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Phase 1b Study Of Intraperitoneal Ipilimumab And Nivolumab In Patients With Recurrent Gynecologic Malignancies With Peritoneal Carcinomatosis, Anne Knisely, Emily Hinchcliff, Bryan Fellman, Ann Mosley, Kathryn Lito, Sara Hull, Shannon N Westin, Anil K Sood, Kathleen M Schmeler, Jolyn S Taylor, Steven Y Huang, Rahul A Sheth, Karen H Lu, Amir A Jazaeri

Faculty, Staff and Student Publications

Background: Intravenous immune checkpoint blockade (ICB) has shown poor response rates in recurrent gynecologic malignancies. Intraperitoneal (i.p.) ICB may result in enhanced T cell activation and anti-tumor immunity.

Methods: In this phase 1b study, registered at Clinical.

Trials: gov (NCT03508570), initial cohorts received i.p. nivolumab monotherapy, and subsequent cohorts received combination i.p. nivolumab every 2 weeks and i.p. ipilimumab every 6 weeks, guided by a Bayesian design. The primary objective was determination of the recommended phase 2 dose (RP2D) of the combination. Secondary outcomes included toxicity, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Findings: …

Combined Deletion Of Men1, Atrx And Pten Triggers Development Of High-Grade Pancreatic Neuroendocrine Tumors In Mice, Mary Esmeralda Fuentes, Xiaoyin Lu, Natasha M Flores, Simone Hausmann, Pawel K Mazur

Faculty, Staff and Student Publications

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of tumors that exhibit an unpredictable and broad spectrum of clinical presentations and biological aggressiveness. Surgical resection is still the only curative therapeutic option for localized PanNET, but the majority of patients are diagnosed at an advanced and metastatic stage with limited therapeutic options. Key factors limiting the development of new therapeutics are the extensive heterogeneity of PanNETs and the lack of appropriate clinically relevant models. In that context, genomic sequencing of human PanNETs revealed recurrent mutations and structural alterations in several tumor suppressors. Here, we demonstrated that combined loss of MEN1, …

Serum Neuroactive Metabolites Of The Tryptophan Pathway In Patients With Acute Phase Of Affective Disorders, Yanli Li, Leilei Wang, Junchao Huang, Ping Zhang, Yanfang Zhou, Jinghui Tong, Wenjin Chen, Mengzhuang Gou, Baopeng Tian, Wei Li, Xingguang Luo, Li Tian, L Elliot Hong, Chiang-Shan R Li, Yunlong Tan

Faculty, Staff and Student Publications

BACKGROUND: Many studies showed disrupted tryptophan metabolism in patients with affective disorders. The aims of this study were to explore the differences in the metabolites of tryptophan pathway (TP) and the relationships between TP metabolites and clinical symptoms, therapeutic effect in patients with bipolar disorder with acute manic episode (BD-M), depressive episode (BD-D) and major depressive disorder (MDD).

METHODS: Patients with BD-M (n=52) and BD-D (n=39), MDD (n=48) and healthy controls (HCs, n=49) were enrolled. The serum neuroactive metabolites levels of the TP were measured by liquid chromatography-tandem mass spectrometry. Hamilton Depression Scale-17 item (HAMD-17) and Young Mania Rating Scale …

Miniature Battery-Free Epidural Cortical Stimulators, Joshua E Woods, Amanda L Singer, Fatima Alrashdan, Wendy Tan, Chunfeng Tan, Sunil A Sheth, Sameer A Sheth, Jacob T Robinson

Faculty, Staff and Student Publications

Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power …

Charting The Cellular Biogeography In Colitis Reveals Fibroblast Trajectories And Coordinated Spatial Remodeling, Paolo Cadinu, Kisha N Sivanathan, Aditya Misra, Rosalind J Xu, Davide Mangani, Evan Yang, Joseph M Rone, Katherine Tooley, Yoon-Chul Kye, Lloyd Bod, Ludwig Geistlinger, Tyrone Lee, Randall T Mertens, Noriaki Ono, Gang Wang, Liliana Sanmarco, Francisco J Quintana, Ana C Anderson, Vijay K Kuchroo, Jeffrey R Moffitt, Roni Nowarski

