Medical Cell Biology Commons^™

Presence Of Circulating Tumor Cells Predates Imaging Detection Of Relapse In Patients With Stage Iii Melanoma, Anthony Lucci, Sridevi Addanki, Yi-Ju Chiang, Salyna Meas, Vanessa N Sarli, Joshua R Upshaw, Mayank Manchem, Sapna P Patel, Jennifer A Wargo, Jeffrey E Gershenwald, Merrick I Ross

Faculty, Staff and Student Publications

Stage III melanoma includes nodal metastasis or in-transit disease. Five-year survival rates vary between 32% and 93%. The identification of high-risk patients is important for clinical decision making. We demonstrated previously that ≥1 circulating tumor cells (CTCs) at baseline was associated with recurrence. In this study, we investigated how frequently CTCs were identified prior to radiologically detected recurrence. Stage III patients (n = 325) had imaging at baseline and q 3 months. Baseline and q 6-12 months blood draws (7.5 mL) were performed to identify CTCs up to 3.5 years from diagnosis. CTC assessment was performed using the immunomagnetic …

Myc Regulates Csf1 Expression Via Microrna 17/20a To Modulate Tumor-Associated Macrophages In Osteosarcoma, Bikesh K Nirala, Tajhal D Patel, Lyazat Kurenbekova, Ryan Shuck, Atreyi Dasgupta, Nino Rainusso, Cristian Coarfa, Jason T Yustein

Faculty, Staff and Students Publications

Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% of OSs carry amplification of chromosome 8q24, which harbors the oncogene c-MYC and correlates with a poor prognosis. To understand the mechanisms that underlie the ability of MYC to alter both the tumor and its surrounding tumor microenvironment (TME), we generated and molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, the Myc-knockin GEMM had rapid tumor development with a high incidence of metastasis. MYC-dependent gene signatures in our murine model demonstrated significant homology to the human hyperactivated MYC OS. We established that …

Unravelling Spatial Gene Associations With Seagal: A Python Package For Spatial Transcriptomics Data Analysis And Visualization, Linhua Wang, Chaozhong Liu, Yang Gao, Xiang H-F Zhang, Zhandong Liu

Faculty, Staff and Students Publications

SUMMARY: In the era where transcriptome profiling moves toward single-cell and spatial resolutions, the traditional co-expression analysis lacks the power to fully utilize such rich information to unravel spatial gene associations. Here, we present a Python package called Spatial Enrichment Analysis of Gene Associations using L-index (SEAGAL) to detect and visualize spatial gene correlations at both single-gene and gene-set levels. Our package takes spatial transcriptomics datasets with gene expression and the aligned spatial coordinates as input. It allows for analyzing and visualizing genes' spatial correlations and cell types' colocalization within the precise spatial context. The output could be visualized as …

A Crispr/Cas9-Engineered Mouse Carrying A Conditional Knockout Allele For The Early Growth Response-1 Transcription Factor, Vineet K Maurya, Yan Ying, Denise G Lanza, Jason D Heaney, John P Lydon

Faculty, Staff and Students Publications

Early growth response 1 (EGR1) mediates transcriptional programs that are indispensable for cell division, differentiation and apoptosis in numerous physiologies and pathophysiologies. Whole-body EGR1 knockouts in mice (Egr1KO) have advanced our understanding of EGR1 function in an in vivo context. To extend the utility of the mouse to investigate EGR1 responses in a tissue- and/or cell-type-specific manner, we generated a mouse model in which exon 2 of the mouse Egr1 gene is floxed by CRISPR/Cas9 engineering. The floxed Egr1 alleles (Egr1f/f) are designed to enable spatiotemporal control of Cre-mediated EGR1 ablation in the …

Identification Of Unique Α4 Chain Structure And Conserved Antiangiogenic Activity Of Α3nc1 Type Iv Collagen In Zebrafish, Valerie S Lebleu, Jianli Dai, Susan Tsutakawa, Brian A Macdonald, Joseph L Alge, Malin Sund, Liang Xie, Hikaru Sugimoto, John Tainer, Leonard I Zon, Raghu Kalluri

Faculty, Staff and Student Publications

BACKGROUND: Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding α1 and α2 chains, in contrast with the six genes in humans, encoding α1-α6 chains. The α chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied.

