Medicine and Health Sciences Commons^™

Sigma1 Inhibitor Suppression Of Adaptive Immune Resistance Mechanisms Mediated By Cancer Cell Derived Extracellular Vesicles, Paola A. Castagnino, Derick A. Haas, Luca Musante, Nathalia A. Tancler, Bach V. Tran, Rhonda Kean, Alexandra R. Steck, Luis A. Martinez, Elahe A. Mostaghel, D. Craig Hooper, Felix J. Kim

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune …

Statistical Identification Of Cell Type-Specific Spatially Variable Genes In Spatial Transcriptomics, Lulu Shang, Peijun Wu, Xiang Zhou

Faculty, Staff and Student Publications

An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power. Celina proves powerful compared to existing methods in single-cell resolution spatial transcriptomics and stands as the only effective solution for spot-resolution spatial transcriptomics. Applied to five real …

Genome-Wide Profiling Of Trna Modifications By Induro-Trnaseq Reveals Coordinated Changes, Yuko Nakano, Howard Gamper, Henri Mcguigan, Sunita Maharjan, Jiatong Li, Zhiyi Sun, Erbay Yigit, Sebastian Grünberg, Keerthana Krishnan, Nan-Sheng Li, Joseph Piccirilli, Ralph Kleiner, Nicole Nichols, Brian Gregory, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

While all native tRNAs undergo extensive post-transcriptional modifications as a mechanism to regulate gene expression, mapping these modifications remains challenging. The critical barrier is the difficulty of readthrough of modifications by reverse transcriptases (RTs). Here we use Induro-a new group-II intron-encoded RT-to map and quantify genome-wide tRNA modifications in Induro-tRNAseq. We show that Induro progressively increases readthrough over time by selectively overcoming RT stops without altering the misincorporation frequency. In a parallel analysis of Induro vs. a related RT, we provide comparative datasets to facilitate the prediction of each modification. We assess tRNA modifications across five human cell lines and …

Correlates Of Inaccuracy In Reporting Of Energy Intake Among Persons With Multiple Sclerosis, Stephanie L Silveira, Brenda Jeng, Barbara A Gower, Gary R Cutter, Robert W Motl

Faculty, Staff and Student Publications

BACKGROUND/OBJECTIVES: Persons with multiple sclerosis (MS) are interested in diet as a second-line approach for disease management. This study examined potential variables that correlate with inaccuracy of self-reported energy intake (EI) in adults with MS.

METHODS: Twenty-eight participants completed two assessment appointments within a 14-day period that included a standard doubly labeled water (DLW) protocol for estimating total energy expenditure (TEE). The participants reported their EI using the Automated Self-Administered 24 h (ASA24) Dietary Assessment Tool. The primary variables of interest for explaining the discrepancy between TEE and ASA24 EI (i.e., inaccuracy) included cognition (processing speed, visuospatial memory, and verbal …

Urine Proteomics Defines An Immune Checkpoint-Associated Nephritis Signature, James P Long, Shailbala Singh, Yanlan Dong, Cassian Yee, Jamie S Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitor (ICI) therapy is a cornerstone treatment for many cancers, but it can induce severe immunotoxicity, including acute interstitial nephritis (AIN). Currently, kidney biopsy is required to differentiate ICI-AIN from other causes of acute kidney injury (AKI). However, this invasive approach can lead to morbidity, delayed glucocorticoid treatment for patients with AIN, and unnecessarily prolonged suspension of ICI therapy in non-AIN patients. Delayed or incorrect diagnosis of ICI-AIN is particularly detrimental, as over 50% of patients are at risk of permanent renal damage. Thus, there is an urgent need for non-invasive biomarkers that can rapidly and accurately distinguish …

Ultra High Density Imaging Arrays In Diffuse Optical Tomography For Human Brain Mapping Improve Image Quality And Decoding Performance, Zachary E Markow, Jason W Trobaugh, Edward J Richter, Kalyan Tripathy, Sean M Rafferty, Alexandra M Svoboda, Mariel L Schroeder, Tracy M Burns-Yocum, Karla M Bergonzi, Mark A Chevillet, Emily M Mugler, Adam T Eggebrecht, Joseph P Culver