Faculty, Staff and Student Publications

Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization …

Nardilysin-Regulated Scission Mechanism Activates Polo-Like Kinase 3 To Suppress The Development Of Pancreatic Cancer, Jie Fu, Jianhua Ling, Ching-Fei Li, Chi-Lin Tsai, Wenjuan Yin, Junwei Hou, Ping Chen, Yu Cao, Ya'an Kang, Yichen Sun, Xianghou Xia, Zhou Jiang, Kenei Furukawa, Yu Lu, Min Wu, Qian Huang, Jun Yao, David H Hawke, Bih-Fang Pan, Jun Zhao, Jiaxing Huang, Huamin Wang, E I Mustapha Bahassi, Peter J Stambrook, Peng Huang, Jason B Fleming, Anirban Maitra, John A Tainer, Mien-Chie Hung, Chunru Lin, Paul J Chiao

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find …

A Novel Lentiviral Vector-Based Approach To Generate Chimeric Antigen Receptor T Cells Targeting, Pappanaicken R Kumaresan, Sebastian Wurster, Karishma Bavisi, Thiago Aparecido Da Silva, Paul Hauser, Jordan Kinnitt, Nathaniel D Albert, Uddalak Bharadwaj, Sattva Neelapu, Dimitrios P Kontoyiannis

Faculty, Staff and Student Publications

Invasive aspergillosis (IA) is a common and deadly mold infection in immunocompromised patients. As morbidity and mortality of IA are primarily driven by poor immune defense, adjunct immunotherapies, such as chimeric antigen receptor (CAR) T cells, are direly needed. Here, we propose a novel approach to generate Aspergillus fumigatus (AF)-CAR T cells using the single-chain variable fragment domain of monoclonal antibody AF-269-5 and a lentiviral vector system. These cells successfully targeted mature hyphal filaments of representative clinical and reference AF isolates and elicited a potent release of cytotoxic effectors and type 1 T cell cytokines. Furthermore, AF-CAR T cells generated …

A Revamped Rat Reference Genome Improves The Discovery Of Genetic Diversity In Laboratory Rats, Tristan V De Jong, Yanchao Pan, Pasi Rastas, Daniel Munro, Monika Tutaj, Huda Akil, Chris Benner, Denghui Chen, Apurva S Chitre, William Chow, Vincenza Colonna, Clifton L Dalgard, Wendy M Demos, Peter A Doris, Erik Garrison, Aron M Geurts, Hakan M Gunturkun, Victor Guryev, Thibaut Hourlier, Kerstin Howe, Jun Huang, Ted Kalbfleisch, Panjun Kim, Ling Li, Spencer Mahaffey, Fergal J Martin, Pejman Mohammadi, Ayse Bilge Ozel, Oksana Polesskaya, Michal Pravenec, Pjotr Prins, Jonathan Sebat, Jennifer R Smith, Leah C Solberg Woods, Boris Tabakoff, Alan Tracey, Marcela Uliano-Silva, Flavia Villani, Hongyang Wang, Burt M Sharp, Francesca Telese, Zhihua Jiang, Laura Saba, Xusheng Wang, Terence D Murphy, Abraham A Palmer, Anne E Kwitek, Melinda R Dwinell, Robert W Williams, Jun Z Li, Hao Chen

Faculty, Staff and Student Publications

The seventh iteration of the reference genome assembly for Rattus norvegicus-mRatBN7.2-corrects numerous misplaced segments and reduces base-level errors by approximately 9-fold and increases contiguity by 290-fold compared with its predecessor. Gene annotations are now more complete, improving the mapping precision of genomic, transcriptomic, and proteomics datasets. We jointly analyzed 163 short-read whole-genome sequencing datasets representing 120 laboratory rat strains and substrains using mRatBN7.2. We defined ∼20.0 million sequence variations, of which 18,700 are predicted to potentially impact the function of 6,677 genes. We also generated a new rat genetic map from 1,893 heterogeneous stock rats and annotated transcription start sites …

