Medical Specialties Commons^™

Machine-Learning Driven Strategies For Adapting Immunotherapy In Metastatic Nsclc, Maliazurina B Saad, Qasem Al-Tashi, Lingzhi Hong, Vivek Verma, Wentao Li, Daniel Boiarsky, Shenduo Li, Milena Petranovic, Carol C Wu, Brett W Carter, Girish S Shroff, Tina Cascone, Xiuning Le, Yasir Y Elamin, Mehmet Altan, Simon Heeke, Ajay Sheshadri, Joe Y Chang, Percy P Lee, Zhongxing Liao, Don L Gibbons, Ara A Vaporciyan, J Jack Lee, Ignacio I Wistuba, Cara Haymaker, Seyedali Mirjalili, David Jaffray, Justin F Gainor, Yanyan Lou, Alessandro Di Federico, Federica Pecci, Mark Awad, Biagio Ricciuti, John V Heymach, Natalie I Vokes, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs), either as monotherapy (ICI-Mono) or combined with chemotherapy (ICI-Chemo), improves survival in advanced non-small cell lung cancer (NSCLC). However, prospective guidance for choosing between these options remains limited, and single-feature biomarkers like PD-L1 prove inadequate. We develop a machine learning model using clinicogenomic data from four cohorts (MD Anderson n = 750; Mayo Clinic n = 80; Dana-Farber n = 1077; Stand Up To Cancer n = 393) to predict individual benefit from adding chemotherapy. Benefit scores are calculated using five distinct functions derived from 28 genomic and 6 clinical features. Our integrated model, A-STEP (Attention-based …

The Histone H3 Lysine 36 Demethylase Kdm2a/Fbxl11 Controls Polycomb-Mediated Gene Repression And Germ Cell Development In Male Mice, Michael T Bocker, Grigorios Fanourgakis, Kristie Wetzel, Pavel A Komarov, Hélène Royo, Alexia Rohmer, Sunwoo Chun, Ching-Yeu Liang, Hubertus Kohler, Taiping Chen, Xiaohong Mao, Mark A Labow, Reginald A Valdez, Michael B Stadler, Dirk G De Rooij, Paola Capodieci, John Tallarico, Antoine H F M Peters, Thomas B Nicholson

Faculty, Staff and Student Publications

KDM2A/FBXL11 is a Jumonji-domain containing lysine demethylase catalyzing the removal of mono- and di-methyl modifications of histone H3 lysine 36 (H3K36me1/2). While Kdm2a is required for mouse embryogenesis, its role in adult physiology has been largely unexplored. Using conditional deletion approaches, we demonstrate that Kdm2a deficiency leads to testicular atrophy and male infertility. Although spermatogonial stem cells remain unaffected, proliferating and differentiating spermatogonia exhibit delayed cell cycle progression and apoptosis. RNA-sequencing of purified spermatogonia and spermatocytes reveals Kdm2a-dependent repression of over 750 genes during spermatogonial differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrates increased H3K36me2 levels at CpG-rich gene promoters …

The Microtubule-Severing Enzyme Spastin Regulates Spindle Dynamics To Promote Chromosome Segregation In Trypanosoma Brucei, Thiago Souza Onofre, Qing Zhou, Ziyin Li

Faculty, Staff and Student Publications

Microtubule-severing enzymes play essential roles in diverse cellular processes, including mitosis and cytokinesis, by modulating microtubule dynamics. In the early branching Trypanosoma brucei, microtubule-severing enzymes are involved in cytokinesis and flagellum length control, but none of them have been found to regulate mitosis. Here we report the characterization of the microtubule-severing enzyme spastin in the procyclic form of T. brucei. We demonstrate that spastin severs microtubule in vitro and overexpression of spastin disrupts spindle microtubules in vivo in trypanosomes, leading to defective chromosome segregation. Knockdown of spastin impairs spindle integrity and disrupts chromosome alignment and segregation. We further show that …

Timing Of Nodal Metastasis In Patients With Eyelid Sebaceous Carcinoma And Implications For Surveillance And Survival, Tracy Lu, Casey Anthony, Xinyang Jiang, Jing Ning, Ryan Goepfert, Bita Esmaeli

Faculty, Staff and Student Publications

Background/aims: Sebaceous carcinoma (SC) is a rare cancer with periocular predilection. Studies focused on patterns and timing of nodal metastasis are scarce.Our aim is to report patterns of regional nodal metastasis in patients with eyelid SC, including results of sentinel lymph node biopsy (SLNB).

