Medicine and Health Sciences Commons^™

Collagen Type Xii Is Undetectable In Keratoconus Bowman’S Layer, Mohammed Rigi, Hyeck-Soo Son, Loren Moon, Mario Matthaei, Divya Srikumaran, Albert S Jun, Charles G Eberhart, Uri S Soiberman

Faculty, Staff and Student Publications

PURPOSE: Corneal biomechanical failure is the hallmark of keratoconus (KC); however, the cause of this failure remains elusive. Collagen type XII (

METHODS: TaqMan quantitative PCR was performed on 31 corneal epithelium samples of progressive KC and myopic control eyes. Tissue microarrays were constructed using full-thickness corneas from 61 KC cases during keratoplasty and 18 non-KC autopsy eyes and stained with an antibody specific to COL12A1. Additionally,

RESULTS: COL12A1 expression was reduced at transcript levels in KC epithelium compared to controls (ratio: 0.58, p<0.03). Immunohistochemical studies demonstrated that COL12A1 protein expression in BL was undetectable, with reduced expression in KC epithelium, basement membrane, and stroma.

CONCLUSIONS: The apparent absence of COL12A1 in KC BL, together with the functional importance that

Data Encoding For Healthcare Data Democratization And Information Leakage Prevention, Anshul Thakur, Tingting Zhu, Vinayak Abrol, Jacob Armstrong, Yujiang Wang, David A Clifton

Faculty, Staff and Student Publications

The lack of data democratization and information leakage from trained models hinder the development and acceptance of robust deep learning-based healthcare solutions. This paper argues that irreversible data encoding can provide an effective solution to achieve data democratization without violating the privacy constraints imposed on healthcare data and clinical models. An ideal encoding framework transforms the data into a new space where it is imperceptible to a manual or computational inspection. However, encoded data should preserve the semantics of the original data such that deep learning models can be trained effectively. This paper hypothesizes the characteristics of the desired encoding …

Predictive Modeling And Cryo-Em: A Synergistic Approach To Modeling Macromolecular Structure, Michael R Corum, Harikanth Venkannagari, Corey F Hryc, Matthew L Baker

Faculty, Staff and Student Publications

Over the last 15 years, structural biology has seen unprecedented development and improvement in two areas: electron cryo-microscopy (cryo-EM) and predictive modeling. Once relegated to low resolutions, single-particle cryo-EM is now capable of achieving near-atomic resolutions of a wide variety of macromolecular complexes. Ushered in by AlphaFold, machine learning has powered the current generation of predictive modeling tools, which can accurately and reliably predict models for proteins and some complexes directly from the sequence alone. Although they offer new opportunities individually, there is an inherent synergy between these techniques, allowing for the construction of large, complex macromolecular models. Here, we …

The Pathogenicity Of Vancomycin-Resistant Enterococcus Faecalis To Colon Cancer Cells, Li Zhang, Mingxia Deng, Jing Liu, Jiajie Zhang, Fangyu Wang, Wei Yu

Faculty, Staff and Student Publications

BACKGROUND: The aim of this study was to investigate the pathogenicity of vancomycin-resistant Enterococcus faecalis (VREs) to human colon cells in vitro.

METHODS: Three E. faecalis isolates (2 VREs and E. faecalis ATCC 29212) were cocultured with NCM460, HT-29 and HCT116 cells. Changes in cell morphology and bacterial adhesion were assessed at different time points. Interleukin-8 (IL-8) and vascular endothelial growth factor A (VEGFA) expression were measured via RT-qPCR and enzyme-linked immunosorbent assay (ELISA), respectively. Cell migration and human umbilical vein endothelial cells (HUVECs) tube formation assays were used for angiogenesis studies. The activity of PI3K/AKT/mTOR signaling pathway was measured …

Susceptible Windows Of Prenatal And Postnatal Fine Particulate Matter Exposures And Attention-Deficit Hyperactivity Disorder Symptoms In Early Childhood, Wei-Jen Chen, Alison M Rector-Houze, Mònica Guxens, Carmen Iñiguez, Michael D Swartz, Elaine Symanski, Jesús Ibarluzea, Antonia Valentin, Aitana Lertxundi, Llúcia González-Safont, Jordi Sunyer, Kristina W Whitworth

Faculty, Staff and Student Publications

Few prior studies have explored windows of susceptibility to fine particulate matter (PM_2.5) in both the prenatal and postnatal periods and children’s attention-deficit/hyperactivity disorder (ADHD) symptoms.

