Digital Commons Network^™

Altered Patterning Of Neural Activity In A Neuropathology, Clarissa Hoffman, Jingheng Cheng, Rodrigo Morales, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

The dynamics of neural circuits and their role in mediating cellular and organismal phenomena remain poorly understood, despite numerous efforts to dissect these processes through precise instantaneous measurements or longer-time averages and approximations. We use an alternative approach: we investigate these dynamics at the system's mesoscale by analyzing spike trains and waveforms. These extended activity patterns carry robust, tractable information, are highly responsive to physiological specifics, and enable detailed tracking of circuit behavior. In particular, this methodology allows for characterizing the functionality of tau-pathology-afflicted hippocampal circuits and identifying circuit-level abnormalities that are missed by through traditional analyses. In healthy mice, …

Elimination Of Hiv Reservoirs Harboring Intact Proviruses, Min Li, Khanghy Truong, Suman Sharma, Baichao Sun, Min Chen, Jason T Kimata, Jin Wang

Faculty, Staff and Students Publications

Background: Human immunodeficiency virus (HIV) establishes persistent infection by integrating its proviral DNA into the host genome. While most integrated proviruses are defective, a small portion of proviruses are intact that represent a major obstacle to achieving an HIV cure. We have designed an approach for selective elimination of host cells harboring replication-competent HIV (SECH), through inhibition of autophagy and anti-apoptotic molecules during viral reactivation. However, the effects of SECH on the dynamics of intact and defective HIV provirus remain unclear.

Methods: We isolated DNA from HIV-infected samples after SECH treatments. We analyzed HIV-1 proviruses in these samples by intact …

Spase: Spatially Resolved Pathology Scores Using Optimal Transport On Spatial Transcriptomics Data, Mohammad Nuwaisir Rahman, Mohammed Abid Abrar, Vikram Rakesh Shaw, James F Martin, M Saifur Rahman, Md Abul Hassan Samee

Faculty, Staff and Students Publications

Pathological events often impact tissue regions in a spatial variable manner, making it challenging to identify therapeutic targets. Spatial transcriptomics (ST) is a powerful technology to map spatially variable molecular mechanisms, yet suitable analytical methods have been lacking. We introduce SPaSE (Spatially-resolved Pathology ScorE), an optimal transport-based algorithm to compare ST data from diseased and control tissues. SPaSE computes a “pathology score” for each spot in the diseased sample, quantifying the pathological impact at that spot. In post-MI (myocardial infarction) mouse hearts, these scores delineated zones that matched independent expert annotations. Modeling pathology scores from gene expression revealed signatures predictive …

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 …

Serum Metabolomic Profiling Of Incident Type 2 Diabetes Mellitus In The Multi-Ethnic Study Of Atherosclerosis And Rotterdam Study, Xuanwei Jiang, Fang Zhu, Gonçalo Graça, Xihao Du, Jinjun Ran, Fariba Ahmadizar, Alexis C Wood, Yanqiu Zhou, Denise M Scholtens, Ali Farzaneh, M Arfan Ikram, Alan Kuang, Carel W Le Roux, Meghana D Gadgil, Marilyn C Cornelis, Kent D Taylor, Xiuqing Guo, Mohsen Ghanbari, Laura J Rasmussen-Torvik, Russell P Tracy, Alain G Bertoni, Jerome I Rotter, David M Herrington, Philip Greenland, Maryam Kavousi, Victor W Zhong

Children’s Nutrition Research Center Staff Publications

Objective: This study aimed to investigate serum metabolomic biomarkers associated with incident type 2 diabetes mellitus (T2DM) and evaluate their performance in improving T2DM risk prediction.

Methods: Untargeted proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics analyses were conducted in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 3460; discovery cohort) and The Rotterdam Study (RS; n = 1556; replication cohort). Multivariable cause-specific hazards models were used to analyze the associations between 23 571 serum metabolomic spectral variables and incident T2DM. Replicated metabolites required an false discovery rate-adjusted P < .01 in MESA, P < .05 in RS, and consistent direction of association. Pathway and network analyses were conducted to elucidate biological mechanisms underlying T2DM development. The utility of the replicated metabolites in improving T2DM risk prediction was assessed based on the Framingham Diabetes Risk Score. A 2-sample Mendelian randomization was conducted to assess causal associations.