Reply To Kidd Et Al., “Inconsistencies Within The Proposed Framework For Stabilizing Fungal Nomenclature Risk Further Confusion”, Sybren De Hoog, Thomas J Walsh, Sarah A Ahmed, Ana Alastruey-Izquierdo, Barbara D Alexander, Maiken Cavling Arendrup, Esther Babady, Feng-Yan Bai, Joan-Miquel Balada-Llasat, Andrew Borman, Anuradha Chowdhary, Andrew Clark, Robert C Colgrove, Oliver A Cornely, Tanis C Dingle, Philippe J Dufresne, Jeff Fuller, Jean-Pierre Gangneux, Connie Gibas, Heather Glasgow, Yvonne Graser, Jacques Guillot, Andreas H Groll, Gerhard Haase, Kimberly Hanson, Amanda Harrington, David L Hawksworth, Randall T Hayden, Martin Hoenigl, Vit Hubka, Kristie Johnson, Julianne V Kus, Ruoyu Li, Jacques F Meis, Michaela Lackner, Fanny Lanternier, Sixto M Leal, Francesca Lee, Shawn R Lockhart, Paul Luethy, Isabella Martin, Kyung J Kwon-Chung, Wieland Meyer, M Hong Nguyen, Luis Ostrosky-Zeichner, Elizabeth Palavecino, Preeti Pancholi, Peter G Pappas, Gary W Procop, Scott A Redhead, Daniel D Rhoads, Stefan Riedel, Bryan Stevens, Kaede Ota Sullivan, Paschalis Vergidis, Emmanuel Roilides, Amir Seyedmousavi, Lili Tao, Vania A Vicente, Roxana G Vitale, Qi-Ming Wang, Nancy L Wengenack, Lars Westblade, Nathan Wiederhold, Lewis White, Christina M Wojewoda, Sean X Zhang

Faculty, Staff and Student Publications

No abstract provided.

Synovial Fibroblast Gene Expression Is Associated With Sensory Nerve Growth And Pain In Rheumatoid Arthritis, Zilong Bai, Nicholas Bartelo, Maryam Aslam, Elisabeth A Murphy, Caryn R Hale, Nathalie E Blachere, Salina Parveen, Edoardo Spolaore, Edward Dicarlo, Ellen M Gravallese, Melanie H Smith, Accelerating Medicines Partnership Ra/Sle Network, Mayu O Frank, Caroline S Jiang, Haotan Zhang, Christina Pyrgaki, Myles J Lewis, Shafaq Sikandar, Costantino Pitzalis, Joseph B Lesnak, Khadijah Mazhar, Theodore J Price, Anne-Marie Malfait, Rachel E Miller, Fan Zhang, Susan Goodman, Robert B Darnell, Fei Wang, Dana E Orange

Faculty, Staff and Student Publications

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of …

Patient Characteristics Of, And Remedial Interventions For, Complaints And Medico-Legal Claims Against Doctors: A Rapid Review Of The Literature, Timothy J Schultz, Michael Zhou, Jodi Gray, Jackie Roseleur, Richard Clark, Dylan A Mordaunt, Peter D Hibbert, Georgie Haysom, Michael Wright

Faculty, Staff and Student Publications

BACKGROUND: It is uncertain if patient's characteristics are associated with complaints and claims against doctors. Additionally, evidence for the effectiveness of remedial interventions on rates of complaints and claims against doctors has not been synthesised.

