Genetic Phenomena Commons^™

Integrative Multi-Omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes In Ovarian Cancer, Spencer R Rosario, Mark D Long, Shanmuga Chilakapati, Eduardo Cortes Gomez, Sebastiano Battaglia, Jianmin Wang, Kristopher Attwood, Suzanne M Hess, A J Robert Mcgray, Kunle Odunsi, Brahm H Segal, Gyorgy Paragh, Song Liu, Jennifer A Wargo, Emese Zsiros

Faculty, Staff and Student Publications

Recurrent ovarian cancer patients, especially those resistant to platinum, lack effective curative treatments. To address this, we conducted a phase 2 clinical trial (NCT02853318) combining pembrolizumab with bevacizumab, to increase T cell infiltration into the tumor, and oral cyclophosphamide, to reduce the number of regulatory T cells. The trial accrued 40 heavily pretreated recurrent ovarian cancer patients. The primary endpoint, progression free survival, was extended to a median of 10.2 months. The secondary endpoints demonstrated an objective response rate of 47.5%, and disease control in 30% of patients for over a year while maintaining a good quality of life. We …

Trajectory, Interactions, And Predictors Of Higher Symptom Burden During Induction Therapy For Multiple Myeloma, Mona Kamal, Qiuling Shi, Shu-En Shen, Charles Cleeland, Xin Shelley Wang

Faculty, Staff and Student Publications

Background: Patients with multiple myeloma (MM) experience disabling symptoms that are difficult to manage and may persist after induction therapy. Monitoring disease-related and induction therapy-induced symptoms and identifying patients at greater risk for high symptom burden are unmet clinical needs. The objective of this study was to examine the trajectories of symptom severity over time and identify predictors of high symptom burden during MM induction therapy.

Methodology: Eligible patients with MM rated their symptoms by completing the MD Anderson Symptom Inventory MM module repeatedly during 16 weeks of induction therapy. Group-based trajectory modeling identified patient groups with persistently high-severity (versus …

Diet And Immune Effects Trial (Diet)- A Randomized, Double-Blinded Dietary Intervention Study In Patients With Melanoma Receiving Immunotherapy, Rachel M Farias, Yan Jiang, Erma J Levy, Cindy Hwang, Jian Wang, Lorenzo Cohen, Jennifer A Wargo, Carrie R Daniel, Jennifer L Mcquade

Faculty, Staff and Student Publications

Background: Gut microbiome modulation is a promising strategy for enhancing the response to immune checkpoint blockade (ICB). Fecal microbiota transplant studies have shown positive signals of improved outcomes in both ICB-naïve and refractory melanoma patients; however, this strategy is challenging to scale. Diet is a key determinant of the gut microbiota, and we have previously shown that (a) habitual high dietary fiber intake is associated with an improved response to ICB and (b) fiber manipulation in mice impacts antitumor immunity. We recently demonstrated the feasibility of a controlled high-fiber dietary intervention (HFDI) conducted in melanoma survivors with excellent compliance and …

Epigenetic Modifiers: Exploring The Roles Of Histone Methyltransferases And Demethylases In Cancer And Neurodegeneration, Lauren Reed, Janak Abraham, Shay Patel, Shilpa S Dhar

Faculty, Staff and Student Publications

Histone methyltransferases (HMTs) and histone demethylases (HDMs) are critical enzymes that regulate chromatin dynamics and gene expression through the addition and removal of methyl groups on histone proteins. HMTs, such as PRC2 and SETD2, are involved in the trimethylation of histone H3 at lysine 27 and lysine 36, influencing gene silencing and activation. Dysregulation of these enzymes often leads to abnormal gene expression and contributes to tumorigenesis. In contrast, HDMs including KDM7A and KDM2A reverse these methylation marks, and their dysfunction can drive disease progression. In cancer, the aberrant activity of specific HMTs and HDMs can lead to the silencing …

Correction: Nepali Oral Microbiomes Reflect A Gradient Of Lifestyles From Traditional To Industrialized, Erica P Ryu, Yoshina Gautam, Diana M Proctor, Dinesh Bhandari, Sarmila Tandukar, Guru Prasad Gautam, Ahmed A Shibl, Jeevan Bahadur Sherchand, Aashish R Jha, Emily R Davenport

Faculty, Staff and Student Publications

No abstract provided.

Individualized Functional Magnetic Resonance Imaging Neuromodulation Enhances Visuospatial Perception: A Proof-Of-Concept Study, Anthony Allam, Vincent Allam, Sandy Reddy, Eric M Rohren, Sameer A Sheth, Emmanouil Froudarakis, T Dorina Papageorgiou

Duncan NRI Faculty and Staff Publications

This proof-of-concept study uses individualized functional magnetic resonance imaging neuromodulation (iNM) to explore the mechanisms that enhance BOLD signals in visuospatial perception (VP) networks that are crucial for navigation. Healthy participants (n = 8) performed a VP up- and down-direction discrimination task at full and subthreshold coherence through peripheral vision, and superimposed direction through visual imagery (VI) at central space under iNM and control conditions. iNM targets individualized anatomical and functional middle- and medial-superior temporal (MST) networks that control VP. We found that iNM engaged selective exteroceptive and interoceptive attention (SEIA) and motor planning (MP) networks. Specifically, iNM increased …