RESULTS: We report on the molecular evolution of type IV collagen genes. The zebrafish α4 non-collagenous (NC1) domain, in …

Targeting The Vulnerabilities Of Oncogene Activation, Christina Huang, Jack L. Arbiser

Student Papers, Posters & Projects

No abstract provided.

Slc7a11 Expression Level Dictates Differential Responses To Oxidative Stress In Cancer Cells, Yuelong Yan, Hongqi Teng, Qinglei Hang, Lavanya Kondiparthi, Guang Lei, Amber Horbath, Xiaoguang Liu, Chao Mao, Shiqi Wu, Li Zhuang, M James You, Masha V Poyurovsky, Li Ma, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show …

Histone H2a Lys130 Acetylation Epigenetically Regulates Androgen Production In Prostate Cancer, Thanh Nguyen, Dhivya Sridaran, Surbhi Chouhan, Cody Weimholt, Audrey Wilson, Jingqin Luo, Tiandao Li, John Koomen, Bin Fang, Nagireddy Putluri, Arun Sreekumar, Felix Y Feng, Kiran Mahajan, Nupam P Mahajan

Faculty, Staff and Students Publications

The testicular androgen biosynthesis is well understood, however, how cancer cells gauge dwindling androgen to dexterously initiate its de novo synthesis remained elusive. We uncover dual-phosphorylated form of sterol regulatory element-binding protein 1 (SREBF1), pY673/951-SREBF1 that acts as an androgen sensor, and dissociates from androgen receptor (AR) in androgen deficient environment, followed by nuclear translocation. SREBF1 recruits KAT2A/GCN5 to deposit epigenetic marks, histone H2A Lys130-acetylation (H2A-K130ac) in SREBF1, reigniting de novo lipogenesis & steroidogenesis. Androgen prevents SREBF1 nuclear translocation, promoting T cell exhaustion. Nuclear SREBF1 and H2A-K130ac levels are significantly increased and directly correlated with late-stage prostate cancer, reversal of …

Cfp1 Governs Uterine Epigenetic Landscapes To Intervene In Progesterone Responses For Uterine Physiology And Suppression Of Endometriosis, Seung Chel Yang, Mira Park, Kwon-Ho Hong, Hyeonwoo La, Chanhyeok Park, Peike Wang, Gaizhen Li, Qionghua Chen, Youngsok Choi, Francesco J Demayo, John P Lydon, David G Skalnik, Hyunjung J Lim, Seok-Ho Hong, So Hee Park, Yeon Sun Kim, Hye-Ryun Kim, Haengseok Song

Faculty, Staff and Students Publications

Progesterone (P4) is required for the preparation of the endometrium for a successful pregnancy. P4 resistance is a leading cause of the pathogenesis of endometrial disorders like endometriosis, often leading to infertility; however, the underlying epigenetic cause remains unclear. Here we demonstrate that CFP1, a regulator of H3K4me3, is required for maintaining epigenetic landscapes of P4-progesterone receptor (PGR) signaling networks in the mouse uterus. Cfp1f/f;Pgr-Cre (Cfp1d/d) mice showed impaired P4 responses, leading to complete failure of embryo implantation. mRNA and chromatin immunoprecipitation sequencing analyses showed that CFP1 regulates uterine mRNA profiles not only in H3K4me3-dependent …

Conjugated Bile Acids Are Nutritionally Re-Programmable Antihypertensive Metabolites, Saroj Chakraborty, Anju Lulla, Xi Cheng, Ji-Youn Yeo, Juthika Mandal, Tao Yang, Xue Mei, Piu Saha, Rachel M Golonka, Beng San Yeoh, Blair Mell, Wei Jia, Vasanta Putluri, Danthasinghe Waduge Badrajee Piyarathna, Nagireddy Putluri, Arun Sreekumar, Katie Meyer, Matam Vijay-Kumar, Bina Joe

Faculty, Staff and Students Publications

BACKGROUND: Hypertension is the largest risk factor affecting global mortality. Despite available medications, uncontrolled hypertension is on the rise, whereby there is an urgent need to develop novel and sustainable therapeutics. Because gut microbiota is now recognized as an important entity in blood pressure regulation, one such new avenue is to target the gut-liver axis wherein metabolites are transacted via host-microbiota interactions. Knowledge on which metabolites within the gut-liver axis regulate blood pressure is largely unknown.