2020-Current year OA Pubs

Functional magnetic resonance imaging (fMRI) has dramatically advanced non-invasive human brain mapping and decoding. Functional near-infrared spectroscopy (fNIRS) and high-density diffuse optical tomography (HD-DOT) non-invasively measure blood oxygen fluctuations related to brain activity, like fMRI, at the brain surface, using more-lightweight equipment that circumvents ergonomic and logistical limitations of fMRI. HD-DOT grids have smaller inter-optode spacing (~ 13 mm) than sparse fNIRS (~ 30 mm) and therefore provide higher image quality, with spatial resolution ~ 1/2 that of fMRI, when using the several source-detector distances (13-40 mm) afforded by the HD-DOT grid. Herein, simulations indicated reducing inter-optode spacing to 6.5 …

Piezo1-Mediated Mechanotransduction Regulates Collagen Synthesis On Nanostructured 2d And 3d Models Of Fibrosis, Neda Rashidi, Natalia S Harasymowicz, Alireza Savadipour, Nancy Steward, Ruhang Tang, Sara Oswald, Farshid Guilak

2020-Current year OA Pubs

Progressive fibrosis can lead to tissue malfunction and organ failure due to the pathologic accumulation of a collagen-rich extracellular matrix. In vitro models provide useful tools for deconstructing the roles of specific biomechanical or biological mechanisms, such as substrate micro- and nanoscale architecture, in these processes for identifying potential therapeutic targets. Here, we investigated how the mechanosensitive ion channel PIEZO1 influences fibrotic gene and protein expression in adipose-derived stem cells (hASCs). Specifically, we examined the role of PIEZO1 and the mechanosensitive transcription factors YAP/TAZ in sensing aligned or non-aligned substrate architecture to regulate collagen formation. We utilized both 2D microphotopatterned …

Dna Polymerase Zeta Can Efficiently Replicate Structures Formed By At/Ta Repeat Sequences And Prevent Their Deletion, Mili Das, Suzanne E Hile, Jennifer Brewster, Jan Leendert Boer, Rachel Bezalel-Buch, Qiong Guo, Wei Yang, Peter M Burgers, Kristin A Eckert, Catherine H Freudenreich

2020-Current year OA Pubs

Long AT repeat tracts form non-B DNA structures that stall DNA replication and cause chromosomal breakage. AT repeats are abundant in human common fragile sites (CFSs), genomic regions that undergo breakage under replication stress. Using an in vivo yeast model system containing AT-rich repetitive elements from human CFS FRA16D, we find that DNA polymerase zeta (Pol ζ) is required to prevent breakage and subsequent deletions at hairpin and cruciform forming (AT/TA)n sequences, with little to no role at an (A/T)28 repeat or a control non-structure forming sequence. DNA polymerase eta is not protective for deletions at AT-rich structures, while DNA …

Methylgrapher: Genome-Graph-Based Processing Of Dna Methylation Data From Whole Genome Bisulfite Sequencing, Wenjin Zhang, Juan F Macias-Velasco, Xiaoyu Zhuo, Edward A Belter, Chad Tomlinson, John Garza, Nina Tekkey, Daofeng Li, Ting Wang

2020-Current year OA Pubs

Genome graphs, including the recently released draft human pangenome graph, can represent the breadth of genetic diversity and thus transcend the limits of traditional linear reference genomes. However, there are no genome-graph-compatible tools for analyzing whole genome bisulfite sequencing (WGBS) data. To close this gap, we introduce methylGrapher, a tool tailored for accurate DNA methylation analysis by mapping WGBS data to a genome graph. Notably, methylGrapher can reconstruct methylation patterns along haplotype paths precisely and efficiently. To demonstrate the utility of methylGrapher, we analyzed the WGBS data derived from five individuals whose genomes were included in the first Human Pangenome …

