Digital Commons Network^™

Timing Of Invasive Mechanical Ventilation And Death In Critically Ill Adults With Covid-19: A Multicenter Cohort Study, Adam Green, Jean-Sebastien Rachoin, Christa Schorr, Phil Dellinger, Jonathan D Casey, Isabel Park, Shruti Gupta, Rebecca M Baron, Shahzad Shaefi, Krystal Hunter, David E Leaf

Faculty, Staff and Student Publications

PURPOSE: To investigate if the timing of initiation of invasive mechanical ventilation (IMV) for critically ill patients with COVID-19 is associated with mortality.

MATERIALS AND METHODS: The data for this study were derived from a multicenter cohort study of critically ill adults with COVID-19 admitted to ICUs at 68 hospitals across the US from March 1 to July 1, 2020. We examined the association between early (ICU days 1-2) versus late (ICU days 3-7) initiation of IMV and time-to-death. Patients were followed until the first of hospital discharge, death, or 90 days. We adjusted for confounding using a multivariable Cox …

Cancer-Associated Pyroptosis: A New License To Kill Tumor, Qing Kong, Zhibin Zhang

Faculty, Staff and Student Publications

Pyroptosis is a programmed necrotic cell death mediated by pore-forming Gasdermin (GSDM) proteins. After being unleashed from the C-terminal auto-inhibitory domains by proteolytic cleavage, the N-terminal domains of GSDMs oligomerize and perforate on the plasma membrane to induce cytolytic pyroptosis, releasing immune mediators and alarming the immune system. Upon infection or danger signal perception, GSDMD that functions downstream of the inflammasome, a supramolecular complex for inflammatory caspase activation, is cleaved and activated by inflammasome-activated caspase-1/4/5/11 in immune cells and epithelial cells to trigger pyroptosis and exert anti-infection protection. Unlike this inflammasome-activated pyroptosis (IAP), recent studies also suggest an emerging role …

Combining Small Angle X-Ray Scattering (Saxs) With Protein Structure Predictions To Characterize Conformations In Solution, Naga Babu Chinnam, Aleem Syed, Greg L Hura, Michal Hammel, John A Tainer, Susan E Tsutakawa

Faculty, Staff and Student Publications

Accurate protein structure predictions, enabled by recent advances in machine learning algorithms, provide an entry point to probing structural mechanisms and to integrating and querying many types of biochemical and biophysical results. Limitations in such protein structure predictions can be reduced and addressed through comparison to experimental Small Angle X-ray Scattering (SAXS) data that provides protein structural information in solution. SAXS data can not only validate computational predictions, but can improve conformational and assembly prediction to produce atomic models that are consistent with solution data and biologically relevant states. Here, we describe how to obtain protein structure predictions, compare them …

Unveiling The Noncanonical Activation Mechanism Of Cdks: Insights From Recent Structural Studies, Tao Li, Hui-Chi Tang, Kuang-Lei Tsai

Faculty, Staff and Student Publications

The Cyclin-dependent kinases (CDKs) play crucial roles in a range of essential cellular processes. While the classical two-step activation mechanism is generally applicable to cell cycle-related CDKs, both CDK7 and CDK8, involved in transcriptional regulation, adopt distinct mechanisms for kinase activation. In both cases, binding to their respective cyclin partners results in only partial activity, while their full activation requires the presence of an additional subunit. Recent structural studies of these two noncanonical kinases have provided unprecedented insights into their activation mechanisms, enabling us to understand how the third subunit coordinates the T-loop stabilization and enhances kinase activity. In this …

Radiotherapy Reimagined: Integrating Nanomedicines Into Radiotherapy Clinical Trials, Allison N Duross, Jack Phan, Alexander J Lazar, Joshua M Walker, Alexander R Guimaraes, Carole Baas, Sunil Krishnan, Charles R Thomas, Conroy Sun, Alexander F Bagley

Faculty, Staff and Student Publications

Radioenhancing nanoparticles (NPs) are being evaluated in ongoing clinical trials for various cancers including head and neck, lung, esophagus, pancreas, prostate, and soft tissue sarcoma. Supported by decades of preclinical investigation and recent randomized trial data establishing clinical activity, these agents are poised to influence future multimodality treatment paradigms involving radiotherapy. Although the physical interactions between NPs and ionizing radiation are well characterized, less is known about how these agents modify the tumor microenvironment, particularly regarding tumor immunogenicity. In this review, we describe the key multidisciplinary considerations related to radiation, surgery, immunology, and pathology for designing radioenhancing NP clinical trials. …