METHODS: We conducted a rapid review of recent literature to answer: Question 1 "What are the common characteristics and circumstances of patients who are most likely to complain or bring a claim about the care they have received from a doctor?" and Question 2 "What initiatives or interventions have been shown to be effective at reducing complaints and claims about the care patients have received …

Wnk Kinase Is A Vasoactive Chloride Sensor In Endothelial Cells, Tessa A C Garrud, Briar Bell, Alejandro Mata-Daboin, Dieniffer Peixoto-Neves, Daniel M Collier, Julio F Cordero-Morales, Jonathan H Jaggar

Faculty, Staff and Student Publications

Endothelial cells (ECs) line the wall of blood vessels and regulate arterial contractility to tune regional organ blood flow and systemic pressure. Chloride (Cl-) is the most abundant anion in ECs and the Cl- sensitive With-No-Lysine (WNK) kinase is expressed in this cell type. Whether intracellular Cl- signaling and WNK kinase regulate EC function to alter arterial contractility is unclear. Here, we tested the hypothesis that intracellular Cl- signaling in ECs regulates arterial contractility and examined the signaling mechanisms involved, including the participation of WNK kinase. Our data obtained using two-photon microscopy and cell-specific inducible knockout mice indicated that acetylcholine, …

Mir-574-5p Activates Human Tlr8 To Promote Autoimmune Signaling And Lupus, Tao Wang, Dan Song, Xuejuan Li, Yu Luo, Dianqiang Yang, Xiaoyan Liu, Xiaodan Kong, Yida Xing, Shulin Bi, Yan Zhang, Tao Hu, Yunyun Zhang, Shuang Dai, Zhiqiang Shao, Dahan Chen, Jinpao Hou, Esteban Ballestar, Jianchun Cai, Feng Zheng, James Y Yang

Faculty, Staff and Student Publications

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling …

Arid1a Orchestrates Swi/Snf-Mediated Sequential Binding Of Transcription Factors With Arid1a Loss Driving Pre-Memory B Cell Fate And Lymphomagenesis, Darko Barisic, Christopher R Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W Scott, Andrew P Weng, Christopher E Mason, Michael R Green, Ari Melnick

Faculty, Staff and Student Publications

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with …

Smarca4 Is A Haploinsufficient B Cell Lymphoma Tumor Suppressor That Fine-Tunes Centrocyte Cell Fate Decisions, Qing Deng, Priya Lakra, Panhong Gou, Haopeng Yang, Cem Meydan, Matthew Teater, Christopher Chin, Wenchao Zhang, Tommy Dinh, Usama Hussein, Xubin Li, Estela Rojas, Weiguang Liu, Patrick K Reville, Atish Kizhakeyil, Darko Barisic, Sydney Parsons, Ashley Wilson, Jared Henderson, Brooks Scull, Channabasavaiah Gurumurthy, Francisco Vega, Amy Chadburn, Branko Cuglievan, Nader Kim El-Mallawany, Carl Allen, Christopher Mason, Ari Melnick, Michael R Green

Faculty, Staff and Student Publications

SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 …

Single-Cell Systems Pharmacology Identifies Development-Driven Drug Response And Combination Therapy In B Cell Acute Lymphoblastic Leukemia, Xin Huang, Yizhen Li, Jingliao Zhang, Lei Yan, Huanbin Zhao, Liang Ding, Sheetal Bhatara, Xu Yang, Satoshi Yoshimura, Wenjian Yang, Seth E Karol, Hiroto Inaba, Charles Mullighan, Mark Litzow, Xiaofan Zhu, Yingchi Zhang, Wendy Stock, Nitin Jain, Elias Jabbour, Steven M Kornblau, Marina Konopleva, Ching-Hon Pui, Elisabeth Paietta, William Evans, Jiyang Yu, Jun J Yang

Faculty, Staff and Student Publications

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By …

Enhanced Plant-Derived Vesicles For Nucleotide Delivery For Cancer Therapy, Sara Corvigno, Yuan Liu, Emine Bayraktar, Elaine Stur, Nazende Nur Bayram, Adrian Lankenau Ahumada, Supriya Nagaraju, Cristian Rodriguez-Aguayo, Hu Chen, Thanh Chung Vu, Yunfei Wen, Han Liang, Li Zhao, Sanghoon Lee, Gabriel Lopez-Berestein, Anil K Sood