METHOD: To address this, we analyzed bile acid profiles of human, hypertensive and germ-free rat models and report that conjugated bile acids are inversely …

Adjuvant Therapy With Oncolytic Adenovirus Delta-24-Rgdox After Intratumoral Adoptive T-Cell Therapy Promotes Antigen Spread To Sustain Systemic Antitumor Immunity, Hong Jiang, Dong Ho Shin, Yanhua Yi, Xuejun Fan, Joy Gumin, Jiasen He, Andrew G Gillard, Frederick F Lang, Candelaria Gomez-Manzano, Juan Fueyo

Faculty, Staff and Student Publications

Cancer cell heterogeneity and immunosuppressive tumor microenvironment (TME) pose a challenge in treating solid tumors with adoptive cell therapies targeting limited tumor-associated antigens (TAA), such as chimeric antigen receptor T-cell therapy. We hypothesize that oncolytic adenovirus Delta-24-RGDOX activates the TME and promote antigen spread to potentiate the abscopal effect of adoptive TAA-targeting T cells in localized intratumoral treatment. Herein, we used C57BL/6 mouse models with disseminated tumors derived from B16 melanoma cell lines to assess therapeutic effects and antitumor immunity. gp100-specific pmel-1 or ovalbumin (OVA)-specific OT-I T cells were injected into the first subcutaneous tumor, followed by three injections of …

Forging New Therapeutic Targets: Efforts Of Tumor Derived Exosomes To Prepare The Pre-Metastatic Niche For Cancer Cell Dissemination And Dormancy, Ranvir Bhatia, Joanna Chang, Jessian L Munoz, Nykia D Walker

Faculty, Staff and Students Publications

Tumor-derived exosomes play a multifaceted role in preparing the pre-metastatic niche, promoting cancer dissemination, and regulating cancer cell dormancy. A brief review of three types of cells implicated in metastasis and an overview of other types of extracellular vesicles related to metastasis are described. A central focus of this review is on how exosomes influence cancer progression throughout metastatic disease. Exosomes are crucial mediators of intercellular communication by transferring their cargo to recipient cells, modulating their behavior, and promoting tumor pro-gression. First, their functional role in cancer cell dissemination in the peripheral blood by facilitating the establishment of a pro-angiogenic …

Gastrulation Morphogenesis In Synthetic Systems, Alyssa A Emig, Margot L K Williams

Faculty, Staff and Students Publications

Recent advances in pluripotent stem cell culture allow researchers to generate not only most embryonic cell types, but also morphologies of many embryonic structures, entirely in vitro. This recreation of embryonic form from naïve cells, known as synthetic morphogenesis, has important implications for both developmental biology and regenerative medicine. However, the capacity of stem cell-based models to recapitulate the morphogenetic cell behaviors that shape natural embryos remains unclear. In this review, we explore several examples of synthetic morphogenesis, with a focus on models of gastrulation and surrounding stages. By varying cell types, source species, and culture conditions, researchers have recreated …

Smarcb1 Regulates The Hypoxic Stress Response In Sickle Cell Trait, Melinda Soeung, Luigi Perelli, Ziheng Chen, Eleonora Dondossola, I-Lin Ho, Federica Carbone, Li Zhang, Hania Khan, Courtney N Le, Cihui Zhu, Michael D Peoples, Ningping Feng, Shan Jiang, Niki Millward Zacharias, Rosalba Minelli, Daniel D Shapiro, Angela K Deem, Sisi Gao, Emily H Cheng, Donatella Lucchetti, Cheryl L Walker, Alessandro Carugo, Virginia Giuliani, Timothy P Heffernan, Andrea Viale, Nizar M Tannir, Giulio F Draetta, Pavlos Msaouel, Giannicola Genovese

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1. Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels …

The Deleted In Oral Cancer (Doc1 Aka Cdk2ap1) Tumor Suppressor Gene Is Downregulated In Oral Squamous Cell Carcinoma By Multiple Micrornas, Roberto Stabile, Mario Román Cabezas, Mathijs P Verhagen, Francesco A Tucci, Thierry P P Van Den Bosch, Maria J De Herdt, Berdine Van Der Steen, Alex L Nigg, Meng Chen, Cristina Ivan, Masayoshi Shimizu, Senada Koljenović, Jose A Hardillo, C Peter Verrijzer, Robert J Baatenburg De Jong, George A Calin, Riccardo Fodde