Atm Expression And Activation In Ataxia Telangiectasia Patients With And Without Class Switch Recombination Defects, Fereshte Salami, Tannaz Moeini Shad, Nazanin Fathi, Hanieh Mojtahedi, Marzie Esmaeili, Sepideh Shahkarami, Ladan Gol Mohammad Pour Afrakoti, Parisa Amirifar, Samaneh Delavari, Hassan Nosrati, Azadehsadat Razavi, Mohammad Reza Ranjouri, Mahsa Yousefpour, Zahra Hamidi Esfahani, Gholamreza Azizi, Mahmoudreza Ashrafi, Nima Rezaei, Reza Yazdani, Hassan Abolhassani

Department of Neurology Faculty Papers

BACKGROUND: Ataxia telangiectasia mutated (ATM) kinase plays a critical role in DNA double-strand break (DSB) repair. Ataxia telangiectasia (A-T) patients exhibit abnormalities in immunoglobulin isotype expression and class switch recombination (CSR). This study investigates the role of residual ATM kinase expression and activity in the severity of A-T disease.

METHODS: A-T patients with defined genetic diagnoses were classified based on CSR and based on the severity of their medical complications. Isolated peripheral blood mononuclear cells from any patient were evaluated before and after exposure to 0.5 Gy ionizing radiation for one minute. Western blotting was performed to identify the expression …

Artificial Intelligence For Optical Coherence Tomography In Glaucoma, Mak B. Djulbegovic, Henry Bair, David J. Taylor Gonzalez, Hiroshi Ishikawa, Gadi Wollstein, Joel S. Schuman

Wills Eye Hospital Papers

PURPOSE: The integration of artificial intelligence (AI), particularly deep learning (DL), with optical coherence tomography (OCT) offers significant opportunities in the diagnosis and management of glaucoma. This article explores the application of various DL models in enhancing OCT capabilities and addresses the challenges associated with their clinical implementation.

METHODS: A review of articles utilizing DL models was conducted, including convolutional neural networks (CNNs), recurrent neural networks (RNNs), generative adversarial networks (GANs), autoencoders, and large language models (LLMs). Key developments and practical applications of these models in OCT image analysis were emphasized, particularly in the context of enhancing image quality, glaucoma …

Spatial Transcriptome Reveals Histology-Correlated Immune Signature Learnt By Deep Learning Attention Mechanism On H&E-Stained Images For Ovarian Cancer Prognosis, Chun Wai Ng, Kwong-Kwok Wong, Barrett C Lawson, Sammy Ferri-Borgogno, Samuel C Mok

Faculty, Staff and Student Publications

Background: The ability to predict the prognosis of patients with ovarian cancer can greatly improve disease management. However, the knowledge on the mechanism of the prediction is limited. We sought to deconvolute the attention feature learnt by a deep learning convolutional neural networks trained with whole-slide images (WSIs) of hematoxylin-and-eosin (H&E)-stained tumor samples using spatial transcriptomic data.

Methods: In this study, 773 WSIs of H&E-stained tumor sections from 335 patients with treatment naïve high-grade serous ovarian cancer who were included in The Cancer Genome Atlas (TCGA) Pan-Cancer study were used to train, and validate, and to test a ResNet101 CNN …

A Paper-Based Hpv E7 Oncoprotein Assay For Cervical Precancer Detection At The Point Of Care, Chelsey A Smith, Sai Paul, Karen E Haney, Sonia G Parra, Meaghan Bond, Leticia López, Mauricio Maza, Juan Felix, Preetha Ramalingam, Pablo Escobar, Philip E Castle, Kathleen M Schmeler, Rebecca R Richards-Kortum

Faculty, Staff and Student Publications

Cervical cancer, while preventable through screening and treatment of cervical precancer, remains a global challenge with a disproportionately high burden of disease in resource-limited settings, especially in low- and middle-income countries (LMICs). Lack of affordable, easy-to-use screening and diagnostic tests contributes to this disparity. Most commercially available tests are not appropriate for use in LMICs due to resource constraints. Specifically, HPV mRNA and oncoprotein tests that have high specificity for cervical precancer and cancer require complex sample preparation protocols and expensive instrumentation. To address these limitations, an HPV E7 oncoprotein assay for HPV16, 18, and 45 was developed that is …

Joint Fluid Multi-Omics Improves Diagnostic Confidence During Evaluation Of Children With Presumed Septic Arthritis, Yolanda Peña-López, Naureen G Tareen, Bo Zhang, Indu Raman, Carlos A Arana, Chengsong Zhu, Yang Liu, Pratibha Selvakumar, Nicolai S C Van Oers, Simrat Morris, Lora V Hooper, Lawson A B Copley, Prithvi Raj

Faculty, Staff and Student Publications

Background: An accurate diagnosis of septic versus reactive or autoimmune arthritis remains clinically challenging. A multi-omics strategy comprising metagenomic and proteomic technologies were undertaken for children diagnosed with presumed septic arthritis to advance clinical diagnoses and care for affected individuals.