We analyzed data from 1,416 mother-child pairs from the Spanish INMA (INfancia y Medio Ambiente) Study (2003–2008). Around 5 years of age, teachers reported the number of ADHD symptoms (i.e., inattention, hyperactivity/impulsivity) using the ADHD Diagnostic and Statistical Manual of Mental Disorders. Around 7 years of age, parents completed the Conner’s Parent Rating Scales, from which we evaluated the ADHD index, cognitive problems/inattention, hyperactivity, and oppositional subscales, reported as age- and sex-standardized …

An Extended Bayesian Semi-Mechanistic Dose-Finding Design For Phase I Oncology Trials Using Pharmacokinetic And Pharmacodynamic Information, Chao Yang, Yisheng Li

Faculty, Staff and Student Publications

We propose a model-based, semi-mechanistic dose-finding (SDF) design for phase I oncology trials that incorporates pharmacokinetic/pharmacodynamic (PK/PD) information when modeling the dose-toxicity relationship. This design is motivated by a phase Ib/II clinical trial of anti-CD20/CD3 T cell therapy in non-Hodgkin lymphoma patients; it extends a recently proposed SDF model framework by incorporating measurements of a PD biomarker relevant to the primary dose-limiting toxicity (DLT). We propose joint Bayesian modeling of the PK, PD, and DLT outcomes. Our extensive simulation studies show that on average the proposed design outperforms some common phase I trial designs, including modified toxicity probability interval (mTPI) …

Uchl1 Is A Potential Molecular Indicator And Therapeutic Target For Neuroendocrine Carcinomas, Shiqin Liu, Timothy Chai, Fernando Garcia-Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Martin Shaw Toland, Abel Bermudez, Alifiani B Hartono, Christopher F Massey, Chung S Lee, Liwei Zheng, Maya Baron, Caden J Denning, Merve Aslan, Holly M Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian A Kunder, Brooke E Howitt, H Tom Soh, Irving L Weissman, Michael A Liss, Arnold I Chin, James D Brooks, Eva Corey, Sharon J Pitteri, Jiaoti Huang, Tanya Stoyanova

Faculty, Staff and Student Publications

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of …

Molecular, Metabolic, And Subcellular Mapping Of The Tumor Immune Microenvironment Via 3d Targeted And Non-Targeted Multiplex Multi-Omics Analyses, Sammy Ferri-Borgogno, Jared K Burks, Erin H Seeley, Trevor D Mckee, Danielle L Stolley, Akshay V Basi, Javier A Gomez, Basant T Gamal, Shamini Ayyadhury, Barrett C Lawson, Melinda S Yates, Michael J Birrer, Karen H Lu, Samuel C Mok

Faculty, Staff and Student Publications

Most platforms used for the molecular reconstruction of the tumor-immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor at a single-cell resolution, and thus lack information about cell-cell or cell-extracellular matrix (ECM) interactions. To address this issue, a pipeline which integrated multiplex spatially resolved multi-omics platforms was developed to identify crosstalk signaling networks among various cell types and the ECM in the 3D TIME of two FFPE (formalin-fixed paraffin embedded) gynecologic tumor samples. These platforms include non-targeted mass spectrometry imaging (glycans, metabolites, and peptides) and Stereo-seq (spatial transcriptomics) …

Circulating Microrna Biomarkers Of Thiazide Response In Hypertension, Lakshmi Manasa S Chekka, Marwa Tantawy, Taimour Langaee, Danxin Wang, Rolf Renne, Arlene B Chapman, John G Gums, Eric Boerwinkle, Rhonda M Cooper-Dehoff, Julie A Johnson

Faculty, Staff and Student Publications

Background: Thiazide diuretics are the second most frequently prescribed class of antihypertensives, but up to 50% of patients with hypertension have minimal antihypertensive response to thiazides. We explored circulating microRNAs (miRNAs) in search of predictive biomarkers of thiazide response.