Faculty, Staff and Student Publications

Small RNAs (microRNAs [miRNAs] or small interfering RNAs [siRNAs]) are effective tools for cancer therapy, but many of the existing carriers for their delivery are limited by low bioavailability, insufficient loading, impaired transport across biological barriers, and low delivery into the tumor microenvironment. Extracellular vesicle (EV)-based communication in mammalian and plant systems is important for many physiological and pathological processes, and EVs show promise as carriers for RNA interference molecules. However, some fundamental issues limit their use, such as insufficient cargo loading and low potential for scaling production. Plant-derived vesicles (PDVs) are membrane-coated vesicles released in the apoplastic fluid of …

Bi-Directional Neuro-Immune Dysfunction After Chronic Experimental Brain Injury, Rodney M Ritzel, Yun Li, Yun Jiao, Sarah J Doran, Niaz Khan, Rebecca J Henry, Kavitha Brunner, David J Loane, Alan I Faden, Gregory L Szeto, Junfang Wu

Faculty, Staff and Student Publications

Background

It is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function and that systemic immune changes contribute to posttraumatic neuroinflammation and neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically and to what extent such changes may negatively impact innate immunity and neurological function has not been examined.

Methods

To further understand the role of BM cell derivatives on TBI outcome, we generated BM chimeric mice by transplanting BM from chronically injured or sham (i.e., 90 days post-surgery) congenic donor mice into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) …

First-In-Human Phase I Study Of Tinengotinib (Tt-00420), A Multiple Kinase Inhibitor, As A Single Agent In Patients With Advanced Solid Tumors, Sarina A Piha-Paul, Binghe Xu, Ecaterina E Dumbrava, Siqing Fu, Daniel D Karp, Funda Meric-Bernstam, David S Hong, Jordi A Rodon, Apostolia M Tsimberidou, Kanwal Raghav, Jaffer A Ajani, Anthony P Conley, Frank Mott, Ying Fan, Jean Fan, Peng Peng, Hui Wang, Shumao Ni, Caixia Sun, Xiaoyan Qiang, Wendy J Levin, Brenda Ngo, Qinhua Cindy Ru, Frank Wu, Milind M Javle

Faculty, Staff and Student Publications

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy.

RESULTS: Forty-eight patients were enrolled (dose escalation, …

Nodal Variants Are Associated With A Continuum Of Laterality Defects From Simple D-Transposition Of The Great Arteries To Heterotaxy, Zain Dardas, Jawid M Fatih, Angad Jolly, Moez Dawood, Haowei Du, Christopher M Grochowski, Edward G Jones, Shalini N Jhangiani, Xander H T Wehrens, Pengfei Liu, Weimin Bi, Eric Boerwinkle, Jennifer E Posey, Donna M Muzny, Richard A Gibbs, James R Lupski, Zeynep Coban-Akdemir, Shaine A Morris

Faculty, Staff and Student Publications

BACKGROUND: NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects.

METHODS: We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with …

Peritoneal Microenvironment Promotes Appendiceal Adenocarcinoma Growth: A Multi-Omics Approach Using Patient-Derived Xenografts, Vinay K Pattalachinti, Ichiaki Ito, Saikat Chowdhury, Abdelrahman Yousef, Yue Gu, Betul Beyza Gunes, Emma R Salle, Melissa W Taggart, Keith Fournier, Natalie W Fowlkes, John Paul Shen

Faculty, Staff and Student Publications

Appendiceal adenocarcinoma (AA) is unique from other gastrointestinal malignancies in that it almost exclusively metastasizes to the peritoneal cavity. However, few studies have investigated the molecular interaction of the peritoneal microenvironment and AA. Here, we use a multi-omics approach with orthotopic and flank-implanted patient-derived xenografts (PDX) to study the effect of the peritoneal microenvironment on AA. AA tumors implanted in the peritoneal microenvironment tended to grow faster and displayed greater nuclear expression of Ki-67 relative to the same tumors implanted in the flank. Comparing the tumor-specific transcriptome (excluding stromal transcription), the peritoneal microenvironment relatively upregulated genes related to proliferation, including …