The Phase 1/2 Trial Of Indomethacin In Chronic Pancreatitis (The Pair Trial): Protocol For A Parallel Multi-Center Randomized Controlled Trial, Samuel Han, Darwin L Conwell, Liang Li, Alejandra Cervantes, Phil A Hart, Zobeida Cruz-Monserrate, Wenrui Hao, Gregory B Lesinski, Thomas Mace, Tonya M Palermo, Jami L Saloman, Dhiraj Yadav, Santhi Swaroop Vege, Mark Topazian, Consortium For The Study Of Chronic Pancreatitis, Diabetes, And Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Background/objectives: Current treatments for chronic pancreatitis focus on symptom management and therapeutics targeting disease reversal are lacking. Given the role of the cyclooxygenase-2 (COX-2) enzyme in producing prostaglandin E2 (PGE2), a key component in the inflammatory pathway of chronic pancreatitis, this study evaluates the physiologic effect of oral indomethacin, a COX-2 inhibitor, on PGE2 levels in pancreatic fluid.

Methods: This pilot two-center randomized controlled trial seeks to examine 32 subjects with chronic pancreatitis who have no contraindications to indomethacin. Subjects will be randomized to either oral indomethacin 50 mg twice a day or placebo twice a day for a total …

Disrupted Ca2+ Homeostasis And Immunodeficiency In Patients With Functional Ip3 Receptor Subtype 3 Defects, Julika Neumann, Erika Van Nieuwenhove, Lara E Terry, Frederik Staels, Taylor R Knebel, Kirsten Welkenhuyzen, Kourosh Ahmadzadeh, Mariah R Baker, Margaux Gerbaux, Mathijs Willemsen, John S Barber, Irina I Serysheva, Liesbeth De Waele, François Vermeulen, Susan Schlenner, Isabelle Meyts, David I Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston

Faculty, Staff and Student Publications

Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca2+) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP3R), a homo- or heterotetramer of the IP3R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca2+ from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP3R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP3R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 …

Dysregulated Coagulation System Links To Inflammation In Diabetic Kidney Disease, Mengyun Xiao, Donge Tang, Shaodong Luan, Bo Hu, Wenyu Gong, Wolfgang Pommer, Yong Dai, Lianghong Yin

Faculty, Staff and Student Publications

Diabetic kidney disease (DKD) is a significant contributor to end-stage renal disease worldwide. Despite extensive research, the exact mechanisms responsible for its development remain incompletely understood. Notably, patients with diabetes and impaired kidney function exhibit a hypercoagulable state characterized by elevated levels of coagulation molecules in their plasma. Recent studies propose that coagulation molecules such as thrombin, fibrinogen, and platelets are interconnected with the complement system, giving rise to an inflammatory response that potentially accelerates the progression of DKD. Remarkably, investigations have shown that inhibiting the coagulation system may protect the kidneys in various animal models and clinical trials, suggesting …

The Genetic Landscape And Clinical Implication Of Pediatric Moyamoya Angiopathy In An International Cohort, Yan-Hao Wei, Ren-Tang Bi, Yan-Mei Qiu, Chun-Lin Zhang, Jian-Zhuang Li, Ya-Nan Li, Bo Hu

Faculty, Staff and Student Publications

Ischemic stroke is a highly complex systemic disease characterized by intricate interactions between the brain and gastrointestinal tract. While our current understanding of these interactions primarily stems from experimental models, their relevance to human stroke outcomes is of considerable interest. After stroke, bidirectional communication between the brain and gastrointestinal tract initiates changes in the gastrointestinal microenvironment. These changes involve the activation of gastrointestinal immunity, disruption of the gastrointestinal barrier, and alterations in gastrointestinal microbiota. Importantly, experimental evidence suggests that these alterations facilitate the migration of gastrointestinal immune cells and cytokines across the damaged blood-brain barrier, ultimately infiltrating the ischemic brain. …

Common Statistical Concepts In The Supervised Machine Learning Arena, Hooman H Rashidi, Samer Albahra, Scott Robertson, Nam K Tran, Bo Hu

Faculty, Staff and Student Publications

One of the core elements of Machine Learning (ML) is statistics and its embedded foundational rules and without its appropriate integration, ML as we know would not exist. Various aspects of ML platforms are based on statistical rules and most notably the end results of the ML model performance cannot be objectively assessed without appropriate statistical measurements. The scope of statistics within the ML realm is rather broad and cannot be adequately covered in a single review article. Therefore, here we will mainly focus on the common statistical concepts that pertain to supervised ML (i.e. classification and regression) along with …