Faculty, Staff and Student Publications

Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1; also known as deleted in oral cancer or DOC1) is a tumor suppressor gene known to play functional roles in both cell cycle regulation and in the epigenetic control of embryonic stem cell differentiation, the latter as a core subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex. In the vast majority of oral squamous cell carcinomas (OSCC), expression of the CDK2AP1 protein is reduced or lost. Notwithstanding the latter (and the DOC1 acronym), mutations or deletions in its coding sequence are extremely rare. Accordingly, CDK2AP1 protein-deficient oral cancer cell lines express as …

Beclin-1-Dependent Autophagy, But Not Apoptosis, Is Critical For Stem-Cell-Mediated Endometrial Programming And The Establishment Of Pregnancy, Pooja Popli, Suni Tang, Sangappa B Chadchan, Chandni Talwar, Edmund B Rucker, Xiaoming Guan, Diana Monsivais, John P Lydon, Christina L Stallings, Kelle H Moley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5+/Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin …

From Bugs To Drugs: Bacterial 3-Iaa Enhances Efficacy Of Chemotherapy In Pancreatic Cancer, Y David Seo, Jennifer A Wargo

Faculty, Staff and Student Publications

Tintelnot et al. identified enrichment of indole-3-acetic acid (3-IAA), a tryptophan metabolite produced by gut microbiota, as a predictor of chemotherapy response in pancreatic adenocarcinoma. Recapitulated in mouse models, 3-IAA represents a novel potential therapeutic approach for chemotherapy sensitization.

Traf4-Mediated Nonproteolytic Ubiquitination Of Androgen Receptor Promotes Castration-Resistant Prostate Cancer, Ramesh Singh, Huan Meng, Tao Shen, Lance Edward V Lumahan, Steven Nguyen, Hong Shen, Subhamoy Dasgupta, Li Qin, Dileep Karri, Bokai Zhu, Feng Yang, Cristian Coarfa, Bert W O'Malley, Ping Yi

Faculty, Staff and Students Publications

Castration-resistant prostate cancer (CRPC) poses a major clinical challenge with the androgen receptor (AR) remaining to be a critical oncogenic player. Several lines of evidence indicate that AR induces a distinct transcriptional program after androgen deprivation in CRPCs. However, the mechanism triggering AR binding to a distinct set of genomic loci in CRPC and how it promotes CRPC development remain unclear. We demonstrate here that atypical ubiquitination of AR mediated by an E3 ubiquitin ligase TRAF4 plays an important role in this process. TRAF4 is highly expressed in CRPCs and promotes CRPC development. It mediates K27-linked ubiquitination at the C-terminal …

Correction Of T-Cell Repertoire And Autoimmune Diabetes In Nod Mice By Non-Myeloablative T-Cell Depleted Allogeneic Hsct, Rakefet Sidlik Muskatel, Bar Nathansohn-Levi, Shlomit Reich-Zeliger, Michal Mark, Liat Stoler-Barak, Chava Rosen, Irit Milman-Krentsis, Esther Bachar Lustig, Robert Pete Gale, Nir Friedman, Yair Reisner

Faculty, Staff and Student Publications

The induction of partial tolerance toward pancreatic autoantigens in the treatment of type 1 diabetes mellitus (T1DM) can be attained by autologous hematopoietic stem cell transplantation (HSCT). However, most patients treated by autologous HSCT eventually relapse. Furthermore, allogeneic HSCT which could potentially provide a durable non-autoimmune T-cell receptor (TCR) repertoire is associated with a substantial risk for transplant-related mortality. We have previously demonstrated an effective approach for attaining engraftment without graft versus host disease (GVHD) of allogeneic T-cell depleted HSCT, following non-myeloablative conditioning, using donor-derived anti-3rd party central memory CD8 veto T cells (Tcm). In the present study, we investigated …

Kras Hijacks The Mirna Regulatory Pathway In Cancer, Angelina S Bortoletto, Ronald J Parchem