Results: Nineteen metabolites were significantly associated with incident T2DM. Pathway analyses …

Epha4 Signaling Dysregulation Links Abnormal Locomotion And The Development Of Idiopathic Scoliosis, Lianlei Wang, Xinyu Yang, Sen Zhao, Pengfei Zheng, Wen Wen, Kexin Xu, Xi Cheng, Qing Li, Anas M Khanshour, Yoshinao Koike, Junjun Liu, Xin Fan, Nao Otomo, Zefu Chen, Yaqi Li, Lulu Li, Haibo Xie, Panpan Zhu, Xiaoxin Li, Yuchen Niu, Shengru Wang, Sen Liu, Suomao Yuan, Chikashi Terao, Ziquan Li, Shaoke Chen, Xiuli Zhao, Pengfei Liu, Jennifer E Posey, Zhihong Wu, Guixing Qiu, Disco Study Group (Deciphering Disorders Involving Scoliosis & Comorbidities), Shiro Ikegawa, James R Lupski, Jonathan J Rios, Carol A Wise, Jianguo T Zhang, Chengtian Zhao, Nan Wu

Faculty, Staff and Students Publications

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited …

Intouch Week Of July 14, 2025, New York Medical College

InTouch

• The 2025 Issue of Chironian is Available
• Medical Student Patricia Curtin Awarded Prestigious Neurology Research Scholarship
• Dr. Walter L. Jenkins Appointed Division Chief and Program Director of Physical Therapy
• TCDM Launches in Albuquerque
• Faculty Spotlight: From Pupil to Professor: Alumni Lighting the Way at NYMC

Exploring The Effect Of Led-To-Photodetector Spacing On Subcutaneous Photoplethysmography For Continuous Blood Pressure Measurement, Dario Cabal, Brian Nguyen, David B. Green, Kevin Kilgore, Varun Thakkar, Michael J. Fu, Steve J. Majerus

Student Scholarship

Photoplethysmography (PPG) is widely used to measure heart rate, blood oxygenation, and more recently, blood pressure. Implanted PPG systems offer the possibility to measure similar real-time measures of cardiovascular health, however, the detection method may vary due to a lack of capillary vessels for PPG sensors to observe in muscle tissue. To improve volumetric blood detection in large muscles, without relying on the capillary density of skin, a flexible PPG sensor was developed. The sensor included multiple spacing of illuminating infrared (IR) light emitting diodes (LEDs) and a single IR photodetector. This arrangement was expected to enable detection of blood …

The Overlooked Impact Of Background Diet And Adherence In Nutrition Trials, Javier I Ottaviani, Hagen Schroeter, Dennis M Bier, John W Erdman, Howard D Sesso, Joann E Manson, Gunter G C Kuhnle

Children’s Nutrition Research Center Staff Publications

Randomised controlled trials in nutrition (RCTN) face unique challenges, including the considerable influence of the background diet and the challenge of assuring intervention adherence by participants. The impact of these factors on the outcome of RCTNs has been difficult to quantify, but nutritional biomarkers represent a valuable tool to address these challenges. Using flavanols as a model dietary intervention and a set of recently validated flavanol biomarkers, we here investigated the impact of background diet and adherence on the outcomes of a subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS, NCT 02422745). We found that 20% of participants …

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 …

Novel Piperidone And Bispidine Derivatives: A New Approach In Cancer Therapy, Lereen Khaled Youssry

Theses and Dissertations

Cancer remains the second leading cause of death worldwide. As a result, scientists have been trying to find novel therapeutic approaches that target specific metabolic pathways selective to tumor cells. In this study, two novel piperidone and bispidine derivatives, organic molecules that target polyamine metabolism, were synthesized, and their potential cytotoxic, antioxidant and anti-inflammatory effects were investigated. Polyamines are naturally occurring metabolites that were reported to be in excess at cancer cells and were accounted for tumor proliferation, invasion and metastasis. Accordingly, the novel piperidone and bispidine derivatives were expected to disrupt tumor growth and progression via up-regulation of key …

Exogenous Arginine Differentially Regulates Inflammatory Cytokine And Inducible Nitric Oxide Synthase Expression In Macrophages, Kelsey Stayer, Saliha Pathan, Aalekhya Biswas, Huiqiao Li, Yi Zhu, Fong Wilson Lam, Juan Marini, Sundararajah Thevananther

Faculty, Staff and Students Publications

Immune dysfunction and late mortality from multiorgan failure are hallmarks of severe sepsis. Arginine, a semi-essential amino acid important for protein synthesis, immune response, and circulatory regulation, is deficient in sepsis. However, arginine supplementation in sepsis remains controversial due to the potential to upregulate inducible nitric oxide synthase (iNOS)-mediated excessive nitric oxide (NO) generation in macrophages, leading to vasodilation and hemodynamic catastrophe. Citrulline supplementation has been considered an alternative to replenishing arginine via de novo synthesis, orchestrated by argininosuccinate synthase 1 (ASS1) and argininosuccinate lyase (ASL). However, the functional relevance of the ASS1-ASL pathway in macrophages after endotoxin stimulation is …

