate estimation of limb state is necessary for movement planning and execution. While state estimation requires both feedforward and feedback information, we focus here on the latter. Prior literature has shown that integrating visual and proprioceptive feedback improves estimates of static limb position. However, differences in visual and proprioceptive feedback delays suggest that multisensory integration could be disadvantageous when the limb is moving. We formalized this hypothesis by modeling feedback-based state estimation using the long-standing maximum likelihood estimation model of multisensory integration, which we updated to account for sensory delays. Our model predicted that the benefit of multisensory integration …

Screening Of Anti-Prion Compounds Using The Protein Misfolding Cyclic Amplification Technology, Sandra Pritzkow, Isaac Schauer, Ananya Tupaki-Sreepurna, Rodrigo Morales, Claudio Soto

Faculty, Staff and Student Publications

Prion diseases are 100% fatal infectious neurodegenerative diseases affecting the brains of humans and other mammals. The disease is caused by the formation and replication of prions, composed exclusively of the misfolded prion protein (PrPSc). We invented and developed the protein misfolding cyclic amplification (PMCA) technology for in vitro prion replication, which allow us to replicate the infectious agent and it is commonly used for ultra-sensitive prion detection in biological fluids, tissues and environmental samples. In this article, we studied whether PMCA can be used to screen for chemical compounds that block prion replication. A small set of compounds previously …

Intracellular Islatravir-Triphosphate Half-Life Supports Extended Dosing Intervals, Xiaowei Zang, Wendy Ankrom, Walter K. Kraft, Ryan Vargo, S Aubrey Stoch, Marian Iwamoto, Randolph P Matthews

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Antiretroviral therapy has substantially reduced morbidity, mortality, and disease transmission in people living with HIV. Islatravir is a nucleoside reverse transcriptase translocation inhibitor that inhibits HIV-1 replication by multiple mechanisms of action, and it is in development for the treatment of HIV-1 infection. In preclinical and clinical studies, islatravir had a long half-life (t½) of 3.0 and 8.7 days (72 and 209 hours, respectively); therefore, islatravir is being investigated as a long-acting oral antiretroviral agent. A study was conducted to definitively elucidate the terminal t½ of islatravir and its active form islatravir-triphosphate (islatravir-TP). A single-site, open-label, non-randomized, single-dose phase 1 …

Molecularly Imprinted Wearable Sensor With Paper Microfluidics For Real-Time Sweat Biomarker Analysis, Mayank Garg, Heng Guo, Ethan Maclam, Elizabeth Zhanov, Sathwika Samudrala, Anton Pavlov, Md Saifur Rahman, Myeong Namkoong, Jennette P Moreno, Limei Tian

Faculty, Staff and Student Publications

The urgent need for real-time and noninvasive monitoring of health-associated biochemical parameters has motivated the development of wearable sweat sensors. Existing electrochemical sensors show promise in real-time analysis of various chemical biomarkers. These sensors often rely on labels and redox probes to generate and amplify the signals for the detection and quantification of analytes with limited sensitivity. In this study, we introduce a molecularly imprinted polymer (MIP)-based biochemical sensor to quantify a molecular biomarker in sweat using electrochemical impedance spectroscopy, which eliminates the need for labels or redox probes. The molecularly imprinted biosensor can achieve sensitive and specific detection of …

G Protein Selectivity Profile Of Gpr56/Adgrg1 And Its Effect On Downstream Effectors, Raida Jallouli, Ana L Moreno-Salinas, Andréanne Laniel, Brian Holleran, Charlotte Avet, Joan Jacob, Trang Hoang, Christine Lavoie, Kendra S Carmon, Michel Bouvier, Richard Leduc

Faculty, Staff and Student Publications

GPR56, an adhesion G-protein coupled receptor (aGPCRs) with constitutive and ligand-promoted activity, is involved in many physiological and pathological processes. Whether the receptor's constitutive or ligand-promoted activation occur through the same molecular mechanism, and whether different activation modes lead to functional selectivity between G proteins is unknown. Here we show that GPR56 constitutively activates both G12 and G13. Unlike constitutive activation and activation with 3-α-acetoxydihydrodeoxygedunin (3αDOG), stimulation with an antibody, 10C7, directed against GPR56's extracellular domain (ECD) led to an activation that favors G13 over G12. An autoproteolytically deficient mutant, GPR56-T383A, was also activated by 10C7 indicating that the tethered …

Crizotinib Enhances Parp Inhibitor Efficacy In Ovarian Cancer Cells And Xenograft Models By Inducing Autophagy, Janice M Santiago-O'Farrill, Alicia Blessing Bollu, Hailing Yang, Vivian Orellana, Marc Pina, Xudong Zhang, Jinsong Liu, Robert C Bast, Zhen Lu