Faculty, Staff and Students Publications

Extensive studies have focused on the misregulation of individual miRNAs in cancer. More recently, mutations in the miRNA biogenesis and processing machinery have been implicated in several malignancies. Such mutations can lead to global miRNA misregulation, which may promote many of the well-known hallmarks of cancer. Interestingly, recent evidence also suggests that oncogenic Kristen rat sarcoma viral oncogene homolog (KRAS) mutations act in part by modulating the activity of members of the miRNA regulatory pathway. Here, we highlight the vital role mutations in the miRNA core machinery play in promoting malignant transformation. Furthermore, we discuss how mutant KRAS can simultaneously …

Preclinical Investigations Of The Efficacy Of The Glutaminase Inhibitor Cb-839 Alone And In Combinations In Chronic Lymphocytic Leukemia, Natalia Timofeeva, Mary L Ayres, Natalia Baran, Janice M Santiago-O'Farrill, Gamze Bildik, Zhen Lu, Marina Konopleva, Varsha Gandhi

Faculty, Staff and Student Publications

INTRODUCTION: Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species.

METHODS: To investigate the

RESULTS: We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in …

Development Of Combination Therapy Strategies To Treat Cancer Using Dihydroorotate Dehydrogenase Inhibitors, Nicholas Mullen

Theses & Dissertations

Cancer cells require supraphysiologic levels of nucleotide triphosphates to fuel their malignant behaviors, including uncontrolled proliferation, immune evasion, metastasis, and therapy resistance. This requirement is met by hyperactive flux through the de novo pyrimidine and de novo purine pathways. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine pathway that can be targeted by FDA approved and experimental drug compounds. A robust body of preclinical evidence, encompassing hundreds of independent studies over several decades, demonstrates impressive activity of DHODH inhibitors in animal models of cancer. Paradoxically, however, all clinical trials to date have failed to demonstrate efficacy …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Osteoprogenitor-Gmp Crosstalk Underpins Solid Tumor-Induced Systemic Immunosuppression And Persists After Tumor Removal, Xiaoxin Hao, Yichao Shen, Nan Chen, Weijie Zhang, Elizabeth Valverde, Ling Wu, Hilda L Chan, Zhan Xu, Liqun Yu, Yang Gao, Igor Bado, Laura Natalee Michie, Charlotte Helena Rivas, Luis Becerra Dominguez, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Fengshuo Liu, Yunfeng Ding, David G Edwards, Jun Liu, Angela Alexander, Naoto T Ueno, Po-Ren Hsueh, Chih-Yen Tu, Liang-Chih Liu, Shu-Hsia Chen, Mien-Chie Hung, Bora Lim, Xiang H-F Zhang

Faculty, Staff and Students Publications

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitors (OPs) expansion, hematopoietic stem cell dislocation and CD41− granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41− GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in hematopoietic program. Importantly, these effects persist …

Examining Ndufab1 Expression In Head And Neck Squamous Cell Carcinoma, Addison Stevens

Poster Presentations

Honors research poster.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is approximately 4% of all cancers and 2% of all cancer associated mortality in the United States. In 2023, there will be an estimated 67,000 new cases of HNSCC, along with 15,400 deaths, in the United States. HNSCC locations include the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx. Major risk factors for HNSCC include tobacco use, alcohol use, and human papilloma virus (HPV). Epidermal growth factor receptor (EGFR) is currently the only approved molecular targeted therapy for HNSCC. Therefore, new therapeutics and biomarkers for HNSCC are warranted. Mitochondria are …

Examining Ndufab1 Expression In Head And Neck Squamous Cell Carcinoma, Addison L. Stevens

Honors Theses

Head and neck squamous cell carcinoma (HNSCC) accounts for around 4% of all cancers in the USA. HNSCC includes cancers of the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx. Reprogramming of mitochondrial metabolism has been known to promote oncogenesis. NDUFAB1, a nuclear encoded subunit of respiratory complex I (RCI) in the inner mitochondrial membrane, is abundantly expressed at the mRNA level in HNSCC patients. Based on this finding, we hypothesize that NDUFAB1 protein expression is high in HNSCC and that NDUFAB1 expression predicts a poor prognosis in HNSCC patients. We determined NDUFAB1 expression in HNSCC using immunohistochemistry and pathology guided …