Methods: All consecutive patients with eyelid SC treated during 1999-2023 were retrospectively reviewed.All subjects had standard of care surgery for eyelid SC and regional lymph node evaluation using physical examination and ultrasonography (US) at baseline and during the surveillance period. 38 patients with negative findings on US had SLNB to rule out microscopic metastasis.The frequency and …

An Alternative Neural Basis Underlying Leptin Resistance, Hongli Li, Cunjin Su, Yuanzhong Xu, Mette Q Ludwig, Jon Davis, Qingchun Tong

Faculty, Staff and Student Publications

Overconsumption of a palatable Western diet, a condition linked to central leptin resistance, contributes extensively to the current obesity epidemic. In this context, intensive efforts have focused on detailing the molecular mechanisms underlying leptin resistance. Here, we demonstrate that chronic inhibition of hypothalamic arcuate GABAergic neurons (ArcGABA) effectively reduced diet-induced obesity (DIO). Interestingly, palatable food exposure increased the activity level of ArcGABA neurons, which do not express the leptin receptor (non-LepR neurons; nonresponsive to leptin). Chronic activation of ArcGABA non-LepR neurons led to massive obesity, which was associated with normal leptin-induced pSTAT3 signaling but phenotypic leptin resistance; i.e., high leptin …

Longitudinal Analysis Of Gut Microbiome And Metabolome Correlates Of Response And Toxicity With Idecabtagene Vicleucel, Satabdi Saha, Lubna Rehman, Abdur Rehman, Faezeh Darbaniyan, Donna M Weber, Melody Becnel, Mahmoud Gaballa, Sheeba K Thomas, Hans C Lee, Chia-Chi Chang, Reetakshi Arora, Meghan Menges, Salvatore Corallo, Marco L Davila, Frederick L Locke, Mark R Tanner, Sattva S Neelapu, Elizabeth J Shpall, Christopher R Flowers, Robert Z Orlowski, Robert R Jenq, Michael D Jain, Christine Peterson, Doris K Hansen, Neeraj Y Saini, Krina K Patel

Faculty, Staff and Student Publications

Increasing evidence suggests that the gut microbiome may influence the responses and toxicities associated with chimeric antigen receptor T-cell (CAR-T) therapy. We conducted whole-genome shotgun sequencing on stool samples (N = 117) collected at various times from patients with multiple myeloma (n = 33) who underwent idecabtagene vicleucel (ide-cel) anti-B-cell maturation antigen CAR-T therapy. We observed a significant decrease in bacterial diversity after ide-cel infusion, along with significant differences in the bacterial composition linked to therapy response and toxicities. Specifically, we found significant enrichment of Flavonifractor plautii, Bacteroides thetaiotaomicron, Blautia fecis, and Dysosmobacter species in ide-cel responders. A notable finding …

Belumosudil Reduces Oral Chronic Graft-Versus-Host Disease Tissue Inflammation And Fibrosis: A Rockstar Companion Study, Rubina Sharma, Noa G Holtzman, Iskra Pusic, Corey Cutler, Nathaniel Treister, Rohtesh S Mehta, Amin S Alousi, Nadarajah Vigneswaran, Ayesha Javaid, Francis Boksa, Drashty P Mody, Ana C Costa-Da-Silva, Olivier Schueller, Sandrine Macé, Yu Yao, Ran Ji, Beifang Hu, Kathy Marshall, Bruce R Blazar, Stephanie J Lee, Steven Z Pavletic, Jacqueline W Mays

Faculty, Staff and Student Publications

Belumosudil (KD025), an oral, selective, Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) inhibitor, is approved for third-line treatment of chronic graft-versus-host disease (cGVHD). Previous studies demonstrated that ROCK2 inhibition reduces blood interleukin-17 (IL-17) activity and promotes regulatory T-cell (Treg cell) recovery. However, these studies did not evaluate immune responses within cGVHD-affected tissues. This study assessed tissue-level immune dynamics in 20 patients with oral cGVHD from the phase 2 ROCKstar trial, before and after 6 months of belumosudil treatment, focusing on key effector sites (oral mucosa [OM], minor salivary glands [MSGs], and skin) and the peripheral blood. After belumosudil treatment, reduction in …

Detection Of Oncogenic Fusions In Colorectal Cancer Using A Partner-Agnostic Next-Generation Sequencing Approach, Andrew J Pellatt, Reagan M Barnett, Sante Gnerre, Kristin Edwards, Jason A Willis, Michael J Overmann, Kanwal Raghav, Christine M Parseghian, Arvind Dasari, M Pia Morelli, Alisha Bent, Madhulika Eluri, Nicholas Hornstein, Leylah M Drusbosky, Scott Kopetz, Van K Morris

Faculty, Staff and Student Publications

Background: Gene fusions exist with low prevalence in colorectal cancer (CRC), and the clinical utility of fusion testing in advanced CRC remains unclear. We sought to identify oncogenic fusions in patients with advanced CRC using a fusion partner-agnostic circulating tumor DNA (ctDNA) assay to better understand their clinical relevance.