Methods: Twelve children with suspected septic arthritis were prospectively enrolled to compare standard of care tests with a rapid multi-omics approach. The multi-omics combined bacterial 16S rRNA metagenomics, single cell transcriptomics, and proteomics on knee joint fluid specimens. The diagnostic value of the multi-omics was ascertained relative to standard of care culture and PCR-negative results.

Results: Ten children with suspected …

Co-Option Of Mitochondrial Nucleic Acid-Sensing Pathways By Hsv-1 Ul12.5 For Reactivation From Latent Infection, Patryk A. Krakowiak, Matthew E. Flores, Sean R. Cuddy, Abigail L. Whitford, Sara A. Dochnal, Aleksandra Babnis, Tsuyoshi Miyake, Marco Tigano, Daniel A. Engel, Anna R. Cliffe

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Although viruses subvert innate immune pathways for their replication, there is evidence they can also co-opt antiviral responses for their benefit. The ubiquitous human pathogen, Herpes simplex virus-1 (HSV-1), encodes a protein (UL12.5) that induces the release of mitochondrial nucleic acid into the cytosol, which activates immune-sensing pathways and reduces productive replication in nonneuronal cells. HSV-1 establishes latency in neurons and can reactivate to cause disease. We found that UL12.5 is required for HSV-1 reactivation in neurons and acts to directly promote viral lytic gene expression during initial exit from latency. Further, the direct activation of innate immune-sensing pathways triggered …

A Randomized, Placebo-Controlled, Cross-Over Trial Of Ketamine In Rett Syndrome, Kathleen Campbell, Jeffrey L Neul, David N Lieberman, Elizabeth Berry-Kravis, Tim A Benke, Cary Fu, Alan Percy, Bernhard Suter, David Morris, Randall L Carpenter, Eric D Marsh, Jana Von Hehn

Faculty, Staff and Students Publications

BACKGROUND: Preclinical studies and anecdotal case reports support the potential therapeutic benefit of low-dose oral ketamine as a treatment of clinical symptoms in Rett syndrome (RTT); however, no controlled studies have been conducted in RTT to evaluate safety, tolerability and efficacy.

DESIGN: This was a sequentially initiated, dose-escalating cohort, placebo-controlled, double blind, randomized sequence, cross-over study of oral ketamine in 6-12-year-old girls with RTT to evaluate short-term safety and tolerability and explore efficacy.

METHODS: Participants were randomized to either five days treatment with oral ketamine or matched placebo, followed by a nine-day wash-out period and then crossed-over to the opposite …

Social Determinants Of Occupational Injuries Among Us-Based Commercial Fishermen: A Systematic Review, Shannon Guillot-Wright, Leonard Kuan-Pei Wang, Bibiana Toro Figueira, Mary Overcash Jones, Ruhi Maredia, Nikhita Kichili

Faculty, Staff and Student Publications

BACKGROUND: Commercial fishing is a multibillion-dollar industry that supports job growth, small- to large- businesses, and port and city revenue. The commercial fishing industry continues to be one of the most dangerous in the US, with a fatality rate nearly 40 times higher than the national average. Dangers of the fishing industry are multi-faceted and include hazardous working conditions, strenuous labor, long work hours, and harsh weather. Moreover, a vast majority of fishermen suffer from economic insecurity, including safe and affordable housing and food insecurity.