Apoptotic Cell Death In Disease-Current Understanding Of The Nccd 2023, Ilio Vitale, Federico Pietrocola, Emma Guilbaud, Stuart A Aaronson, John M Abrams, Dieter Adam, Massimiliano Agostini, Patrizia Agostinis, Emad S Alnemri, Lucia Altucci, Ivano Amelio, David W Andrews, Rami I Aqeilan, Eli Arama, Eric H Baehrecke, Siddharth Balachandran, Daniele Bano, Nickolai A Barlev, Jiri Bartek, Nicolas G Bazan, Christoph Becker, Francesca Bernassola, Mathieu J M Bertrand, Marco E Bianchi, Mikhail V Blagosklonny, J Magarian Blander, Giovanni Blandino, Klas Blomgren, Christoph Borner, Carl D Bortner, Pierluigi Bove, Patricia Boya, Catherine Brenner, Petr Broz, Thomas Brunner, Rune Busk Damgaard, George A Calin, Michelangelo Campanella, Eleonora Candi, Michele Carbone, Didac Carmona-Gutierrez, Francesco Cecconi, Francis K-M Chan, Guo-Qiang Chen, Quan Chen, Youhai H Chen, Emily H Cheng, Jerry E Chipuk, John A Cidlowski, Aaron Ciechanover, Gennaro Ciliberto, Marcus Conrad, Juan R Cubillos-Ruiz, Peter E Czabotar, Vincenzo D'Angiolella, Mads Daugaard, Ted M Dawson, Valina L Dawson, Ruggero De Maria, Bart De Strooper, Klaus-Michael Debatin, Ralph J Deberardinis, Alexei Degterev, Giannino Del Sal, Mohanish Deshmukh, Francesco Di Virgilio, Marc Diederich, Scott J Dixon, Brian D Dynlacht, Wafik S El-Deiry, John W Elrod, Kurt Engeland, Gian Maria Fimia, Claudia Galassi, Carlo Ganini, Ana J Garcia-Saez, Abhishek D Garg, Carmen Garrido, Evripidis Gavathiotis, Motti Gerlic, Sourav Ghosh, Douglas R Green, Lloyd A Greene, Hinrich Gronemeyer, Georg Häcker, György Hajnóczky, J Marie Hardwick, Ygal Haupt, Sudan He, David M Heery, Michael O Hengartner, Claudio Hetz, David A Hildeman, Hidenori Ichijo, Satoshi Inoue, Marja Jäättelä, Ana Janic, Bertrand Joseph, Philipp J Jost, Thirumala-Devi Kanneganti, Michael Karin, Hamid Kashkar, Thomas Kaufmann, Gemma L Kelly, Oliver Kepp, Adi Kimchi, Richard N Kitsis, Daniel J Klionsky, Ruth Kluck, Dmitri V Krysko, Dagmar Kulms, Sharad Kumar, Sergio Lavandero, Inna N Lavrik, John J Lemasters, Gianmaria Liccardi, Andreas Linkermann, Stuart A Lipton, Richard A Lockshin, Carlos López-Otín, Tom Luedde, Marion Macfarlane, Frank Madeo, Walter Malorni, Gwenola Manic, Roberto Mantovani, Saverio Marchi, Jean-Christophe Marine, Seamus J Martin, Jean-Claude Martinou, Pier G Mastroberardino, Jan Paul Medema, Patrick Mehlen, Pascal Meier, Gerry Melino, Sonia Melino, Edward A Miao, Ute M Moll, Cristina Muñoz-Pinedo, Daniel J Murphy, Maria Victoria Niklison-Chirou, Flavia Novelli, Gabriel Núñez, Andrew Oberst, Dimitry Ofengeim, Joseph T Opferman, Moshe Oren, Michele Pagano, Theocharis Panaretakis, Manolis Pasparakis, Josef M Penninger, Francesca Pentimalli, David M Pereira, Shazib Pervaiz, Marcus E Peter, Paolo Pinton, Giovanni Porta, Jochen H M Prehn, Hamsa Puthalakath, Gabriel A Rabinovich, Krishnaraj Rajalingam, Kodi S Ravichandran, Markus Rehm, Jean-Ehrland Ricci, Rosario Rizzuto, Nirmal Robinson, Cecilia M P Rodrigues, Barak Rotblat, Carla V Rothlin, David C Rubinsztein, Thomas Rudel, Alessandro Rufini, Kevin M Ryan, Kristopher A Sarosiek, Akira Sawa, Emre Sayan, Kate Schroder, Luca Scorrano, Federico Sesti, Feng Shao, Yufang Shi, Giuseppe S Sica, John Silke, Hans-Uwe Simon, Antonella Sistigu, Anastasis Stephanou, Brent R Stockwell, Flavie Strapazzon, Andreas Strasser, Liming Sun, Erwei Sun, Qiang Sun, Gyorgy Szabadkai, Stephen W G Tait, Daolin Tang, Nektarios Tavernarakis, Carol M Troy, Boris Turk, Nicoletta Urbano, Peter Vandenabeele, Tom Vanden Berghe, Matthew G Vander Heiden, Jacqueline L Vanderluit, Alexei Verkhratsky, Andreas Villunger, Silvia Von Karstedt, Anne K Voss, Karen H Vousden, Domagoj Vucic, Daniela Vuri, Erwin F Wagner, Henning Walczak, David Wallach, Ruoning Wang, Ying Wang, Achim Weber, Will Wood, Takahiro Yamazaki, Huang-Tian Yang, Zahra Zakeri, Joanna E Zawacka-Pankau, Lin Zhang, Haibing Zhang, Boris Zhivotovsky, Wenzhao Zhou, Mauro Piacentini, Guido Kroemer, Lorenzo Galluzzi