Methods: We performed a retrospective analysis using de-identified data from 18,558 patients with advanced CRC who underwent ctDNA next-generation sequencing with Guardant360® from 2017 to 2022. These samples were subsequently reanalyzed with a partner-agnostic bioinformatics method to identify both clonal and non-clonal fusions. We analyzed for associations between fusions and MSI-H …

Image-Based Inference Of Tumor Cell Trajectories Enables Large-Scale Cancer Progression Analysis, Yang Liu, Ling Cai, Ruichen Rong, Shidan Wang, Liwei Jia, Peiran Quan, Qin Zhou, Guanghua Xiao, Yang Xie

Faculty, Staff and Student Publications

Current approaches to estimating cell trajectories, tumor progression dynamics, and cell population diversity of tumor microenvironment often depend on single-cell RNA sequencing, which is costly and resource intensive. To address this limitation, we developed an artificial intelligence (AI) model that leverages cell morphology features and histological spatial organization to classify tumor cell differentiation status, infer cell dynamic trajectories, and quantify tumor progression from hematoxylin and eosin (H&E)-stained whole-slide images. In three independent lung adenocarcinoma cohorts, our AI-based model accurately predicted cell differential status and provided quantifiable measures of tumor progression that were prognostic of patient survival. Spatial transcriptomic integrative analyses …

A Two-Stage Dual-Task Learning Strategy For Early Prediction Of Pathological Complete Response To Neoadjuvant Chemotherapy For Breast Cancer Using Dynamic Contrast-Enhanced Magnetic Resonance Images, Bowen Jing, Jing Wang

Faculty, Staff and Student Publications

Early prediction of treatment response can facilitate personalized treatment for breast cancer patients. Studies on the I-SPY 2 clinical trial demonstrate that multi-time point dynamic contrast-enhanced magnetic resonance (DCEMR) imaging improves the accuracy of predicting pathological complete response (pCR) to chemotherapy. However, previous image-based prediction models usually rely on mid- or post-treatment images to ensure the accuracy of prediction, which may outweigh the benefit of response-based adaptive treatment strategy. Accurately predicting the pCR at the early time point is desired yet remains challenging. To improve prediction accuracy at the early time point of treatment, we proposed a two-stage dual-task learning …

Truncated Ntrk2 Is Induced In Cap1 Endothelial Cells During Mouse Lung Injury-Repair, Celine Shuet Lin Kong, Mitheera V, Jezreel Pantaleón-García, Scott E Evans, Jichao Chen

Faculty, Staff and Student Publications

Pulmonary capillary endothelial cells (ECs) consist of two populations, CAP1 and CAP2; how each population reacts to diverse tissue injury is incompletely understood. Using single-cell multiome and mouse genetics, we characterize the induction and function of a truncated isoform of Ntrk2, Ntrk2-T1, in multiple lung injury models. Upon Sendai parainfluenza infection, Ntrk2-T1 is broadly induced in CAP1s after the initial interferon response, associated with increased intronic chromatin accessibility, and persists for weeks. Ntrk2-T1 ECs arise from CAP1s but not CAP2s-traced by

Ifn-Β Production Promotes Metabolic Rewiring And Protection Against Oxidative Stress In Hepatitis Delta Virus-Infected Hepatocyte Cultures, Olga A Khomich, Patrick Giavalisco, Romain Parent, George S Krasnov, Peter Tessarz, Philip Meuleman, Rani Burm, Natalia F Zakirova, Jennifer Molle, Enkhtuul Batbold, Eyal Gottlieb, Fabien Zoulim, Alexander V Ivanov, Birke Bartosch

Faculty, Staff and Student Publications

Type I interferons are secreted in response to various stimuli and are used as a treatment for many diseases, including infections with the hepatitis B virus (HBV) and its satellite virus, hepatitis delta (HDV). HDV significantly aggravates HBV-mediated liver damage and is - in contrast to HBV - a strong inducer of interferon responses, including IFN-β. As the role of IFN- β in liver metabolism is so far ill explored, we studied its impact on hepatocyte metabolism in HDV-infected cultures. Transcriptome analysis, isotope tracing and functional tests on differentiated, HDV-infected hepatocytes showed reduction of mitochondrial TCA cycle and respiratory activity …

Nrg Oncology Liver Proton Sbrt And Hypofractionated Radiation Therapy: Current Treatment Technical Assessment And Practice Patterns, Minglei Kang, Paige A Taylor, Jiajian Shen, Jun Zhou, Jatinder Saini, Theodore S Hong, Kristin Higgins, Wei Liu, Ying Xiao, Charles B Simone, Liyong Lin

Faculty, Staff and Student Publications

No abstract provided.