Neutrophil Elastase Remodels Mammary Tumors To Facilitate Lung Metastasis, Amriti R Lulla, Said Akli, Cansu Karakas, Joseph A Caruso, Lucas D Warma, Natalie W Fowlkes, Xiayu Rao, Jing Wang, Kelly K Hunt, Stephanie S Watowich, Khandan Keyomarsi

Faculty, Staff and Student Publications

Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways …

Antigen-Clustered Nanovaccine Achieves Long-Term Tumor Remission By Promoting B/Cd 4 T Cell Crosstalk, Chengyi Li, Ryan Clauson, Luke F Bugada, Fang Ke, Bing He, Zhixin Yu, Hongwei Chen, Binyamin Jacobovitz, Hongxiang Hu, Polina Chuikov, Brett Dallas Hill, Syed M Rizvi, Yudong Song, Kai Sun, Pasieka Axenov, Daniel Huynh, Xinyi Wang, Lana Garmire, Yu Leo Lei, Irina Grigorova, Fei Wen, Marilia Cascalho, Wei Gao, Duxin Sun

Faculty, Staff and Student Publications

Current cancer vaccines using T cell epitopes activate antitumor T cell immunity through dendritic cell/macrophage-mediated antigen presentation, but they lack the ability to promote B/CD4 T cell crosstalk, limiting their anticancer efficacy. We developed antigen-clustered nanovaccine (ACNVax) to achieve long-term tumor remission by promoting B/CD4 T cell crosstalk. The topographic features of ACNVax were achieved using an iron nanoparticle core attached with an optimal number of gold nanoparticles, where the clusters of HER2 B/CD4 T cell epitopes were conjugated on the gold surface with an optimal intercluster distance of 5-10 nm. ACNVax effectively trafficked to lymph nodes and cross-linked with …

Targeting Branched N-Glycans And Fucosylation Sensitizes Ovarian Tumors To Immune Checkpoint Blockade, Hao Nie, Pratima Saini, Taito Miyamoto, Liping Liao, Rafal J Zielinski, Heng Liu, Wei Zhou, Chen Wang, Brennah Murphy, Martina Towers, Tyler Yang, Yuan Qi, Toshitha Kannan, Andrew Kossenkov, Hiroaki Tateno, Daniel T Claiborne, Nan Zhang, Mohamed Abdel-Mohsen, Rugang Zhang

Faculty, Staff and Student Publications

Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their …

Analyzing Pelvic Asymmetry By Sex And Ancestry: Insights From An Osteological Collection, Bryan O Ren, Robert W Goldberg, Karen D Standefer, Jason R Teplensky, Joseph P Drain, Conor F Mccarthy, John G Birch, Raymond W Liu

Faculty, Staff and Student Publications

Introduction: Pelvic asymmetry has been noted in pelvic imaging, and might influence the development of various spinal pathologies, most notably scoliosis. There is a limited understanding of the relationship between pelvic asymmetry and sex and ancestry, and limited use of 3D modeling. The purpose of this study was to identify pelvic asymmetry and morphology differences between sex and ancestry utilizing 3D modeling on young adults in an osteological collection.

Methods: Thirty-three osteological pelvic specimens aged 18-25 years (average age 21.4 ± 2.0 years) were scanned to create virtual 3D models for analysis. Pelvic asymmetry and morphology were measured and compared …

Robust Capital Cost Optimization Of Generation And Multitimescale Storage Requirements For A 100% Renewable Australian Electricity Grid, Raheel A Shaikh, David J Vowles, Alex Dinovitser, Andrew Allison, Derek Abbott