Conformational Rearrangements In The Sensory Rcsf/Omp Complex Mediate Signal Transduction Across The Bacterial Cell Envelope, Sarah R Lach, Santosh Kumar, Seonghoon Kim, Wonpil Im, Anna Konovalova

Faculty, Staff and Student Publications

Timely detection and repair of envelope damage are paramount for bacterial survival. The Regulator of Capsule Synthesis (Rcs) stress response can transduce the stress signals across the multilayered gram-negative cell envelope to regulate gene expression in the cytoplasm. Previous studies defined the overall pathway, which begins with the sensory lipoprotein RcsF interacting with several outer membrane proteins (OMPs). RcsF can also interact with the periplasmic domain of the negative regulator IgaA, derepressing the downstream RcsCDB phosphorelay. However, how the RcsF/IgaA interaction is regulated at the molecular level to activate the signaling in response to stress remains poorly understood. In this …

Interplay Between Liver Type 1 Innate Lymphoid Cells And Nk Cells Drives The Development Of Alcoholic Steatohepatitis, Chen Cheng, Qian Zhang, Yue Li, Jiali Jiang, Linxi Xie, Haiyuan Shen, Dongqing Wu, Hejiao Zhang, Huiru Zhang, Xuan Wang, Hongyu Wu, Jingjing Xu, Li Gui, Bao Li, Cynthia Ju, Hui Peng, Shi Yin, Long Xu

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Liver contains high frequency of group 1 innate lymphoid cells (ILC), which are composed of comparable number of type 1 ILC (ILC1) and natural killer (NK) cells in steady state. Little is known about whether and how the interaction between ILC1 and NK cells affects the development of alcoholic liver disease.

METHODS: A mouse model of chronic alcohol abuse plus single-binge (Gao-Binge model) was established. The levels of alanine aminotransferase/aspartate aminotransferase, hepatic lipid, and inflammatory cytokines or neutrophils were measured to evaluate the degree of liver injury, steatosis, and inflammation. Flow cytometric analysis, cell depletion, or adoptive …

Risk Factors Associated With Severe Clostridioides Difficile Infection In Patients With Cancer, Denise Marie A Francisco, Liangliang Zhang, Ying Jiang, Adilene Olvera, Javier Adachi, Eduardo Yepez Guevara, Samuel L Aitken, Kevin W Garey, Christine B Peterson, Kim-Anh Do, Ryan Dillon, Engels N Obi, Robert Jenq, Pablo C Okhuysen

Faculty, Staff and Student Publications

INTRODUCTION: Antibiotic use is a risk factor for Clostridioides difficile infection (CDI). Few studies have correlated use of prior antibiotic classes with CDI, microbiome composition, and disease severity in patients with cancer. We hypothesized that previous antibiotic exposure and fecal microbiome composition at time of presentation are risk factors for severe CDI in patients with cancer.

METHODS: This non-interventional, prospective, cohort study examined 200 patients with cancer who had their first episode or first recurrence of CDI. C. difficile was identified using nucleic acid amplification testing. Univariate analysis was used to determine significant risk factors for severe CDI. Fecal microbiome …

Clinical, Dosimetric, And Reporting Considerations For Y-90 Glass Microspheres In Hepatocellular Carcinoma: Updated 2022 Recommendations From An International Multidisciplinary Working Group, Riad Salem, Siddharth A Padia, Marnix Lam, Carlo Chiesa, Paul Haste, Bruno Sangro, Beau Toskich, Kirk Fowers, Joseph M Herman, S Cheenu Kappadath, Thomas Leung, Daniel Y Sze, Edward Kim, Etienne Garin

Faculty, Staff and Student Publications

PURPOSE: In light of recently published clinical reports and trials, the TheraSphere Global Dosimetry Steering Committee (DSC) reconvened to review new data and to update previously published clinical and dosimetric recommendations for the treatment of hepatocellular carcinoma (HCC).