Efficacy Of A Novel Bcl-Xl Degrader, Dt2216, In Preclinical Models Of Jak2-Mutated Post-Mpn Aml, Zhe Wang, Anna Skwarska, Gowri Poigaialwar, Sovira Chaudhry, Alba Rodriguez-Meira, Pinpin Sui, Emmanuel Olivier, Yannan Jia, Varun Gupta, Warren Fiskus, Cassandra L Ramage, Guangrong Zheng, Alexandra Schurer, Kira Gritsman, Eirini P Papapetrou, Kapil Bhalla, Daohong Zhou, Adam J Mead, Raajit K Rampal, Jeffrey W Tyner, Hussein A Abbas, Naveen Pemmaraju, Qi Zhang Tatarata, Marina Konopleva

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments do not significantly extend survival beyond 12 months. B-cell lymphoma-extra large (BCL-xL) has been found to be overexpressed in leucocytes from patients with MPN, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera, in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in patients with post-MPN AML than in those with de novo AML. Single-cell multiomics …

Facts And Hopes: Toward The Next Quantum Leap In Melanoma, Keith T Flaherty, Andrew E Aplin, Michael A Davies, Nir Hacohen, Meenhard Herlyn, Dave Hoon, Patrick Hwu, Michal Lotem, James Mulé, Jennifer A Wargo, David E Fisher

Faculty, Staff and Student Publications

Outcomes from advanced melanoma, the deadliest of the skin cancers arising from melanocytes and capable of widely metastasizing, have greatly improved, with death rates decreasing for patients with American Joint Committee on Cancer stage 4 melanoma by 3% to 5% annually over the past 10 years. This improvement is a result of advances in both targeted therapy and immunotherapy. BRAF and MEK inhibitors for advanced melanoma have led the way for targeted cancer strategies and first-in-class approvals for immune checkpoint blockers targeting CTLA4, PD-1, and LAG3; T-cell engager therapy targeting the antigen gp100; and tumor-infiltrating lymphocyte therapy. All of these …

Technology Roadmap Of Micro/Nanorobots, Xiaohui Ju, Chuanrui Chen, Cagatay M Oral, Semih Sevim, Ramin Golestanian, Mengmeng Sun, Negin Bouzari, Xiankun Lin, Mario Urso, Jong Seok Nam, Yujang Cho, Xia Peng, Fabian C Landers, Shihao Yang, Azin Adibi, Nahid Taz, Raphael Wittkowski, Daniel Ahmed, Wei Wang, Veronika Magdanz, Mariana Medina-Sánchez, Maria Guix, Naimat Bari, Bahareh Behkam, Raymond Kapral, Yaxin Huang, Jinyao Tang, Ben Wang, Konstantin Morozov, Alexander Leshansky, Sarmad Ahmad Abbasi, Hongsoo Choi, Subhadip Ghosh, Bárbara Borges Fernandes, Giuseppe Battaglia, Peer Fischer, Ambarish Ghosh, Beatriz Jurado Sánchez, Alberto Escarpa, Quentin Martinet, Jérémie Palacci, Eric Lauga, Jeffrey Moran, Miguel A Ramos-Docampo, Brigitte Städler, Ramón Santiago Herrera Restrepo, Gilad Yossifon, James D Nicholas, Jordi Ignés-Mullol, Josep Puigmartí-Luis, Yutong Liu, Lauren D Zarzar, C Wyatt Shields, Longqiu Li, Shanshan Li, Xing Ma, David H Gracias, Orlin Velev, Samuel Sánchez, Maria Jose Esplandiu, Juliane Simmchen, Antonio Lobosco, Sarthak Misra, Zhiguang Wu, Jinxing Li, Alexander Kuhn, Amir Nourhani, Tijana Maric, Ze Xiong, Amirreza Aghakhani, Yongfeng Mei, Yingfeng Tu, Fei Peng, Eric Diller, Mahmut Selman Sakar, Ayusman Sen, Junhui Law, Yu Sun, Abdon Pena-Francesch, Katherine Villa, Huaizhi Li, Donglei Emma Fan, Kang Liang, Tony Jun Huang, Xiang-Zhong Chen, Songsong Tang, Xueji Zhang, Jizhai Cui, Hong Wang, Wei Gao, Vineeth Kumar Bandari, Oliver G Schmidt, Xianghua Wu, Jianguo Guan, Metin Sitti, Bradley J Nelson, Salvador Pané, Li Zhang, Hamed Shahsavan, Qiang He, Il-Doo Kim, Joseph Wang, Martin Pumera