METHODS: We followed the recommendations and standards set by the Campbell and Cochrane Equity Methods …

Inhibition Of Vascular Smooth Muscle Cell Perk/Atf4 Er Stress Signaling Protects Against Abdominal Aortic Aneurysms, Brennan Callow, Xiaobing He, Nicholas Juriga, Kevin D Mangum, Amrita Joshi, Xianying Xing, Andrea Obi, Abhijnan Chattopadhyay, Dianna M Milewicz, Mary X O'Riordan, Johann Gudjonsson, Katherine Gallagher, Frank M Davis

Faculty, Staff and Student Publications

Abdominal aortic aneurysms (AAA) are a life-threatening cardiovascular disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by vascular smooth muscle cell (VSMC) dysfunction and apoptosis, for which the mechanisms regulating loss of VSMCs within the aortic wall remain poorly defined. Using single-cell RNA-Seq of human AAA tissues, we identified increased activation of the endoplasmic reticulum stress response pathway, PERK/eIF2α/ATF4, in aortic VSMCs resulting in upregulation of an apoptotic cellular response. Mechanistically, we reported that aberrant TNF-α activity within the aortic wall induces VSMC ATF4 activation through the …

Fairs - A Framework For Evaluating The Inclusion Of Sex In Clinical Algorithms, Katherine E Goodman, Jennifer Blumenthal-Barby, Rita F Redberg, Diane E Hoffmann

Center for Medical Ethics and Health Policy Staff Publications

No abstract provided.

Stratification System With Dual Human Endogenous Retroviruses For Predicting Immunotherapy Efficacy In Metastatic Clear-Cell Renal Cell Carcinoma, Xiaofan Lu, Yann-Alexandre Vano, Xiaoping Su, Virginie Verkarre, Cheng-Ming Sun, Wenxuan Cheng, Li Xu, Fangrong Yan, Salma Kotti, Wolf Hervé Fridman, Catherine Sautes-Fridman, Stéphane Oudard, Gabriel G Malouf

Faculty, Staff and Student Publications

Background: Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. While the dysregulation of ERV transcription has been linked to immune cell infiltration in various cancers, its relationship with immune checkpoint inhibitor (ICI) response in solid tumors, particularly metastatic clear-cell renal cell carcinoma (ccRCC), remains inadequately explored.

Methods: This study analyzed patients with metastatic ccRCC from two prospective clinical trials, encompassing 181 patients receiving nivolumab in the CheckMate trials (-009 to -010 and -025) and 48 patients treated with the ipilimumab-nivolumab combination in the BIONIKK trial. ERV expression was quantified using the ERVmap algorithm …

Dna Methylation Profiling At Base-Pair Resolution Reveals Unique Epigenetic Features Of Early-Onset Colorectal Cancer In Underrepresented Populations, Jason Sheng Li, Karen Riggins, Li Yang, Chaorong Chen, Patricia Castro, Wedad Alfarkh, Neda Zarrin-Khameh, Michael E Scheurer, Chad J Creighton, Benjamin Musher, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC) has been rising at an alarming rate in the USA, and EOCRC disproportionately affects racial/ethnic minorities. Here, we construct comprehensive profiles of EOCRC DNA methylomes at base-pair resolution for a cohort of Hispanic and African American patients.

RESULTS: We show the epigenetic landscape of these EOCRC patients differs from that of late-onset colorectal cancer patients, and methylation canyons in EOCRC tumor tissue preferentially overlapped genes in cancer-related pathways. Furthermore, we identify epigenetic alterations in metabolic genes that are specific to our racial/ethnic minority EOCRC cohort but not Caucasian patients from TCGA. Top …

A Deconvolution Framework That Uses Single-Cell Sequencing Plus A Small Benchmark Data Set For Accurate Analysis Of Cell Type Ratios In Complex Tissue Samples, Shuai Guo, Xiaoqian Liu, Xuesen Cheng, Yujie Jiang, Shuangxi Ji, Qingnan Liang, Andrew Koval, Yumei Li, Leah A Owen, Ivana K Kim, Ana Aparicio, Sanghoon Lee, Anil K Sood, Scott Kopetz, John Paul Shen, John N Weinstein, Margaret M Deangelis, Rui Chen, Wenyi Wang