Gene Expression In Tumor And Adjacent Normal Tissues In Lung Adenocarcinoma Subtypes, Olga Y Gorlova, Ivan P Gorlov, R Taylor Ripley, Chao Cheng, Yafang Li, Bo Peng, Yanhong Liu, Hee-Jin Jang, Sung Wook Kang, Claire Lee, Priyanka Ranchod, Bryan M Burt, Hyun-Sung Lee, Christopher I Amos

Faculty, Staff and Students Publications

Background: Lung adenocarcinoma (LUAD) has several histologically distinct subtypes that differ by a number of clinical features including patient survival. Molecular mechanisms underlying histological and clinical differences between subtypes remain poorly understood.

Methods: We conducted a comparative analyses of gene expression in acinar, lepidic, papillary and solid subtypes, as well as mucinous adenocarcinoma. We used a novel, more efficient approach to identify subtype-specific genes. We compared the mean gene expression level separately for tumors and adjacent normal tissue with pure or a highly represented (≥ 75%) subtype of interest to the mean expression in tumors where the subtype of interest …

Spatial Proximity Of Immune Cell Pairs To Cancer Cells In The Tumor Microenvironment As Biomarkers For Patient Stratification, Jian-Rong Li, Xingxin Pan, Yupei Lin, Yanding Zhao, Yanhong Liu, Yong Li, Christopher I Amos, Chao Cheng

Faculty, Staff and Students Publications

Background/objectives: The tumor microenvironment (TME) plays a critical role in cancer progression by shaping immune responses and influencing patient outcomes. We hypothesized that the relative proximity of specific immune cell pairs to cancer cells within the TME could help predict their pro- or anti-tumor functions and reflect clinically relevant immune dynamics.

Methods: We analyzed imaging mass cytometry (IMC) data from lung adenocarcinoma (LUAD) and triple-negative breast cancer (TNBC) cohorts. For each immune cell pair, we calculated a relative distance (RD) score, which quantifies the spatial difference in proximity to cancer cells. We assessed the prognostic and predictive significance of these …

Ovochymase 2 Is A Key Regulatory Factor Modulating Proteolytic Pathways And Sperm Maturation In The Mammalian Epididymis, Katarzyna Kent, Kaori Nozawa, Antrix Jain, Anna Malovannaya, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

Spermatozoa acquire fertilizing competence during epididymal transit through proteolytic, chaperone-mediated, and post-translational modifications. Ovochymase 2, an epididymis-specific trypsin-like serine protease, has emerged as a central regulator of this maturation process. Here, we integrate targeted gene disruption, comprehensive proteomic profiling, and affinity-based proteome enrichment to delineate how Ovochymase 2 influences sperm functionality. Deletion of Ovochymase 2 disrupts the proteome of epididymal sperm, resulting in diminished levels of core fertility-related factors-including a disintegrin and metalloprotease domain 3, β-defensins, and protease-inhibitor complexes-while inducing compensatory upregulation of alternate proteases and chaperones. Interaction assays confirm direct or indirect associations between Ovochymase 2 and sperm surface …

A Mouse Model Engineered To Spatiotemporally Control Cre Expression In Progesterone Receptor Positive Cells†, Elvis Quiroz, Ryan M Marquardt, Shu-Yun Li, Artiom Gruzdev, David Cunefare, Charan Ganta, San-Pin Wu, John P Lydon, Francesco J Demayo

Faculty, Staff and Students Publications

The Cre/loxP system is widely used for site-specific genetic manipulation in mice. The PgrCre mouse model, where Cre recombinase is driven by the progesterone receptor promoter, is commonly used for gene ablation in Pgr-positive uterine cells. However, the PgrCre is active in the neonatal uterus and does not allow temporal control. To enhance the functionality of the PgrCre mouse, we generated and characterized an inducible PgriCreERT2 mouse, in which iCreERT2 is inserted downstream of the endogenous Pgr promoter. PgriCreERT2 mice crossed with Rosa26-CAG-LSL-Sun1-sfGFP-myc reporter mice demonstrated tamoxifen-dependent recombination in uterine stromal fibroblasts and a subset of epithelial cells. Tamoxifen-induced ablation …

Investigation Of Subcellular Damage And Long-Term Non-Cancerous Cardiovascular Effects Following Whole-Body Photon Irradiation, Nousha Afshari

LSU Doctoral Dissertations

Current radiobiological models focus primarily on nuclear DNA damage and fail to fully explain radiation-induced noncancerous health effects. This dissertation investigates whether non-nuclear subcellular structures contribute to radiation-induced biological damage through experimental biomarker analysis and computational microdosimetry. The central hypothesis posits that whole-body photon irradiation results in subcellular non-nuclear damage, specifically increased circulating mitochondrial DNA concentrations, that correlates with radiation dose and long-term noncancerous effects such as cardiovascular disease.