Faculty, Staff and Student Publications

Inspired by Richard Feynman’s 1959 lecture and the 1966 film Fantastic Voyage, the field of micro/nanorobots has evolved from science fiction to reality, with significant advancements in biomedical and environmental applications. Despite the rapid progress, the deployment of functional micro/nanorobots remains limited. This review of the technology roadmap identifies key challenges hindering their widespread use, focusing on propulsion mechanisms, fundamental theoretical aspects, collective behavior, material design, and embodied intelligence. We explore the current state of micro/nanorobot technology, with an emphasis on applications in biomedicine, environmental remediation, analytical sensing, and other industrial technological aspects. Additionally, we analyze issues related to …

The Integrated Stress Response Pathway Coordinates Translational Control Of Multiple Immune Checkpoints In Lung Cancer, Shayna Thomas-Jardin, Shruthy Suresh, Ariana Arce, Nicole Novaresi, Qing Deng, Emily Stein, Lisa Thomas, Cheryl Lewis, Chul Ahn, Bret M Evers, Esra A Akbay, Maria E Salvatierra, Wei Lu, Khaja Khan, Luisa M Solis Soto, Ignacio I Wistuba, John D Minna, Kathryn A O'Donnell

Faculty, Staff and Student Publications

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces PD-L1, leading to suppression of antitumor immunity. In this study, we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. The ISR coordinately induced cluster of differentiation 155 (CD155) and PD-L1, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames in their 5' untranslated regions. Analysis of primary human lung tumors identified a significant correlation between expression of PD-L1 and …

Ctdna Analysis In Erbb2-Amplified Colorectal Cancer: Biomarker Analysis Of The Mypathway Trial, Funda Meric-Bernstam, Kanwal Pratap Singh Raghav, Christopher J Sweeney, Charles Swanton, David R Spigel, Ron Bose, Howard A Burris, Claire F Friedman, Carin R Espenschied, Jessica M Grindheim, Julia Malato, Katja Schulze, Richard Price, Razelle Kurzrock

Faculty, Staff and Student Publications

Purpose: A combination of two HER2-directed antibodies, pertuzumab and trastuzumab (P + T), has antitumor activity in HER2-positive colorectal cancer. Although liquid biopsies are increasingly being used in clinical oncology, the association between tumor and ctDNA ERBB2 status and ctDNA monitoring for early response and resistance are unknown.

Patients and methods: Eighty-five patients with ERBB2-amplified and/or -overexpressed colorectal cancer were treated with P + T in the MyPathway trial; 42 had ctDNA testing at cycle (C) 1 day (D) 1, and 38 had longitudinal plasma tested for ctDNA. We analyzed the ctDNA versus tissue ERBB2 concordance, genomic co-alterations, and ctDNA …

Met Pathway Inhibition Increases Chemo-Immunotherapy Efficacy In Small Cell Lung Cancer, Raúl Del Rey-Vergara, Miguel Alejandro Galindo-Campos, Pedro Rocha, Marina Carpes, Carlos Martínez, Laura Masfarré, Silvia Menéndez, Fabricio Quimis, Adrià Rossell, Albert Iñañez, Sandra Pérez-Buira, Federico Rojo, Ramon Gimeno, Dolores Isla, Jon Zugazagoitia, Cristina Martí Blanco, Rosario García-Campelo, Alberto Moreno-Vega, Luis León-Mateos, Ángel Callejo Mellén, Kwon-Sik Park, Simon Heeke, John V Heymach, Álvaro Taus, Luis Paz-Ares, Ana Rovira, Edurne Arriola

Faculty, Staff and Student Publications

The introduction of immunotherapy as a first-line treatment for advanced small cell lung cancer (SCLC) represents significant progress, yet there remains an opportunity to further improve patient outcomes. Hepatocyte growth factor (HGF) receptor (MET) pathway activation promotes epithelial-mesenchymal transition, driving chemoresistance and potentially impairing the efficacy of immunotherapy. In SCLC mouse models, adding MET inhibition to chemo-immunotherapy (anti-PD-L1) reduces tumor growth, extends survival, and reshapes the tumor microenvironment by decreasing suppressive myeloid cell infiltration and enhancing the immune response. Analysis of pretreatment human SCLC tumor samples reveals that myeloid-enriched immune infiltrates may contribute to chemo-immunotherapy resistance. Elevated serum HGF levels …