METHODS: The TheraSphere Global DSC is comprised of health care providers across multiple disciplines involved in the treatment of HCC with yttrium-90 (Y-90) glass microsphere-based transarterial radioembolization (TARE). Literature published between January 2019 and September 2021 was reviewed, discussed, and adjudicated by the Delphi method. Recommendations included in this updated document incorporate both the results of the literature review and the expert …

The Interplay Between Neoantigens And Immune Cells In Sarcomas Treated With Checkpoint Inhibition, Irantzu Anzar, Brandon Malone, Pubudu Samarakoon, Ioannis Vardaxis, Boris Simovski, Hugues Fontenelle, Leonardo A Meza-Zepeda, Richard Stratford, Emily Z Keung, Melissa Burgess, Hussein A Tawbi, Ola Myklebost, Trevor Clancy

Faculty, Staff and Student Publications

INTRODUCTION: Sarcomas are comprised of diverse bone and connective tissue tumors with few effective therapeutic options for locally advanced unresectable and/or metastatic disease. Recent advances in immunotherapy, in particular immune checkpoint inhibition (ICI), have shown promising outcomes in several cancer indications. Unfortunately, ICI therapy has provided only modest clinical responses and seems moderately effective in a subset of the diverse subtypes.

METHODS: To explore the immune parameters governing ICI therapy resistance or immune escape, we performed whole exome sequencing (WES) on tumors and their matched normal blood, in addition to RNA-seq from tumors of 31 sarcoma patients treated with pembrolizumab. …

A Novel Case Of Eus-Guided Targeted Radiofrequency Ablation Of Metastatic Duodenal Renal Cell Carcinoma, Muhammad Vohra, Hemant Goyal, Putao Cen, Mairin Joseph-Talreja, Nirav Thosani

Faculty, Staff and Student Publications

No abstract provided.

Lysosomal Tmem9-Lamtor4-Controlled Mtor Signaling Integrity Is Required For Mammary Tumorigenesis, Shengzhe Zhang, Sung Ho Lee, Litong Nie, Yuanjian Huang, Gengyi Zou, Youn-Sang Jung, Sohee Jun, Jie Zhang, Esther M Lien, Junjie Chen, Jae-Il Park

Faculty, Staff and Student Publications

No abstract provided.

Severe Radiation-Induced Lymphopenia During Concurrent Chemoradiotherapy For Stage Iii Non-Small Cell Lung Cancer: External Validation Of Two Prediction Models, Peter S N Van Rossum, Celia Juan-Cruz, Barbara Stam, Maddalena M G Rossi, Steven H Lin, Azadeh Abravan, José S A Belderbos, Jan-Jakob Sonke

Faculty, Staff and Student Publications

BACKGROUND: Severe radiation-induced lymphopenia (RIL) in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with decreased immunotherapy efficacy and survival. At The Christie and MD Anderson Cancer Center (MDACC), prediction models for lymphopenia were developed in lung and esophageal cancer patients, respectively. The aim of this study was to externally validate both models in patients with stage III NSCLC.

METHODS: Patients who underwent concurrent CRT for stage III NSCLC in 2019-2021 were studied. Outcomes were grade ≥3 and grade 4 lymphopenia during CRT. The Christie model predictors for grade ≥3 lymphopenia included age, baseline lymphocyte count, …

Potential Chemoprotective Effects Of Active Ingredients In Salvia Miltiorrhiza On Doxorubicin-Induced Cardiotoxicity: A Systematic Review Of In Vitro And In Vivo Studies, Qingqing Wang, Jiaxian Li, Xuelei Chu, Xiaochen Jiang, Chuanlong Zhang, Fudong Liu, Xiyuan Zhang, Yi Li, Qian Shen, Bo Pang

Faculty, Staff and Student Publications

BACKGROUND: Recently, attention has been paid to the protective properties of active ingredients in

METHODS: According to the PRISMA guideline, the current systematic review was conducted in the Web of Science, PubMed, Embase, and the Cochrane Library to collect all relevant

RESULTS: Twenty-two eligible articles were included in this systematic review. Eleven types of active ingredients in

CONCLUSION: This systematic review demonstrated that AISM have chemoprotective effects on DIC

Lysosomes, Curcumin, And Anti-Tumor Effects: How Are They Linked?, Qian Shen, Xue Pan, Yi Li, Junchen Li, Chuanlong Zhang, Xiaochen Jiang, Fudong Liu, Bo Pang

Faculty, Staff and Student Publications

Curcumin is a natural active ingredient from traditional Chinese medicine (TCM) that has multi-target characteristics to exert extensive pharmacological activities and thus has been applied in the treatment of various diseases such as cancer, cardiovascular diseases, nervous system, and autoimmune disorders. As an important class of membranous organelles in the intracellular membrane system, lysosomes are involved in biological processes such as programmed cell death, cell metabolism, and immune regulation, thus affecting tumor initiation and progression. It has been shown that curcumin can modulate lysosomal function through the aforementioned pathways, thereby affecting tumor proliferation, invasion, metastasis, drug resistance, and immune function. …