Specific Aim 1 measured mitochondrial and nuclear DNA concentrations in banked blood samples from 72 Chinese rhesus macaques that previously received whole-body photon irradiation ($0-10$ Gy) from Cobalt-60 or LINAC sources. …

Conformational Ligand-Directed Targeting Of Calcium-Dependent Receptors In Acute Trauma, Renata Pasqualini, Christopher Markosian, Daniela I Staquicini, Andrey S Dobroff, Esteban Dodero-Rojas, Paul C Whitford, E Magda Barbu, Julianna K Bronk, Marina Cardó-Vila, Dawn R Christianson, Emmanuel Dias-Neto, Wouter H P Driessen, Liliana Guzman-Rojas, Serena Marchiò, Diana N Nunes, Francislon S De Oliveira, Michael G Ozawa, Bettina Proneth, Roberto Rangel, Tracey L Smith, Glauco R Souza, Fernanda I Staquicini, Fenny H F Tang, Wallace B Baze, João C Setubal, John W Burns, Michael A Dubick, Juri G Gelovani, Andriy I Batchinsky, Jon E Mogford, Charles E Wade, John B Holcomb, Stephen K Burley, José N Onuchic, Wadih Arap

Faculty, Staff and Student Publications

Background: Trauma is a leading cause of mortality, but injury-specific molecular targets remain largely unknown. We hypothesized that distinctive yet unrecognized tissue targets accessible to circulating ligands might emerge during trauma, thereby underscoring a trauma-related proteome.

Methods: We screened a peptide library to discover targets in a porcine model of major trauma: compound femur fracture with hemorrhagic shock. Bioinformatics yielded conserved motifs, and candidate receptors were affinity purified. In silico and in vitro approaches served to investigate possible associations between candidate receptors and calcium, a major component of skeletal muscle and bone. In vivo homing and molecular imaging (PET/MRI and …

Oral Dosing Of The Nucleoside Analog Obeldesivir Is Efficacious Against Rsv Infection In African Green Monkeys, Jared Pitts, J Lizbeth Reyes Zamora, Savrina Manhas, Thomas Aeschbacher, Josolyn Chan, Vincent Cutillas, Varsha Nair, Nicholas C Riola, Arya Vijjapurapu, Meghan S Vermillion, Stacey Eng, Christopher Richards, Dong Han, Jason K Perry, Subhra Chaudhuri, Szu-Wen Liu, Clarissa Martinez, Nadine Peinovich, Kai-Hui Sun, Arthur Cai, Ross Martin, Jasmine Moshiri, Charlotte Hedskog, Darius Babusis, Dustin S Siegel, Rao Kalla, Vasanthi Avadhanula, Pedro A Piedra, Kim Stobbelaar, Peter L Delputte, Caleb Marceau, Roberto Mateo, Evguenia Maiorova, Hongmei Mo, Raju Subramanian, Richard L Mackman, Tomas Cihlar, Simon P Fletcher, John P Bilello

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20–0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identify a single amino acid substitution, I777L, in the L polymerase with …

Src/Fn1 Pathway Activation Drives Tumor Cell Cluster Formation And Metastasis In Lung Cancer: A Promising Therapeutic Target, Zujun Que, Zhichao Xi, Dan Qi, Rongchen Dai, Yang Li, Mengfan Liu, Bin Luo, Jiajun Liu, Pan Yu, Yun Yang, Erxi Wu, Hongxi Xu, Jianhui Tian

Children’s Nutrition Research Center Staff Publications

Lung cancer remains the leading cause of cancer-related death globally, with metastasis driven by circulating tumor cells (CTCs)-particularly clusters-being a major treatment challenge. Despite their critical role, the biological differences between single CTCs and CTC clusters remain unclear. Here, we comprehensively compared their behavioral, transcriptomic, and proteomic profiles in lung cancer models. Compared with single cells, CTC clusters present enhanced metastatic potential, greater survival in the bloodstream and increased resistance to microenvironment. Mechanistically, the Src/FN1 pathway is centrally activated in clusters, promoting intercellular cohesion and protecting against immune clearance and stress in circulation. Pharmacological inhibition of Src with the clinical …