Faculty, Staff and Student Publications

Bulk deconvolution with single-cell/nucleus RNA-seq data is critical for understanding heterogeneity in complex biological samples, yet the technological discrepancy across sequencing platforms limits deconvolution accuracy. To address this, we utilize an experimental design to match inter-platform biological signals, hence revealing the technological discrepancy, and then develop a deconvolution framework called DeMixSC using this well-matched, that is, benchmark, data. Built upon a novel weighted nonnegative least-squares framework, DeMixSC identifies and adjusts genes with high technological discrepancy and aligns the benchmark data with large patient cohorts of matched-tissue-type for large-scale deconvolution. Our results using two benchmark data sets of healthy retinas and …

Ecological Trait Differences Are Associated With Gene Expression In The Primary Visual Cortex Of Primates, Trisha M Zintel, John J Ely, Mary Ann Raghanti, William D Hopkins, Patrick R Hof, Chet C Sherwood, Jason M Kamilar, Amy L Bauernfeind, Courtney C Babbitt

2020-Current year OA Pubs

UNLABELLED: Primate species differ drastically from most other mammals in how they visually perceive their environments, which is particularly important for foraging, predator avoidance, and detection of social cues.

BACKGROUND/OBJECTIVES: Although it is well established that primates display diversity in color vision and various ecological specializations, it is not understood how visual system characteristics and ecological adaptations may be associated with gene expression levels within the primary visual cortex (V1).

METHODS: We performed RNA-Seq on V1 tissue samples from 28 individuals, representing 13 species of primates, including hominoids, cercopithecoids, and platyrrhines. We explored trait-dependent differential expression (DE) by contrasting species …

Precision Data-Driven Modeling Of Cortical Dynamics Reveals Person-Specific Mechanisms Underpinning Brain Electrophysiology, Matthew F Singh, Todd S Braver, Michael Cole, Shinung Ching

2020-Current year OA Pubs

Task-free brain activity affords unique insight into the functional structure of brain network dynamics and has been used to identify neural markers of individual differences. In this work, we present an algorithmic optimization framework that directly inverts and parameterizes brain-wide dynamical-systems models involving hundreds of interacting neural populations, from single-subject M/EEG time-series recordings. This technique provides a powerful neurocomputational tool for interrogating mechanisms underlying individual brain dynamics ("precision brain models") and making quantitative predictions. We extensively validate the models' performance in forecasting future brain activity and predicting individual variability in key M/EEG metrics. Last, we demonstrate the power of our …

Faculty Perceptions On The Roles Of Mentoring, Advising, And Coaching In An Anesthesiology Residency Program: Mixed Methods Study, Sydney Nykiel-Bailey, Kathryn Burrows, Bianca E Szafarowicz, Rachel Moquin

2020-Current year OA Pubs

BACKGROUND: Mentoring, advising, and coaching are essential components of resident education and professional development. Despite their importance, there is limited literature exploring how anesthesiology faculty perceive these practices and their role in supporting residents.

OBJECTIVE: This study aims to investigate anesthesiology faculty perspectives on the significance, implantation strategies, and challenges associated with mentorship, advising, and coaching in resident education.

METHODS: A comprehensive survey was administrated to 93 anesthesiology faculty members at Washington University School of Medicine. The survey incorporated quantitative Likert-scale questions and qualitative short-answer responses to assess faculty perceptions of the value, preferred formats, essential skills, and capacity for …

Real-Time Cbct Imaging And Motion Tracking Via A Single Arbitrarily-Angled X-Ray Projection By A Joint Dynamic Reconstruction And Motion Estimation (Dreme) Framework, Hua-Chieh Shao, Tielige Mengke, Tinsu Pan, You Zhang

Faculty, Staff and Student Publications

Objective: Real-time cone-beam computed tomography (CBCT) provides instantaneous visualization of patient anatomy for image guidance, motion tracking, and online treatment adaptation in radiotherapy. While many real-time imaging and motion tracking methods leveraged patient-specific prior information to alleviate under-sampling challenges and meet the temporal constraint (< 500 ms), the prior information can be outdated and introduce biases, thus compromising the imaging and motion tracking accuracy. To address this challenge, we developed a framework dynamic reconstruction and motion estimation (DREME) for real-time CBCT imaging and motion estimation, without relying on patient-specific prior knowledge.