Methods and results: We profiled 754 miRNAs in baseline plasma samples of 36 hypertensive European American adults treated with hydrochlorothiazide, categorized into responders (n=18) and nonresponders (n=18) on the basis of diastolic blood pressure response to hydrochlorothiazide. miRNAs with ≥2.5-fold differential expression between responders and nonresponders were considered for validation in 3 cohorts (n=50 each): hydrochlorothiazide-treated European Americans, chlorthalidone-treated European Americans, …

Multivalent Cytomegalovirus Glycoprotein B Nucleoside Modified Mrna Vaccines Did Not Demonstrate A Greater Antibody Breadth, Hsuan-Yuan Wang, Leike Li, Cody S Nelson, Richard Barfield, Sarah Valencia, Cliburn Chan, Hiromi Muramatsu, Paulo J C Lin, Norbert Pardi, Zhiqiang An, Drew Weissman, Sallie R Permar

Faculty, Staff and Student Publications

Human cytomegalovirus (HCMV) remains the most common congenital infection and infectious complication in immunocompromised patients. The most successful HCMV vaccine to date, an HCMV glycoprotein B (gB) subunit vaccine adjuvanted with MF59, achieved 50% efficacy against primary HCMV infection. A previous study demonstrated that gB/MF59 vaccinees were less frequently infected with HCMV gB genotype strains most similar to the vaccine strain than strains encoding genetically distinct gB genotypes, suggesting strain-specific immunity accounted for the limited efficacy. To determine whether vaccination with multiple HCMV gB genotypes could increase the breadth of anti-HCMV gB humoral and cellular responses, we immunized 18 female …

Mortality Outcomes In A Large Population With And Without Covert Cerebrovascular Disease, Úna Clancy, Eric J Puttock, Wansu Chen, William Whiteley, Ellen M Vickery, Lester Y Leung, Patrick H Luetmer, David F Kallmes, Sunyang Fu, Chengyi Zheng, Hongfang Liu, David M Kent

Faculty, Staff and Student Publications

Covert cerebrovascular disease (CCD) is frequently reported on neuroimaging and associates with increased dementia and stroke risk. We aimed to determine how incidentally-discovered CCD during clinical neuroimaging in a large population associates with mortality. We screened CT and MRI reports of adults aged ≥50 in the Kaiser Permanente Southern California health system who underwent neuroimaging for a non-stroke clinical indication from 2009-2019. Natural language processing identified incidental covert brain infarcts (CBI) and/or white matter hyperintensities (WMH), grading WMH as mild/moderate/severe. Models adjusted for age, sex, ethnicity, multimorbidity, vascular risks, depression, exercise, and imaging modality. Of n=241,028, the mean age was …

Cancergpt For Few Shot Drug Pair Synergy Prediction Using Large Pretrained Language Models, Tianhao Li, Sandesh Shetty, Advaith Kamath, Ajay Jaiswal, Xiaoqian Jiang, Ying Ding, Yejin Kim

Faculty, Staff and Student Publications

Large language models (LLMs) have been shown to have significant potential in few-shot learning across various fields, even with minimal training data. However, their ability to generalize to unseen tasks in more complex fields, such as biology and medicine has yet to be fully evaluated. LLMs can offer a promising alternative approach for biological inference, particularly in cases where structured data and sample size are limited, by extracting prior knowledge from text corpora. Here we report our proposed few-shot learning approach, which uses LLMs to predict the synergy of drug pairs in rare tissues that lack structured data and features. …

Correction: Neural Correlates Of Automatic Emotion Regulation And Their Association With Suicidal Ideation In Adolescents During The First 90-Days Of Residential Care, Matthew Dobbertin, Karina S Blair, Joseph Aloi, Sahil Bajaj, Johannah Bashford-Largo, Avantika Mathur, Ru Zhang, Erin Carollo, Amanda Schwartz, Jaimie Elowsky, J L Ringle, Patrick Tyler, R James Blair

Faculty, Staff and Student Publications

No abstract provided.

Comparison Of Thulium Fiber Laser Versus Holmium Laser In Ureteroscopic Lithotripsy: A Meta-Analysis And Systematic Review, Xiaoyu Tang, Shaojie Wu, Zhilong Li, Du Wang, Cheng Lei, Tongzu Liu, Xinghuan Wang, Sheng Li

Faculty, Staff and Student Publications

OBJECTIVES: To compare the efficacy and safety of thulium fiber laser (TFL) to holmium: YAG (Ho: YAG) laser in ureteroscopic lithotripsy for urolithiasis.

METHODS: PubMed, Web of Science, Embase, CENTRAL, SinoMed, CNKI database, VIP and Wanfang Database were systematically searched for all relevant clinical trials until September 2023. References were explored to identify the relevant articles. Meta-analysis was carried out for the retrieved studies using RevMan5.4.1 software, and the risk ratio, mean difference and 95% confidence interval were expressed. Statistical significance was set at p < 0.05. The main outcomes of this meta-analysis were stone-free rate (SFR), perioperative outcomes and intraoperative or postoperative complications.

