Biological Phenomena, Cell Phenomena, and Immunity Commons^™

The Role Of Ceramides As Biomarkers And Therapeutic Targets For Cardiometabolic Disease And Its Intersection With Cellular Aging, Youssef Moustafa Shalaby

Thesis/ Dissertation Defenses

Ceramides (Cer), a subclass of sphingolipids with potent bioactive properties, have gained recognition as key players in the pathogenesis of cardiometabolic diseases (CMD). They modulate critical cellular functions such as apoptosis, inflammation, insulin signaling, and oxidative stress. This dissertation explores the dual role of Cer as both early diagnostic markers and therapeutic targets, bridging clinical insights with mechanistic understanding through a combination of human and experimental studies.

A highly sensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was developed and validated to quantify intracellular levels of specific Cer species, including CerC16:0, CerC18:0, CerC22:0, CerC24:0, and CerC24:1. This method was translated into …

Genomic Biomarkers To Predict Response To Atezolizumab Plus Bevacizumab Immunotherapy In Hepatocellular Carcinoma: Insights From The Imbrave150 Trial, Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Kena Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee

Faculty, Staff and Student Publications

Background/aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.

Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full …

Prognostic Impact Of Notch1 Intracellular Domain, P63, And C-Myc In Lacrimal Gland Adenoid Cystic Carcinoma, Jiawei Zhao, Michelle D Williams, Mike Hernandez, Grace Kuang, Hila Goldberg, Jing Ning, Bita Esmaeli

Faculty, Staff and Student Publications

PURPOSE: We assessed whether NICD1 expression, c-MYC expression, and P63 expression by immunohistochemistry (IHC) correlate with prognosis and high-risk clinicopathological features in lacrimal gland adenoid cystic carcinoma (ACC).

METHODS: Records of patients with lacrimal gland ACC who underwent surgery between 1998 to 2018 were reviewed. Clinicopathologic and treatment data were collected. Tumor tissues were subjected to light microscopy and IHC.

RESULTS: Of 43 patients treated during the study period, 21 had archived tumor tissue available and were included. The median age at diagnosis was 47 years, and 13 patients (62%) were male. Thirteen patients (62%) had T2 disease, and none …

Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation In Melanoma: Impact Of Antibiotic Preconditioning On Microbiome And Immunity, Isabella C Glitza, Yongwoo David Seo, Christine N Spencer, Jennifer R Wortman, Elizabeth M Burton, Christopher P Loo, Ashish Damania, Julie Densmore, Justin Fairchild, Christopher R Cabanski, Matthew C Wong, Christine B Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher Mcchalicher, Emily Walsh, Michael T Tetzlaff, Omid Hamid, Patrick A Ott, Genevieve M Boland, Ryan J Sullivan, Kenneth F Grossmann, Nadim J Ajami, Theresa Lavallee, Matthew R Henn, Hussein A Tawbi, Jennifer A Wargo

Faculty, Staff and Student Publications

Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate …

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …

Circulating Microrna Panel For Prediction Of Recurrence And Survival In Early-Stage Lung Adenocarcinoma, Mei-Chee Tai, Leonidas E Bantis, Gargy Parhy, Taketo Kato, Ichidai Tanaka, Junya Fujimoto, Tetsunari Hase, Koji Kawaguchi, Johannes F Fahrmann, Edwin J Ostrin, Kohei Yokoi, Toyofumi F Chen-Yoshikawa, Yoshinori Hasegawa, Samir M Hanash, Ignacio I Wistuba, Ayumu Taguchi

Faculty, Staff and Student Publications

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and …

Delineating The Mechanism Of Fragility At Bcl6 Breakpoint Region Associated With Translocations In Diffuse Large B Cell Lymphoma, Vidya Gopalakrishnan, Urbi Roy, Shikha Srivastava, Khyati M Kariya, Shivangi Sharma, Bibha Choudhary

Faculty, Staff and Student Publications

BCL6 translocation is one of the most common chromosomal translocations in cancer and results in its enhanced expression in germinal center B cells. It involves the fusion of BCL6 with any of its twenty-six Ig and non-Ig translocation partners associated with diffuse large B cell lymphoma (DLBCL). Despite being discovered long back, the mechanism of BCL6 fragility is largely unknown. Analysis of the translocation breakpoints in 5' UTR of BCL6 reveals the clustering of most of the breakpoints around a region termed Cluster II. In silico analysis of the breakpoint cluster sequence identified sequence motifs that could potentially fold into …

Siglec15, Negatively Correlated With Pd-L1 In Hcc, Could Induce Cd8+ T Cell Apoptosis To Promote Immune Evasion, Qiang Yu, Shuang Liu, Binghai Zhou, Jiuliang Yan, Wentao Zhang, Xiaoqiang Li, Yongfeng Xu, Yongsheng Xiao, Jian Zhou, Jia Fan, Mien-Chie Hung, Qinghai Ye, Hui Li, Lei Guo