Approach: DREME incorporates a deep learning-based real-time CBCT imaging and motion estimation method into a dynamic CBCT reconstruction framework. The reconstruction framework reconstructs a dynamic sequence of CBCTs in a data-driven manner from a standard pre-treatment scan, without requiring patient-specific prior knowledge. Meanwhile, a convolutional neural network-based motion encoder is jointly trained during the reconstruction …

The Association Between Thyroid Differentiation Score And Survival Outcomes In Papillary Thyroid Carcinoma, Jennifer R Wang, Mark E Zafereo, Maria E Cabanillas, Chia Chin Wu, Li Xu, Yaoyi Dai, Wenyi Wang, Stephen Y Lai, Ying Henderson, Lauren Erasmus, Michelle D Williams, Corinne Joshu, Debashree Ray

Faculty, Staff and Student Publications

Context: Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in papillary thyroid carcinoma (PTC).

Objective: The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts.

Methods: Two independent cohorts of patients with PTC were used: (1) The Cancer Genome Atlas (TCGA) thyroid cancer study (N = 372), (2) MD Anderson Cancer Center (MDACC) cohort (N = 111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was …

Mitochondrial Uncouplers Inhibit Oncogenic E2f1 Activity And Prostate Cancer Growth, Ohuod Hawsawi, Weinan Xue, Tingting Du, Mengqi Guo, Xiaolin Yu, Mingyi Zhang, Paul S Hoffman, Roni Bollag, Jun Li, Jia Zhou, Hongbo Wang, Junran Zhang, Zheng Fu, Xiaoguang Chen, Chunhong Yan

Faculty, Staff and Student Publications

Mitochondrial uncouplers dissipate proton gradients and deplete ATP production from oxidative phosphorylation (OXPHOS). While the growth of prostate cancer depends on OXPHOS-generated ATP, the oncogenic pathway mediated by the transcription factor E2F1 is crucial for the progression of this deadly disease. Here, we report that mitochondrial uncouplers, including tizoxanide (TIZ), the active metabolite of the Food and Drug Administration (FDA)-approved anthelmintic nitazoxanide (NTZ), inhibit E2F1-mediated expression of genes involved in cell cycle progression, DNA synthesis, and lipid synthesis. Consequently, NTZ/TIZ induces S-phase kinase-associated protein 2 (SKP2)-mediated G1 arrest while impeding DNA synthesis, lipogenesis, and the growth of prostate cancer cells. …

Gut Microbial Changes Associated With Obesity In Youth With Type 1 Diabetes, Heba M Ismail, Dimuthu Perera, Rabindra Mandal, Linda A Dimeglio, Carmella Evans-Molina, Tamara Hannon, Joseph Petrosino, Sara Javornik Cregeen, Nathan W Schmidt

Faculty, Staff and Students Publications

Context: Obesity is prevalent in type 1 diabetes (T1D) and is problematic with higher risk for diabetes complications. It is unknown to what extent gut microbiome changes are associated with obesity and T1D.

Objective: This work aimed to describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized statistically significant gut microbial and metabolite differences in lean T1D youth (body mass index [BMI]: 5%-< 85%) vs those with obesity (BMI: ≥95%).

Methods: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) differences in lean (n = 27) and obese (n = 21) T1D youth in …

Gut Microbial Changes Associated With Obesity In Youth With Type 1 Diabetes, Heba M Ismail, Dimuthu Perera, Rabindra Mandal, Linda A Dimeglio, Carmella Evans-Molina, Tamara Hannon, Joseph Petrosino, Sara Javornik Cregeen, Nathan W Schmidt

Center for Medical Ethics and Health Policy Staff Publications

Context: Obesity is prevalent in type 1 diabetes (T1D) and is problematic with higher risk for diabetes complications. It is unknown to what extent gut microbiome changes are associated with obesity and T1D.

Objective: This work aimed to describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized statistically significant gut microbial and metabolite differences in lean T1D youth (body mass index [BMI]: 5%-< 85%) vs those with obesity (BMI: ≥95%).

Methods: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) differences in lean (n = 27) and obese (n = 21) T1D youth in …