RESULTS: Thirteen studies, including 1394 patients, were included. According to the results of pooled analysis, …

Retreatment Strategies For Cases Containing Calcium Silicate-Based Root Canal Sealers: A Comprehensive Review, Hussain Al Akam, Hyeon-Cheol Kim, Ji Wook Jeong

Faculty, Staff and Student Publications

This review explores the field of retreatment strategies for cases filled with calcium silicate-based root canal sealers. Since the introduction of calcium silicate-based materials in dentistry, calcium silicate-based root canal sealers have become popular among dentists because of their biocompatibility, bioactivity, and sealing ability. Therefore, effective retreatment strategies are indispensable. This article aims to identify the challenges associated with the removal of calcium silicate-based sealers themselves and removal of gutta-percha with the sealers during retreatment, evaluate current techniques and materials, and provide future directions for research in this field. Regarding the strategies of removal of root canal sealers, calcium silicate-based …

Uterine Leiomyomata As A Cause Of Abdominal Compartment Syndrome In The Postpartum Period, Mason Hui, Baha Sibai, Alvaro Montealegre, Mateo G Leon

Faculty, Staff and Student Publications

Uterine leiomyomas are common benign smooth muscle tumors that often occur during the reproductive years. Although many cases may not result in significant complications, negative pregnancy outcomes have been associated with the size and location of the fibroids. Degeneration of fibroids can occur as early as the late first trimester when they undergo significant volumetric growth, contributing to pain during pregnancy. While myomectomy is typically avoided during pregnancy, conservative management with anti-inflammatory medications may be effective. Surgical removal or preterm delivery may be necessary if symptoms persist. Abdominal compartment syndrome (ACS) is a rare condition characterized by sustained elevated intra-abdominal …

Clinical Outcomes And Bacterial Characteristics Of Carbapenem-Resistant Acinetobacter Baumannii Among Patients From Different Global Regions., Minggui Wang, Lizhao Ge, Liang Chen, Lauren Komarow, Blake Hanson, Jinnethe Reyes, Eric Cober, Thamer Alenazi, Zhiyong Zong, Qing Xie, Zhengyin Liu, Lanjuan Li, Yunsong Yu, Hainv Gao, Souha S Kanj, Jairo Figueroa, Erica Herc, Ezequiel Cordova, Gregory Weston, Paul Ananth Tambyah, Julia Garcia-Diaz, Keith S Kaye, Sorabh Dhar, Jose M Munita, Robert A Salata, Samuel Vilchez, Martin E Stryjewski, Maria Virginia Villegas Botero, Alina Iovleva, Scott R Evans, Keri Baum, Carol Hill, Barry N Kreiswirth, Robin Patel, David L Paterson, Cesar A Arias, Robert A Bonomo, Henry F Chambers, Vance G Fowler, Michael J Satlin, David Van Duin, Yohei Doi

Faculty, Staff and Student Publications

Background: Carbapenem-resistant Acinetobacter baumannii (CRAb) is 1 of the most problematic antimicrobial-resistant bacteria. We sought to elucidate the international epidemiology and clinical impact of CRAb.

Methods: In a prospective observational cohort study, 842 hospitalized patients with a clinical CRAb culture were enrolled at 46 hospitals in five global regions between 2017 and 2019. The primary outcome was all-cause mortality at 30 days from the index culture. The strains underwent whole-genome analysis.

Results: Of 842 cases, 536 (64%) represented infection. By 30 days, 128 (24%) of the infected patients died, ranging from 1 (6%) of 18 in Australia-Singapore to 54 (25%) …

Immunity From Nk Cell Subsets Is Important For Vaccine-Mediated Protection In Hpv+ Cancers, Madison P O'Hara, Ananta V Yanamandra, K Jagannadha Sastry

Faculty, Staff and Student Publications

High-risk human papillomaviruses (HPVs) are associated with genital and oral cancers, and the incidence of HPV+ head and neck squamous cell cancers is fast increasing in the USA and worldwide. Survival rates for patients with locally advanced disease are poor after standard-of-care chemoradiation treatment. Identifying the antitumor host immune mediators important for treatment response and designing strategies to promote them are essential. We reported earlier that in a syngeneic immunocompetent preclinical HPV tumor mouse model, intranasal immunization with an HPV peptide therapeutic vaccine containing the combination of aGalCer and CpG-ODN adjuvants (TVAC) promoted clearance of HPV vaginal tumors via induction …

Description Of Cryptococcosis Following Sars-Cov-2 Infection: A Disease Survey Through The Mycosis Study Group Education And Research Consortium (Msg-19), Jeremey Walker, Todd Mccarty, Gerald Mcgwin, Eloy E Ordaya, Paschalis Vergidis, Luis Ostrosky-Zeichner, Mehriban Mammadova, Andrej Spec, Adriana M Rauseo, John Perfect, Julia Messina, Gabriel Vilchez, Rachel Mcmullen, Carolynn T Jones, Peter G Pappas

Faculty, Staff and Student Publications

BACKGROUND: Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes.