Pepsim: T-Cell Cross-Reactivity Prediction Via Comparison Of Peptide Sequence And Peptide-Hla Structure, Sarah Hall-Swan, Jared Slone, Mauricio M Rigo, Dinler A Antunes, Gregory Lizée, Lydia E Kavraki

Faculty, Staff and Student Publications

INTRODUCTION: Peptide-HLA class I (pHLA) complexes on the surface of tumor cells can be targeted by cytotoxic T-cells to eliminate tumors, and this is one of the bases for T-cell-based immunotherapies. However, there exist cases where therapeutic T-cells directed towards tumor pHLA complexes may also recognize pHLAs from healthy normal cells. The process where the same T-cell clone recognizes more than one pHLA is referred to as T-cell cross-reactivity and this process is driven mainly by features that make pHLAs similar to each other. T-cell cross-reactivity prediction is critical for designing T-cell-based cancer immunotherapies that are both effective and safe. …

The Cx3cl1-Cx3cr1 Chemokine Axis Can Contribute To Tumor Immune Evasion And Blockade With A Novel Cx3cr1 Monoclonal Antibody Enhances Response To Anti-Pd-1 Immunotherapy, Apoorvi Chaudhri, Xia Bu, Yunfei Wang, Michael Gomez, James A Torchia, Ping Hua, Shao-Hsi Hung, Michael A Davies, Gregory A Lizee, Ulrich Von Andrian, Patrick Hwu, Gordon J Freeman

Faculty, Staff and Student Publications

CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble …

Nano-Embedded Medical Devices And Delivery Systems In Interventional Radiology, Erin Marie D San Valentin, Allan John R Barcena, Carleigh Klusman, Benjamin Martin, Marites P Melancon

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Nanomaterials research has significantly accelerated the development of the field of vascular and interventional radiology. The incorporation of nanoparticles with unique and functional properties in medical devices and delivery systems has paved the way for the creation of novel diagnostic and therapeutic procedures for various clinical disorders. In this review, we discuss the advancements in the field of interventional radiology and the role of nanotechnology in maximizing the benefits and mitigating the disadvantages of interventional radiology theranostic procedures. Several nanomaterials have been studied to improve the efficacy of interventional radiology interventions, reduce the complications associated with medical devices, improve the …

A Novel Humanized Chi3l1 Blocking Antibody Attenuates Acetaminophen-Induced Liver Injury In Mice, Leike Li, Yankai Wen, Daniel Wrapp, Jongmin Jeong, Peng Zhao, Wei Xiong, Constance Lynn Atkins, Zhao Shan, Deng Hui, Jason S Mclellan, Ningyan Zhang, Cynthia Ju, Zhiqiang An

Faculty, Staff and Student Publications

Acetaminophen (APAP) overdose is a leading cause of acute liver injury in the USA. The chitinase 3-like-1 (Chi3l1) protein contributes to APAP-induced liver injury (AILI) by promoting hepatic platelet recruitment. Here, we report the development of a Chi3l1-targeting antibody as a potential therapy for AILI. By immunizing a rabbit successively with the human and mouse Chi3l1 proteins, we isolated cross-reactive monoclonal antibodies (mAbs) from single memory B cells. One of the human and mouse Chi3l1 cross-reactive mAbs was humanized and characterized in both

Spatial And Temporal Organization Of The Genome: Current State And Future Aims Of The 4d Nucleome Project, Clara Agudo-Rios, Amber Rogers, Isaiah King, Virali Bhagat, Le My Tu Nguyen, Carlos Córdova-Fletes, Diego Krapf, Jerome F Strauss, Lena Arévalo, Gina Esther Merges, Hubert Schorle, Eduardo R S Roldan, Maria Eugenia Teves

Faculty, Staff and Student Publications

Protamines (PRM1 and PRM2) are small, arginine-rich, nuclear proteins that replace histones in the final stages of spermiogenesis, ensuring chromatin compaction and nuclear remodeling. Defects in protamination lead to increased DNA fragmentation and reduced male fertility. Since efficient sperm production requires the translocation of protamines from the cytoplasm to the nucleus, we investigated whether SPAG17, a protein crucial for intracellular protein trafficking during spermiogenesis, participates in protamine transport. Initially, we assessed the protein-protein interaction between SPAG17 and protamines using proximity ligation assays, revealing a significant interaction originating in the cytoplasm and persisting within the nucleus. Subsequently, immunoprecipitation and mass spectrometry …