Faculty, Staff and Student Publications

Functional roles of SIGLEC15 in hepatocellular carcinoma (HCC) were not clear, which was recently found to be an immune inhibitor with similar structure of inhibitory B7 family members. SIGLEC15 expression in HCC was explored in public databases and further examined by PCR analysis. SIGLEC15 and PD-L1 expression patterns were examined in HCC samples through immunohistochemistry. SIGLEC15 expression was knocked-down or over-expressed in HCC cell lines, and CCK8 tests were used to examine cell proliferative ability in vitro. Influences of SIGLEC15 expression on tumor growth were examined in immune deficient and immunocompetent mice respectively. Co-culture system of HCC cell lines and …

Genomic Profiles And Clinical Outcomes Of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden, Petros Grivas, Jeffrey S Ross, Joseph M Jacob, Rebecca A Sager, Alina Basnet, Gerald Li, Ryon P Graf, Dean C Pavlick, Gennady Bratslavsky

Faculty, Staff and Student Publications

IMPORTANCE: Tumor mutational burden (TMB) is a putative biomarker of efficacy for immune checkpoint inhibitor (ICI) therapies of solid tumors, but not specifically for penile squamous cell carcinoma (PSCC).

OBJECTIVE: To characterize biomarker features and ICI therapy outcomes associated with high TMB in PSCC in the routine clinical practice setting.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, 397 PSCC cases were analyzed to identify genomic alterations in more than 300 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture-based comprehensive genomic profiling assay. Tumor mutational burden was categorized as low ([mut/Mb]), high (10-19 mut/Mb), or very high …

Blood-Based Transcriptomic Biomarkers Are Predictive Of Neurodegeneration Rather Than Alzheimer's Disease, Artur Shvetcov, Shannon Thomson, Jessica Spathos, Ann-Na Cho, Heather M Wilkins, Fabien Delerue, Jasmeen Kaur Issar, Finula Isik, Simranpreet Kaur, Eleanor Drummond, Carol Dobson-Stone, Shantel L Duffy, Natasha M Rogers, Daniel Catchpoole, Wendy A Gold, Russell H Swerdlow, David A Brown, Caitlin A Finney

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is a growing global health crisis affecting millions and incurring substantial economic costs. However, clinical diagnosis remains challenging, with misdiagnoses and underdiagnoses being prevalent. There is an increased focus on putative, blood-based biomarkers that may be useful for the diagnosis as well as early detection of AD. In the present study, we used an unbiased combination of machine learning and functional network analyses to identify blood gene biomarker candidates in AD. Using supervised machine learning, we also determined whether these candidates were indeed unique to AD or whether they were indicative of other neurodegenerative diseases, such as …

The Gut Microbiome As A Biomarker And Therapeutic Target In Hepatocellular Carcinoma, Betul Gok Yavuz, Saumil Datar, Shadi Chamseddine, Yehia I Mohamed, Michael Lapelusa, Zishuo Ian Hu, Hop S Tran Cao, Prasun Kumar Jalal, Carrie Daniel-Macdougall, Manal Hassan, Dan G Duda, Hesham M Amin, Ahmed O Kaseb

Faculty, Staff and Student Publications

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, …

A Multiparameter Molecular Classifier To Predict Response To Neoadjuvant Lapatinib Plus Trastuzumab Without Chemotherapy In Her2+ Breast Cancer, Tao Wang, Hiroaki Nitta, Monesh Kapadia, Anne C Pavlick, Patricia Galvan, Brent Rexer, Andres Forero-Torres, Rita Nanda, Anna M Storniolo, Ian E Krop, Matthew P Goetz, Julie R Nangia, Antonio C Wolff, Britta Weigelt, Jorge S Reis-Filho, Susan G Hilsenbeck, Aleix Prat, C Kent Osborne, Rachel Schiff, Mothaffar F Rimawi

Faculty, Staff and Student Publications

PURPOSE: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy.

EXPERIMENTAL DESIGN: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based …

The Glycoprotein Cd147 Defines Mirna-Enriched Extracellular Vesicles That Derive From Cancer Cells, Song Yi Ko, Wonjae Lee, Melanie Weigert, Eric Jonasch, Ernst Lengyel

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) are ideal for liquid biopsy, but distinguishing cancer cell‐derived EVs and subpopulations of biomarker‐containing EVs in body fluids has been challenging. Here, we identified that the glycoproteins CD147 and CD98 define subpopulations of EVs that are distinct from classical tetraspanin+ EVs in their biogenesis. Notably, we identified that CD147+ EVs have substantially higher microRNA (miRNA) content than tetraspanin+ EVs and are selectively enriched in miRNA through the interaction of CD147 with heterogeneous nuclear ribonucleoprotein A2/B1. Studies using mouse xenograft models showed that CD147+ EVs predominantly derive from cancer cells, whereas the majority of tetraspanin+ EVs are not …