Inherited Retinal Degenerations And Non-Neovascular Age-Related Macular Degeneration: Progress And Unmet Needs, Jacque L Duncan, Angela Bowman, Amy Laster, Claire Gelfman, David G Birch, Stephen P Daiger, Donald J Zack, James T Handa

Faculty, Staff and Student Publications

Inherited retinal degeneration (IRD) disease and age-related macular degeneration (AMD) are leading causes of irreversible vision loss and blindness. Although significant progress has advanced the field in the past 5 years, significant challenges remain. The current article reviews the accomplishments and research advances that have fueled the development of treatments for patients with IRD and AMD, including the first approved gene-augmentation treatment for RPE65-related retinal degeneration and complement inhibition therapies to slow progression of geographic atrophy (GA) in AMD. The article outlines opportunities to address gaps and unmet needs that should lead to additional progress toward the development of treatments …

Rna Shielding Of P65 Is Required To Potentiate Oncogenic Inflammation In Tet2-Mutated Clonal Hematopoiesis, Nana Adjoa Ben-Crentsil, Wazim Mohammed Ismail, Maria E Balasis, Hannah Newman, Ariel Quintana, Traci Kruer, Meghan C Ferrall-Fairbanks, Jenna Fernandez, Terra L Lasho, Christy M Finke, Mohammed L Ibrahim, Kathy L Mcgraw, Michael Wysota, Amy L Aldrich, Christopher B Ryder, Christopher T Letson, Joshua Traina, Amy F Mclemore, Nathalie Droin, Aditi Shastri, Seongseok Yun, Eric Solary, David A Sallman, Amer A Beg, Li Ma, Alexandre Gaspar-Maia, Mrinal M Patnaik, Eric Padron

Faculty, Staff and Student Publications

This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 "shields" p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

Myeloid Activation Clears Ascites And Reveals Il27-Dependent Regression Of Metastatic Ovarian Cancer, Brennah Murphy, Taito Miyamoto, Bryan S Manning, Gauri Mirji, Alessio Ugolini, Kohei Hamada, Daniel T Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang

Faculty, Staff and Student Publications

Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of < 30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.

Systemic Administration Of A Site-Targeted Complement Inhibitor Attenuates Chronic Stress-Induced Social Behavior Deficits And Neuroinflammation In Mice, Amit Kumar Madeshiya, Brandi Quintanilla, Carl Whitehead, Stephen Tomlinson, Anilkumar Pillai

Faculty, Staff and Student Publications

Chronic stress, a risk factor for many neuropsychiatric conditions, causes dysregulation in the immune system in both humans and animal models. Additionally, inflammation and synapse loss have been associated with deficits in social behavior. The complement system, a key player of innate immunity, has been linked to social behavior impairments caused by chronic stress. However, it is not known whether complement inhibition can help prevent neuroinflammation and behavioral deficits caused by chronic stress. In this study, we investigated the potential of a site-targeted complement inhibitor to ameliorate chronic stress-induced changes in social behavior and inflammatory markers in the prefrontal cortex …

Private-Sector Readmissions For Inpatient Surgery In Veterans Health Administration Hospitals, Mary Vaughan Sarrazin, Yubo Gao, Carly A Jacobs, Michael A Jacobs, Susanne Schmidt, Katherine Hadlandsmyth, John Cashy, George Wehby, Paula K Shireman, Daniel E Hall

Faculty, Staff and Student Publications

Importance: The Veterans Health Administration (VHA) reports multiple indicators of hospital surgical performance, including hospital risk-standardized 30-day readmission rates (RSRRs). Currently, most routinely reported measures do not include readmissions that occur outside VHA hospitals. The impact of readmissions outside the VHA on hospital RSRR is not known.

Objective: To measure the impact of including non-VHA readmissions on VHA hospital performance rankings for 30-day readmission.

Design, setting, and participants: This retrospective cohort study included patients aged at least 65 years from 2013 to 2019 from the Veterans Affairs Surgical Quality Improvement Program linked to patient-level data from the VHA and Medicare. …

Impact Of Prenatal Genomics On Clinical Genetics Practice, Roni Zemet, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Genetic testing for prenatal diagnosis in the pre-genomic era primarily focused on detecting common fetal aneuploidies, using methods that combine maternal factors and imaging findings. The genomic era, ushered in by the emergence of new technologies like chromosomal microarray analysis and next-generation sequencing, has transformed prenatal diagnosis. These new tools enable screening and testing for a broad spectrum of genetic conditions, from chromosomal to monogenic disorders, and significantly enhance diagnostic precision and efficacy. This chapter reviews the transition from traditional karyotyping to comprehensive sequencing-based genomic analyses. We discuss both the clinical utility and the challenges of integrating prenatal exome and …

Individual Dynamic Prediction For Cure And Survival Based On Longitudinal Biomarkers, Can Xie, Xuelin Huang, Ruosha Li, Alexander Tsodikov, Kapil Bhalla