Synergistic Activity Of Combined Flt3-Itd And Mdm2 Inhibition With Quizartinib And Milademetan In Flt3-Itd Mutant/Tp53 Wild-Type Acute Myeloid Leukemias, Weiguo Zhang, Li Li, Muharrem Muftuoglu, Mahesh Basyal, Noriko Togashi, Koichi Iwanaga, Fumie Tanzawa, Masashi Numata, Dale L Bixby, Harry P Erba, Nikolai Podoltsev, Gary J Schiller, Prasanna Kumar, Arnaud Lesegretain, Takeshi Isoyama, Takahiko Seki, Naval Daver, Michael Andreeff

Faculty, Staff and Student Publications

Purpose: Acute myeloid leukemia (AML) is characterized by frequent mutations in FMS-like tyrosine kinase 3 (FLT3), overexpression of murine double minute 2 (MDM2), and TP53 wild-type (WT). Monotherapies targeting FLT3 frequently result in the development of resistant disease. In this study, we investigated the antileukemic efficacy of co-targeting FLT3 and MDM2 with quizartinib and milademetan (Q/M) in FLT3 internal tandem duplication (FLT3-ITD) AML cell lines, xenograft and patient-derived xenograft (PDX) models, and a phase I clinical trial.

Experimental design: Preclinical studies used human and murine cell lines carrying FLT3-ITD and/or tyrosine kinase domain mutations, TP53 WT/knockdown, leukemia cell xenograft models, …

Targeting The Cd40 Costimulatory Receptor To Improve Virotherapy Efficacy In Diffuse Midline Gliomas, Sara Labiano, Javier Marco-Sanz, Iker Ausejo-Mauleon, Virginia Laspidea, Reyes Hernández-Osuna, Marc Garcia-Moure, Daniel De La Nava, Sara Nuin, Marisol Gonzalez-Huarriz, Timothy N Phoenix, Ibon Tamayo, Marta Zalacain, Andrea Lacalle, Lucía Marrodan, Montserrat Puigdelloses, Irati Hervás-Corpión, Maria C Ochoa, Noelia Casares, Oren J Becher, Candelaria Gomez-Manzano, Juan Fueyo, Jaime Gallego Perez-Larraya, Ana Patiño-Garcia, Marta M Alonso

Faculty, Staff and Student Publications

Diffuse midline glioma (DMG) is a devastating pediatric brain tumor. The oncolytic adenovirus Delta-24-RGD has shown promising efficacy and safety in DMG patients but is not yet curative. Thus, we hypothesized that activating dendritic cells (DCs) through the CD40 costimulatory receptor could increase antigen presentation and enhance the anti-tumor effect of the virus, resulting in long-term responses. This study shows that the intratumoral co-administration of Delta-24-RGD and a CD40 agonistic antibody is well tolerated and induces long-term anti-tumor immunity, including complete responses (up to 40%) in DMG preclinical models. Mechanistic studies revealed that this therapy increased tumor-proliferating T lymphocytes and …

Antitumor Efficacy Of Intermittent Low-Dose Erlotinib Plus Sulindac Via Mhc Upregulation And Remodeling Of The Immune Cell Niche, Chakrapani Tripathi, Jorge E Tovar Perez, Sabeeta Kapoor, Ahmed Muhsin, Wan Mohaiza Dashwood, Yunus Demirhan, Melek Demirhan, Alessandro Shapiro, Altaf Mohammed, Shizuko Sei, Jacklyn Thompson, Mahira Zaheer, Krishna M Sinha, Powel H Brown, Michelle I Savage, Eduardo Vilar, Praveen Rajendran, Roderick H Dashwood

Faculty, Staff and Student Publications

A previously reported clinical trial in familial adenomatous polyposis (FAP) patients treated with erlotinib plus sulindac (ERL + SUL) highlighted immune response/interferon-γ signaling as a key pathway. In this study, we combine intermittent low-dose ERL ± SUL treatment in the polyposis in rat colon (Pirc) model with mechanistic studies on tumor-associated immune modulation. At clinically relevant doses, short-term (16 weeks) and long-term (46 weeks) ERL ± SUL administration results in near-complete tumor suppression in Pirc colon and duodenum (p < 0.0001). We identify a low-dose threshold for significant antitumor activity in Pirc rats given SUL at 125 ppm in the diet plus ERL at 5 mg/kg body weight via twice-weekly oral gavage (SUL125 + ERL5 × 2). Longitudinal analyses show diminished expression of MHC class I and II genes in polyps larger than Grade 5, a novel finding in the Pirc model. Treatment with ERL ± SUL upregulates the corresponding MHC and immune-associated factors in a subset of Pirc colon polyps, Pirc tumor cell lines, murine colon carcinoma cells, and FAP patient-derived organoids, with Nlrc5 playing a critical role in this effect. Imaging mass cytometry reveals that SUL125 + ERL5 × 2 increases tumor-associated Cd4+ T cells by ~2.6-fold (p < 0.05), with no apparent effect on Cd8+ T cells. The treatment also increases tumor-associated Cd68+ cells (p < 0.05) and decreases Foxp3+ (p < 0.01) and Arg1+ (p < 0.05) cells. Thus, intermittent low-dose ERL + SUL treatment enhances tumor-associated MHC expression and remodels the immune cell niche toward a more permissive "helper" immune microenvironment. We conclude that early immune-interception strategies targeting interferon-γ signaling may benefit FAP patients at drug doses below the clinical standard of care.