METHODS: We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap …

Long Trimer-Immunization Interval And Appropriate Adjuvant Reduce Immune Responses To The Soluble Hiv-1-Envelope Trimer Base, Hongying Duan, Angela R Corrigan, Cheng Cheng, Andrea Biju, Christopher A Gonelli, Adam S Olia, I-Ting Teng, Kai Xu, Sijy O'Dell, Sandeep Narpala, Mike Castro, Leonid Serebryannyy, Jennifer Wang, Danealle K Parchment, Edward K Sarfo, Jelle Van Schooten, John-Paul Todd, Shuishu Wang, Darcy R Harris, Hui Geng, Alexander J Jafari, Vrc Production Program, Ruth A Woodward, Nicole A Doria-Rose, Kathryn E Foulds, Adrian B Mcdermott, Marit J Van Gils, Richard A Koup, Theodore C Pierson, Peter D Kwong, John R Mascola

Faculty, Staff and Student Publications

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth. Here, we demonstrate that long trimer-boosting intervals, but not long FP immunization intervals, reduce the anti-base response. Additionally, we identify that FP priming before trimer immunization enhances antibody avidity to the Env trimer. We also establish that adjuvants Matrix …

Strategies To Combine 3d Vasculature And Brain Cta With Deep Neural Networks: Application To Lvo, Uma M Lal-Trehan Estrada, Arnau Oliver, Sunil A Sheth, Xavier Lladó, Luca Giancardo

Faculty, Staff and Student Publications

Automated tools to detect large vessel occlusion (LVO) in acute ischemic stroke patients using brain computed tomography angiography (CTA) have been shown to reduce the time for treatment, leading to better clinical outcomes. There is a lot of information in a single CTA and deep learning models do not have an obvious way of being conditioned on areas most relevant for LVO detection, i.e., the vasculature structure. In this work, we compare and contrast strategies to make convolutional neural networks focus on the vasculature without discarding context information of the brain parenchyma and propose an attention-inspired strategy to encourage this. …

Predictive Criterion Validity Of The Parsley Symptom Index Against The Patient-Reported Outcomes Measurement Information System-10 In A Chronic Disease Cohort: Retrospective Cohort Study, Hants Williams, Sarah Steinberg, Kendall Leon, Ryan Vingum, Mengyao Hu, Robin Berzin, Heather Hagg, Patrick Hanaway

Faculty, Staff and Student Publications

BACKGROUND: Approximately 60% of US adults live with chronic disease, imposing a significant burden on patients and the health care system. With the rise of telehealth, patient-reported outcomes measures (PROMs) have emerged as pivotal tools for managing chronic disease. While numerous PROMs exist, few have been designed explicitly for telehealth settings. The Parsley Symptom Index (PSI) is an electronic patient-reported outcome measure (ePROM) developed specifically for telehealth environments.

OBJECTIVE: Our aim is to determine whether the PSI predicts changes in the established Patient-Reported Outcomes Measurement Information System-10 (PROMIS-10) Global Health, a 10-question short form.

METHODS: We conducted a retrospective cohort …

A Small Molecule With Big Impact: Mrtx1133 Targets The Krasg12d Mutation In Pancreatic Cancer, Daoyan Wei, Liang Wang, Xiangsheng Zuo, Anirban Maitra, Robert S Bresalier

Faculty, Staff and Student Publications

KRAS mutations drive oncogenic alterations in numerous cancers, particularly in human pancreatic ductal adenocarcinoma (PDAC). About 93% of PDACs have KRAS mutations, with G12D (∼42% of cases) and G12V (∼32% of cases) being the most common. The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. However, there is a need to develop other much-needed KRAS-mutant inhibitors for PDAC therapy. Notably, Mirati Therapeutics recently developed MRTX1133, a small-molecule, noncovalent, and selective KRASG12D inhibitor through extensive structure-based drug design. MRTX1133 has demonstrated potent …