Faculty, Staff and Student Publications

To optimize personalized treatment strategies and extend patients' survival times, it is critical to accurately predict patients' prognoses at all stages, from disease diagnosis to follow-up visits. The longitudinal biomarker measurements during visits are essential for this prediction purpose. Patients' ultimate concerns are cure and survival. However, in many situations, there is no clear biomarker indicator for cure. We propose a comprehensive joint model of longitudinal and survival data and a landmark cure model, incorporating proportions of potentially cured patients. The survival distributions in the joint and landmark models are specified through flexible hazard functions with the proportional hazards as …

Nuclear Expression Of Dynamin 2 Is Associated With Tumor Aggressiveness In Bladder Cancer Patients: A Bioinformatics And Experimental Approach, Mahdieh Razmi, Leili Saeednejad Zanjani, Mandana Rahimi, Roya Sajed, Sadegh Safaei, Zahra Madjd, Roya Ghods

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: Dynamin 2 (DNM2) is aberrantly expressed in different malignancies and exerts a function in tumor progression.

AIMS: This study, for the first time, aimed to evaluate the clinical and prognostic value of DNM2 in the pathophysiology of bladder cancer using bioinformatics analysis and experimental evaluation.

METHODS AND RESULTS: We analyzed gene expression of DNM2 in bladder tumor by GEPIA2 and GENT2 platforms. Cluster subnetworks were recognized from the protein-protein interaction (PPI) network using the MCODE plugin to screen the key genes. Subsequently, the pathway enrichment analysis was evaluated. Then, the immunohistochemical examination was conducted on 209 paraffin-embedded bladder cancer …

Why And When Do We Invasively Restage After Neoadjuvant Chemoimmunotherapy?, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Karen L Kelly

Faculty, Staff and Student Publications

No abstract provided.

Ecological And Pathological Applications Of The Heat Shock Response, Taylor Rae Stanley

Theses and Dissertations

The heat shock response (HSR) is a cytoprotective stress response pathway that regulates cellular proteostasis. The HSR is an evolutionarily conserved pathway that is essential for normal cellular functioning. Here, we explore the broad ecological and pathological impacts of the HSR. In an ecological context, we perform gene level analysis of the transcriptomes of two closely related sunfish. We found that the more invasive bluegill sunfish has gene expansions in two HSR gene families, the HSP70 family and the HSP90 family compared to the redear sunfish. These gene expansions were also observed in several other teleost fish species and were …

Impact Of Human Immunoglobulin Genetic Variants On The Expressed Antibody Repertoire., Eric Engelbrecht

Electronic Theses and Dissertations

B cells produce immunoglobulins (IGs; antibodies), which are critical protein components of the immune system. Human IGs are composed of two pairs of identical ‘heavy’ chains and ‘light’ kappa or lambda chains, encoded by genes located at three loci in the genome: the IG heavy chain locus (IGH, chromosome 14), and the IG lambda (IGL, chromosome 22) and kappa (IGK, chromosome 2) loci. Each locus spans ~920-100 kilobase pairs (Kbp) of DNA and harbors families of gene segments that are somatically rearranged during B cell development. The IG loci collectively harbor >180 functional genes, many of which are part of …

The Role Of Epigenetic Aberrations In The Cold Tumor Phenotype And Inflammatory Signaling In High-Risk Neuroblastoma, Pamela Morgan Watson

Alternative Theses and Dissertations (AETDs)

Neuroblastoma (NB) is a highly aggressive, heterogeneous disease that arises from the sympathetic nervous system (SNS) and originates from neural crest cells (NCCs) (1). NB is the most common extracranial cancer in pediatric accounts for 15% of pediatric cancer deaths (2). This high mortality rate is the result of the metastatic, immune evasive, and treatment resistant characteristics of the disease (3). It has been proposed that NB arises from blocks in differentiation during development, resulting in a mixture of two distinct cell types within the tumor: mesenchymal and adrenergic (Figure 1.1) (4,5). The adrenergic cell type is more differentiated, and …

Genetic Testing And Anorexia Nervosa: Knowledge, Attitudes And Awareness, Sarah Ramsay

All Dissertations

This dissertation consists of three parts, each building on the results of the former, evaluating the treatment and research of anorexia nervosa (AN) from a healthcare genetics perspective. These three parts are bookended by an introduction and a conclusion summarizing key findings and providing suggestions for future work. First, in order to assess how Severe and Enduring Anorexia Nervosa (SE-AN) is defined in the literature, and inclusion of those with SE-AN in genetics research, a comprehensive literature review was performed. The review found a lack of consistent identification and inclusion of the SE-AN subtype in AN genetic study participants. Second, …

Receipt Of Home Health And 30-Day Outcomes Among Veterans With Dementia Following Inpatient Surgery, Heather Davila, Yubo Gao, Katherine E Hadlandsmyth, Andrea L Strayer, Michael A Jacobs, Paula K Shireman, Susanne Schmidt, Leslie R M Hausmann, Carly A Jacobs, Daniel E Hall, Mary Vaughan Sarrazin

Faculty, Staff and Student Publications

No abstract provided.