Faculty, Staff and Student Publications

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. …

Enhancing Cancer Diagnosis With Real-Time Feedback: Tumor Metabolism Through Hyperpolarized 1-13c Pyruvate Mrsi, Gaurav Sharma, José S Enriquez, Ryan Armijo, Muxin Wang, Pratip Bhattacharya, Shivanand Pudakalakatti

Faculty, Staff and Student Publications

This review article discusses the potential of hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) as a noninvasive technique for identifying altered metabolism in various cancer types. Hyperpolarization significantly improves the signal-to-noise ratio for the identification of 13C-labeled metabolites, enabling dynamic and real-time imaging of the conversion of [1-13C] pyruvate to [1-13C] lactate and/or [1-13C] alanine. The technique has shown promise in identifying upregulated glycolysis in most cancers, as compared to normal cells, and detecting successful treatment responses at an earlier stage than multiparametric MRI in breast and prostate cancer patients. The review provides a concise overview of the applications …

Serinc5 Restricts Hiv Membrane Fusion By Altering Lipid Order And Heterogeneity In The Viral Membrane, Amanda E Ward, Daria Sokovikova, Melvin Neal Waxham, Frederick A Heberle, Ilya Levental, Kandice R Levental, Volker Kiessling, Judith M White, Lukas K Tamm

Faculty, Staff and Student Publications

The host restriction factor, Serinc5, incorporates into budding HIV particles and inhibits their infection by an incompletely understood mechanism. We have previously reported that Serinc5 but not its paralogue, Serinc2, blocks HIV cell entry by membrane fusion, specifically by inhibiting fusion pore formation and dilation. A body of work suggests that Serinc5 may alter the conformation and clustering of the HIV fusion protein, Env. To contribute an additional perspective to the developing model of Serinc5 restriction, we assessed Serinc2 and Serinc5's effects on HIV pseudoviral membranes. By measuring pseudoviral membrane thickness via cryo-electron microscopy and order via the fluorescent dye, …

Toward Practical Integration Of Omic And Imaging Data In Co-Clinical Trials, Emel Alkim, Heidi Dowst, Julie Dicarlo, Lacey E Dobrolecki, Anadulce Hernández-Herrera, David A Hormuth, Yuxing Liao, Apollo Mcowiti, Robia Pautler, Mothaffar Rimawi, Ashley Roark, Ramakrishnan Rajaram Srinivasan, Jack Virostko, Bing Zhang, Fei Zheng, Daniel L Rubin, Thomas E Yankeelov, Michael T Lewis

Faculty, Staff and Students Publications

Co-clinical trials are the concurrent or sequential evaluation of therapeutics in both patients clinically and patient-derived xenografts (PDX) pre-clinically, in a manner designed to match the pharmacokinetics and pharmacodynamics of the agent(s) used. The primary goal is to determine the degree to which PDX cohort responses recapitulate patient cohort responses at the phenotypic and molecular levels, such that pre-clinical and clinical trials can inform one another. A major issue is how to manage, integrate, and analyze the abundance of data generated across both spatial and temporal scales, as well as across species. To address this issue, we are developing MIRACCL …