Associative Learning Contributes To The Persistence Of Fatigue-Like Behavior In Male Mice In A Model Of Cancer Survivorship, Elisabeth G Vichaya, Josephine K Darpolor, Phillip S Gross, Jessica M Molkentine, Daniel W Vermeer, Paola D Vermeer, John H Lee, Cullen M Taniguchi, Robert Dantzer

Faculty, Staff and Student Publications

Persistent fatigue is a debilitating side effect that impacts a significant proportion of cancer survivors for which there is not yet an FDA-approved treatment. While certainly a multi-factorial problem, persistent fatigue could be due, in part, to associations learned during treatment. Therefore, we sought to investigate the role of associative learning in the persistence of fatigue using a preclinical model of cancer survivorship. For this purpose, we used a murine model of human papilloma virus-related head and neck cancer paired with a curative regimen of cisplatin-based chemoradiation in male C57BL/6J mice. Fatigue-like behavior was assessed by measuring variations in voluntary …

Small Molecule Inhibitor Of Tau Self-Association In A Mouse Model Of Tauopathy: A Preventive Study In P301l Tau Jnpl3 Mice, Eliot J Davidowitz, Patricia Lopez, Heidy Jimenez, Leslie Adrien, Peter Davies, James G Moe

Faculty, Staff and Student Publications

Advances in tau biology and the difficulties of amyloid-directed immunotherapeutics have heightened interest in tau as a target for small molecule drug discovery for neurodegenerative diseases. Here, we evaluated OLX-07010, a small molecule inhibitor of tau self-association, for the prevention of tau aggregation. The primary endpoint of the study was statistically significant reduction of insoluble tau aggregates in treated JNPL3 mice compared with Vehicle-control mice. Secondary endpoints were dose-dependent reduction of insoluble tau aggregates, reduction of phosphorylated tau, and reduction of soluble tau. This study was performed in JNPL3 mice, which are representative of inherited forms of 4-repeat tauopathies with …

Artificial Intelligence-Driven Meta-Analysis Of Brain Gene Expression Identifies Novel Gene Candidates And A Role For Mitochondria In Alzheimer’S Disease, Caitlin A Finney, Fabien Delerue, Wendy A Gold, David A Brown, Artur Shvetcov

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is the most common form of dementia. There is no treatment and AD models have focused on a small subset of genes identified in familial AD. Microarray studies have identified thousands of dysregulated genes in the brains of patients with AD yet identifying the best gene candidates to both model and treat AD remains a challenge. We performed a meta-analysis of microarray data from the frontal cortex (n = 697) and cerebellum (n = 230) of AD patients and healthy controls. A two-stage artificial intelligence approach, with both unsupervised and supervised machine learning, combined with a functional …

A Unified Mediation Analysis Framework For Integrative Cancer Proteogenomics With Clinical Outcomes, Licai Huang, James P Long, Ehsan Irajizad, James D Doecke, Kim-Anh Do, Min Jin Ha

Faculty, Staff and Student Publications

MOTIVATION: Multilevel molecular profiling of tumors and the integrative analysis with clinical outcomes have enabled a deeper characterization of cancer treatment. Mediation analysis has emerged as a promising statistical tool to identify and quantify the intermediate mechanisms by which a gene affects an outcome. However, existing methods lack a unified approach to handle various types of outcome variables, making them unsuitable for high-throughput molecular profiling data with highly interconnected variables.

RESULTS: We develop a general mediation analysis framework for proteogenomic data that include multiple exposures, multivariate mediators on various scales of effects as appropriate for continuous, binary and survival outcomes. …

Sparse Tree-Based Clustering Of Microbiome Data To Characterize Microbiome Heterogeneity In Pancreatic Cancer, Yushu Shi, Liangliang Zhang, Kim-Anh Do, Robert Jenq, Christine B Peterson

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There is a keen interest in characterizing variation in the microbiome across cancer patients, given increasing evidence of its important role in determining treatment outcomes. Here our goal is to discover subgroups of patients with similar microbiome profiles. We propose a novel unsupervised clustering approach in the Bayesian framework that innovates over existing model-based clustering approaches, such as the Dirichlet multinomial mixture model, in three key respects: we incorporate feature selection, learn the appropriate number of clusters from the data, and integrate information on the tree structure relating the observed features. We compare the performance of our proposed method to …