Sting Licensing Of Type I Dendritic Cells Potentiates Antitumor Immunity, Jian Wang, Suxin Li, Maggie Wang, Xu Wang, Shuqing Chen, Zhichen Sun, Xiubao Ren, Gang Huang, Baran D Sumer, Nan Yan, Yang-Xin Fu, Jinming Gao

Faculty, Staff and Student Publications

Stimulator of interferon genes (STING) is an immune adaptor protein that senses cyclic GMP-AMP (cGAMP) in response to self or microbial cytosolic DNA as a danger signal. STING is ubiquitously expressed in diverse cell populations including cancer cells with distinct cellular functions such as activation of type I interferons, autophagy induction, or triggering apoptosis. It is not well understood whether and which subsets of immune cells, stromal cells, or cancer cells are particularly important for STING-mediated antitumor immunity. Here using a polymeric STING-activating nanoparticle (PolySTING) with a “shock-and-lock” dual activation mechanism, we show type 1 conventional dendritic cell (cDC1) is …

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Backfilling Patients In Phase I Dose-Escalation Trials Using Bayesian Optimal Interval Design (Boin), Yixuan Zhao, Ying Yuan, Edward L Korn, Boris Freidlin

Faculty, Staff and Student Publications

In recent years, there has been increased interest in incorporation of backfilling into dose-escalation clinical trials, which involves concurrently assigning patients to doses that have been previously cleared for safety by the dose-escalation design. Backfilling generates additional information on safety, tolerability, and preliminary activity on a range of doses below the maximum tolerated dose (MTD), which is relevant for selection of the recommended phase II dose and dose optimization. However, in practice, backfilling may not be rigorously defined in trial protocols and implemented consistently. Furthermore, backfilling designs require careful planning to minimize the probability of treating additional patients with potentially …

Neoadjuvant Trebananib Plus Paclitaxel-Based Chemotherapy For Stage Ii/Iii Breast Cancer In The Adaptively Randomized I-Spy2 Trial-Efficacy And Biomarker Discovery, Kathy S Albain, Christina Yau, Emanuel F Petricoin, Denise M Wolf, Julie E Lang, A Jo Chien, Tufia Haddad, Andres Forero-Torres, Anne M Wallace, Henry Kaplan, Lajos Pusztai, David Euhus, Rita Nanda, Anthony D Elias, Amy S Clark, Constantine Godellas, Judy C Boughey, Claudine Isaacs, Debu Tripathy, Janice Lu, Rachel L Yung, Rosa I Gallagher, Julia D Wulfkuhle, Lamorna Brown-Swigart, Gregor Krings, Yunn Yi Chen, David A Potter, Erica Stringer-Reasor, Sarah Blair, Smita M Asare, Amy Wilson, Gillian L Hirst, Ruby Singhrao, Meredith Buxton, Julia L Clennell, Ashish Sanil, Scott Berry, Adam L Asare, Jeffrey B Matthews, Angela M Demichele, Nola M Hylton, Michelle Melisko, Jane Perlmutter, Hope S Rugo, W Fraser Symmans, Laura J Van't Veer, Douglas Yee, Donald A Berry, Laura J Esserman

Faculty, Staff and Student Publications

Purpose: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial.

Patients and methods: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. …

Strategies To Combine 3d Vasculature And Brain Cta With Deep Neural Networks: Application To Lvo, Uma M Lal-Trehan Estrada, Arnau Oliver, Sunil A Sheth, Xavier Lladó, Luca Giancardo

Faculty, Staff and Student Publications

Automated tools to detect large vessel occlusion (LVO) in acute ischemic stroke patients using brain computed tomography angiography (CTA) have been shown to reduce the time for treatment, leading to better clinical outcomes. There is a lot of information in a single CTA and deep learning models do not have an obvious way of being conditioned on areas most relevant for LVO detection, i.e., the vasculature structure. In this work, we compare and contrast strategies to make convolutional neural networks focus on the vasculature without discarding context information of the brain parenchyma and propose an attention-inspired strategy to encourage this. …

Inter-Individual Variations In Circadian Misalignment-Induced Nafld Pathophysiology In Mice, Nobuya Koike, Yasuhiro Umemura, Hitoshi Inokawa, Isao Tokuda, Yoshiki Tsuchiya, Yuh Sasawaki, Atsushi Umemura, Naoko Masuzawa, Kazuya Yabumoto, Takashi Seya, Akira Sugimoto, Seung-Hee Yoo, Zheng Chen, Kazuhiro Yagita

Faculty, Staff and Student Publications

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of …

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, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, 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 …