Towards A Biomarker For Acute Arterial Thrombosis Using Complete Blood Count And White Blood Cell Differential Parameters In Mice, Hee Jeong Jang, Dawid Schellingerhout, Jiwon Kim, Jinyong Chung, Dong-Eog Kim

Faculty, Staff and Student Publications

There is no blood biomarker diagnostic of arterial thrombosis. We investigated if arterial thrombosis per se was associated with alterations in complete blood count (CBC) and white blood cell (WBC) differential count in mice. Twelve-week-old C57Bl/6 mice were used for FeCl3-mediated carotid thrombosis (n = 72), sham-operation (n = 79), or non-operation (n = 26). Monocyte count (/µL) at 30-min after thrombosis (median 160 [interquartile range 140-280]) was ~ 1.3-fold higher than at 30-min after sham-operation (120 [77.5-170]), and twofold higher than in non-operated mice (80 [47.5-92.5]). At day-1 and -4 post-thrombosis, compared with 30-min, monocyte count decreased by about …

Role Of Vascular Endothelial Growth Factor Receptor 2 Pathway Due To Preeclampsia: A Review, Firdous Ali

Williams Honors College, Honors Research Projects

Preeclampsia is a pregnancy complication that is characterized mainly by hypertension in the mother. The exact pathogenesis of preeclampsia is unknown, although the disease is attributed to a number of factors such as angiogenic factor levels and endothelial dysfunction. Presently, the control program for the disease involves the delivery of the fetus and the placenta. There is a need to develop novel therapies that would control preeclampsia from the moment it is diagnosed to minimize the effects on the mother and child. VEGF is a protein involved in the pathogenesis of the condition. The defect in one of its receptors, …

Investigation Of The Functional Impact Of Anti-Pd-1 On Tumor-Infiltrating Lymphocytes (Til) And Mapping Of Tumor Genomic Features Relevant For Response To Til Therapy, Caitlin Creasy

Dissertations and Theses (Open Access)

With the growing use of both cellular and antibody-based immunotherapies, it has become more important to uncover biomarkers to predict patient response to therapy and ideally aid in patient selection for specific therapeutics, thereby enhancing treatment outcome. At MD Anderson, we have a 43% response rate to therapy when treating metastatic melanoma patients with adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL), but it is unknown what makes the other 57% of patients not respond to therapy. It is further unknown how particularly early doses of checkpoint inhibitors, like anti-PD-1, attribute to TIL functionality, adding another confounding factor in determining …

Natural Autoantibodies: Origin, Function And Utility For Diagnosis Of Disease, Abhirup Sarkar

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and …

Antibodies In The Diagnosis, Prognosis, And Prediction Of Psychotic Disorders., Thomas A Pollak, Jonathan P Rogers, Robert G Nagele, Mark Peakman, James M Stone, Anthony S David, Philip Mcguire

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Blood-based biomarker discovery for psychotic disorders has yet to impact upon routine clinical practice. In physical disorders antibodies have established roles as diagnostic, prognostic and predictive (theranostic) biomarkers, particularly in disorders thought to have a substantial autoimmune or infective aetiology. Two approaches to antibody biomarker identification are distinguished: a "top-down" approach, in which antibodies to specific antigens are sought based on the known function of the antigen and its putative role in the disorder, and emerging "bottom-up" or "omics" approaches that are agnostic as to the significance of any one antigen, using high-throughput arrays to identify distinctive components of the …

Role Of Oxidized Extracellular Vesicles As Early Biomarkers And Inflammatory Mediators In Chemotherapy-Induced Normal Tissue Injury, Chontida Yarana

Theses and Dissertations--Toxicology and Cancer Biology

Significant advances in the efficacy of cancer therapy have been accompanied by an escalation of side effects that result from therapy-induced injury to normal tissues. Patients with high grade cancer or metastasis are often treated with chemotherapy, 50% of which are associated with reactive oxygen species generation and cellular oxidative stress. Heart is the normal tissue most susceptible to chemotherapy-induced oxidative stress and heart disease is the most common leading cause of death in cancer survivors. However, early and sensitive biomarkers to identify heart disease are still lacking. Extracellular vesicles (EVs) are released from cells during oxidative stress and send …

Utility And Origin Of Blood-Based Autoantibodies For Early Detection And Diagnosis Of Neurodegenerative Diseases, Cassandra Demarshall

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies are self-reactive antibodies that have been widely implicated as causal agents of autoimmune diseases. They are found in the blood of all human sera, regardless of age, gender, or the presence or absence of disease. While the underlying reason for their ubiquity remains unknown, it has been hypothesized that they participate in the clearance of blood-borne cell and tissue debris generated in both healthy and diseased individuals on a daily basis. Although much evidence supports this debris clearance role, recent studies also suggest a causal role for autoantibodies in disease. My thesis work has focused on this "cause and/or …