Sensory Neuron-Expressed Fgf13 Controls Nociceptive Signaling In Diabetic Neuropathy Models, Aditya K Singh, Matteo Bernabucci, Nolan M Dvorak, Zahra Haghighijoo, Jessica Di Re, Nana A Goode, Feni K Kadakia, Laura A Maile, Olumarotimi O Folorunso, Paul A Wadsworth, Cynthia M Tapia, Pingyuan Wang, Jigong Wang, Haiying Chen, Yu Xue, Jully Singh, Kali Hankerd, Isaac J Gamez, Makenna Kager, Vincent Truong, Patrick Walsh, Stephanie I Shiers, Nishka Kuttanna, Hanyue Liao, Margherita Marchi, Erika Salvi, Ilaria D'Amato, Daniela D'Amico, Parsa Arman, Catharina G Faber, Rayaz A Malik, Marina De Tommaso, Dan Ziegler, Krishna Rajarathnam, Thomas A Green, Peter M Grace, Matthew R Sapio, Michael J Iadarola, Gregory D Cuny, Diana S Chow, Giuseppe Lauria Pinter, Steve Davidson, Dustin P Green, Jun-Ho La, Jin Mo Chung, Jia Zhou, Theodore J Price, Elizabeth Salisbury, Subo Yuan, Fernanda Laezza

Faculty, Staff and Student Publications

Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 …

Fgfr3-Induced Y158 Parp1 Phosphorylation Promotes Parp Inhibitor Resistance Via Brg1/Mre11-Mediated Dna Repair In Breast Cancer Models, Mei-Kuang Chen, Hirohito Yamaguchi, Yuan Gao, Weiya Xia, Jeffrey T Chang, Yu-Chun Hsiao, Tewodros W Shegute, Zong-Shin Lin, Chen-Shiou Wu, Yu-Han Wang, Jennifer K Litton, Qingqing Ding, Yongkun Wei, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Jinsong Liu, Jun Yao, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T Albarracin, Khandan Keyomarsi, Shao-Chun Wang, Ying-Nai Wang, Gabriel N Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively …

Large B Cell Lymphoma Microenvironment Archetype Profiles, Xubin Li, Kartik Singhal, Qing Deng, Dai Chihara, David Russler-Germain, R Andrew Harkins, Jared Henderson, Kotaro Arita, Atish Kizhakeyil, Ryan Sun, Priya Lakra, Usama Hussein, Jennifer A Foltz, Ashley Wilson, Evelyn Schmidt, Imran Nizamuddin, Tommy Dinh, Akhil Kesaraju, Mark P Hamilton, Carl Allen, Maher K Gandhi, Joshua Tobin, Aixiang Jiang, Laura Hilton, David W Scott, Francisco Vega, Christopher R Flowers, Jason R Westin, Obi L Griffith, Todd A Fehniger, Malachi Griffith, Michael R Green

Faculty, Staff and Student Publications

Large B cell lymphomas (LBCL) are clinically and biologically heterogeneous lymphoid malignancies with complex microenvironments that are central to disease etiology. Here we have employed single-nucleus multiome profiling of 232 tumor and control biopsies to characterize diverse cell types and subsets that are present in LBCL tumors, effectively capturing the lymphoid, myeloid, and non-hematopoietic cell compartments. Cell subsets co-occurred in stereotypical Lymphoma Microenvironment Archetype Profiles (LymphoMAPs) defined by; (i) a sparsity of T cells and high frequencies of cancer-associated fibroblasts and tumor-associated macrophages [FMAC]; (ii) lymph node architectural cell types with naïve and memory T cells [LN]; or (iii) activated …

Selective Alanine Transporter Utilization Is A Therapeutic Vulnerability In Arid1a-Mutant Ovarian Cancer, Hao Nie, Liping Liao, Rafal J Zielinski, Javier A Gomez, Akshay V Basi, Erin H Seeley, Lin Tan, Agnes Julia Bilecz, Wei Zhou, Heng Liu, Chen Wang, Shuai Wu, Yuan Qi, Taito Miyamoto, Federica Severi, Aaron R Goldman, Shengqing Gu, Anil K Sood, Amir A Jazaeri, Ronny Drapkin, Daniel T Claiborne, Nan Zhang, Philip L Lorenzi, Jared K Burks, Ernst Lengyel, Eyal Gottlieb, Rugang Zhang