Faculty, Staff and Student Publications

Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and …

Preexisting Skin-Resident Cd8 And Γδ T-Cell Circuits Mediate Immune Response In Merkel Cell Carcinoma And Predict Immunotherapy Efficacy, Zachary Z Reinstein, Yue Zhang, Oscar E Ospina, Matt D Nichols, Victoria A Chu, Alvaro De Mingo Pulido, Karol Prieto, Jonathan V Nguyen, Rui Yin, Carlos Moran Segura, Ahmed Usman, Brittney Sell, Spencer Ng, Janis V De La Iglesia, Sunandana Chandra, Jeffrey A Sosman, Raymond J Cho, Jeffrey B Cheng, Ellie Ivanova, Sergei B Koralov, Robbert J C Slebos, Christine H Chung, Nikhil I Khushalani, Jane L Messina, Amod A Sarnaik, Jonathan S Zager, Vernon K Sondak, Charles Vaske, Sungjune Kim, Andrew S Brohl, Xinlei Mi, Brian G Pierce, Xuefeng Wang, Brooke L Fridley, Kenneth Y Tsai, Jaehyuk Choi

Staff and Researcher Publications

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a ~50% response rate to immune checkpoint blockade (ICB) therapy. To identify predictive biomarkers, we integrated bulk and single-cell RNA-seq with spatial transcriptomics from a cohort of 186 samples from 116 patients, including bulk RNA-seq from 14 matched pairs pre- and post-ICB. In non-responders, tumors show evidence of increased tumor proliferation, neuronal stem cell markers, and IL-1. Responders have increased type I/II interferons and pre-existing tissue resident (Trm) CD8 or Vδ1 γδ T cells that functionally converge with overlapping antigen-specific transcriptional programs and clonal expansion of public TCRs. Spatial …

Myc Induces Oncogenic Stress Through Rna Decay And Ribonucleotide Catabolism In Breast Cancer, Jitendra K Meena, Jarey H Wang, Nicholas J Neill, Dianne Keough, Nagireddy Putluri, Panagiotis Katsonis, Amanda M Koire, Hyemin Lee, Elizabeth A Bowling, Siddhartha Tyagi, Mayra Orellana, Rocio Dominguez-Vidaña, Heyuan Li, Kenneth Eagle, Charles Danan, Hsiang-Ching Chung, Andrew D Yang, William Wu, Sarah J Kurley, Brian M Ho, Joseph R Zoeller, Calla M Olson, Kristen L Meerbrey, Olivier Lichtarge, Arun Sreekumar, Clifford C Dacso, Luke W Guddat, Dominik Rejman, Dana Hocková, Zlatko Janeba, Lukas M Simon, Charles Y Lin, Monica C Pillon, Thomas F Westbrook

Faculty, Staff and Students Publications

Upregulation of MYC is a hallmark of cancer, wherein MYC drives oncogenic gene expression and elevates total RNA synthesis across cancer cell transcriptomes. Although this transcriptional anabolism fuels cancer growth and survival, the consequences and metabolic stresses induced by excess cellular RNA are poorly understood. Herein, we discover that RNA degradation and downstream ribonucleotide catabolism is a novel mechanism of MYC-induced cancer cell death. Combining genetics and metabolomics, we find that MYC increases RNA decay through the cytoplasmic exosome, resulting in the accumulation of cytotoxic RNA catabolites and reactive oxygen species. Notably, tumor-derived exosome mutations abrogate MYC-induced cell death, suggesting …

Prospects And Challenges Of Tissue-Derived Extracellular Vesicles, Justin C Lee, Roslyn M Ray, Tristan A Scott

Faculty, Staff and Students Publications

Extracellular vesicles (EVs) are considered a vital component of cell-to-cell communication and represent a new frontier in diagnostics and a means to identify pathways for therapeutic intervention. Recently, studies have revealed the importance of tissue-derived EVs (Ti-EVs), which are EVs present in the interstitial spaces between cells, as they better represent the underlying physiology of complex, multicellular tissue microenvironments in biology and disease. EVs are native, lipid bilayer membraned nano-sized particles produced by all cells that are packaged with varied functional biomolecules including proteins, lipids, and nucleic acids. They are implicated in short- and long-range cellular communication and may elicit …

Cystic Fibrosis-Related Diabetes Screening At A Large Pediatric Center, Anil K Chokkalla, Pamela Tuley, Miray Kurtca, Herda Ona, Fadel E Ruiz, Sridevi Devaraj

Faculty, Staff and Students Publications

Objective: Cystic Fibrosis Foundation guidelines recommend annual diabetes screening by oral glucose tolerance test (OGTT) in pediatric patients with cystic fibrosis (CF) starting at the age of 10 years. Adherence to these guidelines proves to be challenging, and the nationwide screening rates are still considered suboptimal. The aim of this study was to assess and improve the screening rates at our large pediatric center.

Methods: A 4-year retrospective audit of OGTT completion among pediatric patients with CF of age ≥10 years who are not yet diagnosed with diabetes was conducted. A collaborative working group was formed to identify the barriers …

The Prognostic Effect Of Infiltrating Immune Cells Is Shaped By Proximal M2 Macrophages In Lung Adenocarcinoma, Jian-Rong Li, Vikram Shaw, Yupei Lin, Xiang Wang, Muhammad Aminu, Yong Li, Jia Wu, Jianjun Zhang, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

The spatial arrangement of immune cells within the tumor microenvironment (TME) and their interactions play critical roles in the initiation and development of cancer. Several advanced technologies such as imaging mass cytometry (IMC) providing the immunological landscape of the TME with single-cell resolution. In this study, we develop a new method to quantify the spatial proximity between different cell types based on single-cell spatial data. Using this method on IMC data from 416 lung adenocarcinoma patients, we show that the proximity between different cell types is more correlated with patient prognosis compared to the traditional features such immune cell density …