Faculty, Staff and Student Publications

Transitioning from a fossil-fuel-dependent economy to one based on renewable energy requires significant investment and technological advancement. While wind and solar technologies provide lower cost electricity, enhanced energy storage and transmission infrastructure come at a cost for managing renewable intermittency. Energy storage systems vary in characteristics and costs, and future grids will incorporate multiple technologies, yet the optimal combination of storage technologies and the role of interconnectors in alleviating storage needs are not widely explored. This study focuses on optimal generation-storage capacity requirements to elucidate associated investments. We propose a multitimescale storage solution consisting of three storage categories and an …

Population Coding Of Strategic Variables During Foraging In Freely Moving Macaques, Neda Shahidi, Melissa Franch, Arun Parajuli, Paul Schrater, Anthony Wright, Xaq Pitkow, Valentin Dragoi

Faculty, Staff and Student Publications

Until now, it has been difficult to examine the neural bases of foraging in naturalistic environments because previous approaches have relied on restrained animals performing trial-based foraging tasks. Here we allowed unrestrained monkeys to freely interact with concurrent reward options while we wirelessly recorded population activity in the dorsolateral prefrontal cortex. The animals decided when and where to forage based on whether their prediction of reward was fulfilled or violated. This prediction was not solely based on a history of reward delivery, but also on the understanding that waiting longer improves the chance of reward. The task variables were continuously …

Intraprocedural Versus Initial Follow-Up Minimal Ablative Margin Assessment After Colorectal Liver Metastasis Thermal Ablation: Which One Better Predicts Local Outcomes?, Yuan-Mao Lin, Iwan Paolucci, Jessica Albuquerque Marques Silva, Caleb S O'Connor, Bryan M Fellman, Aaron K Jones, Joshua D Kuban, Steven Y Huang, Zeyad A Metwalli, Kristy K Brock, Bruno C Odisio

Faculty, Staff and Student Publications

Objectives: The aim of this study was to investigate the prognostic value of 3-dimensional minimal ablative margin (MAM) quantified by intraprocedural versus initial follow-up computed tomography (CT) in predicting local tumor progression (LTP) after colorectal liver metastasis (CLM) thermal ablation.

Materials and methods: This single-institution, patient-clustered, tumor-based retrospective study included patients undergoing microwave and radiofrequency ablation between 2016 and 2021. Patients without intraprocedural and initial follow-up contrast-enhanced CT, residual tumors, or with follow-up less than 1 year without LTP were excluded. Minimal ablative margin was quantified by a biomechanical deformable image registration method with segmentations of CLMs on intraprocedural preablation …

C2h2 Zinc Finger Transcription Factors Associated With Hemoglobinopathies, Xing Zhang, Fangfang Xia, Xiaotian Zhang, Robert M Blumenthal, Xiaodong Cheng

Faculty, Staff and Student Publications

In humans, specific aberrations in β-globin results in sickle cell disease and β-thalassemia, symptoms of which can be ameliorated by increased expression of fetal globin (HbF). Two recent CRISPR-Cas9 screens, centered on ∼1500 annotated sequence-specific DNA binding proteins and performed in a human erythroid cell line that expresses adult hemoglobin, uncovered four groups of candidate regulators of HbF gene expression. They are (1) members of the nucleosome remodeling and deacetylase (NuRD) complex proteins that are already known for HbF control; (2) seven C2H2 zinc finger (ZF) proteins, including some (ZBTB7A and BCL11A) already known for directly silencing the fetal γ-globin …

Mitochondrial Regulation Of Gpx4 Inhibition-Mediated Ferroptosis In Acute Myeloid Leukemia, Hiroki Akiyama, Ran Zhao, Lauren B Ostermann, Ziyi Li, Matthew Tcheng, Samar J Yazdani, Arman Moayed, Malcolm L Pryor, Sandeep Slngh, Natalia Baran, Edward Ayoub, Yuki Nishida, Po Yee Mak, Vivian R Ruvolo, Bing Z Carter, Aaron D Schimmer, Michael Andreeff, Jo Ishizawa

Faculty, Staff and Student Publications

Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q