Faculty, Staff and Student Publications

Subunits of the SWI/SNF chromatin remodeling complex are altered in ~20% of human cancers. Exemplifying the alterations is the ARID1A mutation that occurs in ~50% ovarian clear cell carcinoma (OCCC), a disease with limited therapeutic options. Here, we showed that ARID1A mutations create a dependence on alanine by regulating alanine transporters to increase intracellular alanine levels. ARID1A directly repressed alanine importer SLC38A2 and simultaneously promoted alanine exporter SLC7A8. ARID1A inactivation increased alanine utilization predominantly in protein synthesis and passively through the tricarboxylic acid cycle. Indeed, ARID1A-mutant OCCCs were hyper-sensitive to inhibition of SLC38A2. In addition, SLC38A2 inhibition enhanced chimeric antigen …

Hepatitis Patients Undergoing Cardiac Surgery: A Single-Center Retrospective Study, Jin-Long Ju, Yun-Tai Yao, Jun Li, Zhi Cheng, Ling-Ling Fan, Yu-Long Zhong

Faculty, Staff and Student Publications

This study aimed to investigate whether there is difference among various clinical variables, especially blood loss and total drainage volume, among patients with different types of hepatitis undergoing cardiac surgery. A retrospective study was performed on 150 hepatitis patients (127 hepatitis B and 23 hepatitis C) who underwent cardiac surgery at a single cardiovascular center in 2020. Data on their preoperative, intraoperative, and postoperative variables were collected and statistically analyzed to assess the inter-group differences in the following variables: intraoperative blood loss, postoperative drainage volume, proportion of patients treated with blood transfusion, proportion of patients treated with vasoactive drugs, and …

Blunted Cd40-Responsive Enhancer Activation In Crebbp-Mutant Lymphomas Can Be Restored By Enforced Cd4 T-Cell Engagement, Haopeng Yang, Wenchao Zhang, Vida Ravanmehr, Guiling Cui, Kevin Bowman, Ruidong Chen, Jared M Henderson, Shyanne Lockman, Estela Rojas, Ashley Wilson, Sydney Parsons, Ariel Mechaly, Leslie Regad, Ahmed Haouz, Christopher R Flowers, Sattva Neelapu, Loretta Nastoupil, R Eric Davis, Qing Deng, Fernando Rodrigues-Lima, Michael R Green

Faculty, Staff and Student Publications

The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma and diffuse large B-cell lymphoma and has been studied using gene knockout in murine and human cells. However, most CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation, and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in …

The Impact Of Genetic Ancestry On Survival Outcomes In Pediatric Rhabdomyosarcoma: A Report From The Children’S Oncology Group, Ekene A Onwuka, Christina L Magyar, Bailey A Martin-Giacalone, Michael E Scheurer, Deborah A Marquez-Do, Mark Zobeck, Elizabeth G Atkinson, Erin R Rudzinski, Michael A Arnold, Donald A Barkauskas, David Hall, Javed Khan, Jack F Shern, Paul Scheet, Brian Crompton, Corinne M Linardic, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Chad D Huff, Melissa A Richard, Philip J Lupo

Faculty, Staff and Student Publications

Emerging evidence suggests genetic ancestry may influence childhood cancer outcomes, but its impact on pediatric rhabdomyosarcoma (RMS) is unknown. We explored genetic ancestry's impact on survival among children with RMS. This multi-center observational cohort study is a secondary analysis of previously collected biobanking, genomic, and clinical data. The study included 920 individuals with newly diagnosed RMS under 40 years of age enrolled from 2005 to 2017 under the COG soft tissue sarcoma biobanking protocol D9902. The primary endpoints were (1) event-free survival (EFS), defined as the time from study enrollment to tumor recurrence/progression, secondary malignancy, or death from any cause; …

From Novice To Expert: Preparing Your Peer Review, Diana M Proctor, Rachy Abraham, Shannon Esher Righi

Faculty, Staff and Student Publications

Peer review is the process by which the quality of scholarly work is assessed prior to being published, presented, or funded. The consequences of flawed research entering the public domain in the "post-truth" era highlight the need to improve peer review quality, which we believe can be achieved by standardizing training. Here, we aim to enhance the quality of published literature by presenting a systematic guide to train new reviewers (and aid experienced ones) in the art of peer reviewing the rigor of scientific manuscripts.