Digital Commons Network^™

Ogg1s326c Variant Frequent In Human Populations Facilitates Inflammatory Responses Due To Its Extended Interaction With Dna Substrate, Jinling Han, Meichen Zhang, Jiakun Ge, Zhihua Ji, Jianyi Zhao, Yinchao Hu, Chunshuang Li, Yaoyao Xue, Xining Li, Haiwang Zhao, Zixu Cui, Miaomiao Tian, Xu Zheng, Dapeng Wang, Jing Wang, Min Wei, Zsolt Radak, Yusaku Nakabeppu, Istvan Boldogh, Xueqing Ba

Faculty, Staff and Student Publications

8-oxoguanine (8-oxoGua) is one of the most frequent forms of oxidative DNA base lesions, repaired by 8-oxoguanine DNA glycosylase 1 (OGG1) via base excision repair (BER) pathway to maintain genome fidelity. The human allelic variant hOGG1^S326C, prevalent in Caucasians and Asians, has been regarded as a susceptibility factor for various diseases, yet its pathogenic mechanism remains elusive. In this study, we demonstrate that Ogg1^S326C/S326C mice exhibit increased and sustained airway inflammation compared with wild-type (WT) Ogg1^S326/S326 mice. Mechanistically, in response to inflammatory stimulation, OGG1S326C undergoes reactive oxygen species-induced dimerization, which impairs its base excision function, but …

Soft, Skin-Interfaced Wireless Electrogoniometry Systems For Continuous Monitoring Of Finger And Wrist Joints, Hee-Sup Shin, Jihye Kim, Nicholas Fadell, Logan B Pewitt, Yusuf Shaaban, Claire Liu, Min-Seung Jo, Josif Bozovic, Andreas Tzavelis, Minsu Park, Kelly Koogler, Jin-Tae Kim, Jae-Young Yoo, John A Rogers, Mitchell A Pet

2020-Current year OA Pubs

Continuous kinematic biofeedback during exercise interventions can lead to improved therapeutic outcomes in hand and wrist rehabilitation. Conventional methods for measuring joint kinematics typically allow only static measurements performed by specially trained therapists. This paper introduces skin-conformal, wearable wireless systems designed to continuously and accurately capture the angles of target joints, specifically in hand and wrist. Supported by a computer vision-based calibration protocol run on a smart device, these magnetometer-based standalone systems provide patients and clinicians with continuous, real-time data on joint angles and ranges of motion through an intuitive graphical interface. Human trials in healthy volunteers demonstrate the accuracy …

Narratives Or Not? Examining The Roles Of Message Format And Individuals' Stages Of Change In The Context Of Hpv Vaccination Promotion, Mengfei Guan, Shawn C. Chiang, Regan M. Murray, Wen-Juo Lo, Larry T. Hill, Ann C. Klassen, Jennifer A. Manganello, Amy E. Leader, Philip M. Massey

Department of Medical Oncology Faculty Papers

Narrative persuasion has been widely used in health communication campaigns and persuasive message design. However, several meta-analyses showed that the relative effectiveness of narratives in promoting behavior change was not consistently observed in the existing literature. With the goal of exploring boundary conditions of narrative effects, this study investigates the interaction effects of narrative persuasion and stages of change on promoting behavior change in the context of encouraging parents to vaccinate their children against human papillomavirus (HPV). Findings from an online experiment (N = 593) showed that non-narrative messages were more effective in bolstering behavioral intention than narrative messages among …

Structural Proteomics Defines A Sequential Priming Mechanism For The Progesterone Receptor, Matthew D Mann, Min Wang, Josephine C Ferreon, Phoebe S Tsoi, Michael P Suess, Antrix Jain, Anna Malovannaya, Roberto Vera Alvarez, Bruce D Pascal, Raj Kumar, Dean P Edwards, Patrick R Griffin

Faculty, Staff and Students Publications

The progesterone receptor (PR) is a steroid-responsive nuclear receptor with two isoforms: PR-A and PR-B. Disruption of PR-A:PR-B signaling is associated with breast cancer through interactions with oncogenic co-regulatory proteins (CoRs). However, molecular details of isoform-specific PR-CoR interactions remain poorly understood. Using structural mass spectrometry, we investigate the sequential binding mechanism of purified full-length PR and intact CoRs, steroid receptor coactivator 3 (SRC3) and p300, as complexes on target DNA. Our findings reveal selective CoR NR-box binding by PR and unique interaction surfaces between PR and CoRs during complex assembly, providing a structural basis for CoR sequential binding on PR. …

A Comparison Of Resurgence Following Dra And Dro, Alysa Georgopoulos

Theses & Dissertations

Resurgence, a form of behavioral relapse, occurs when a previously reduced target behavior reemerges after an alternative source of reinforcement is discontinued. Differential reinforcement of alternative behavior (DRA) and differential reinforcement of other behavior (DRO) are commonly used strategies to reduce undesired behaviors. Although both are effective, unanticipated periods of extinction (e.g., service lapses or staff turnover) may lead to resurgence of the original target behavior. Romano and St. Peter (2017) found that behavior reduced via DRO was more prone to resurgence than behavior reduced via DRA. However, their study used a different number of response options between conditions (one …

Molecular Basis Of Trpv3 Channel Blockade By Intracellular Polyamines, Jingying Zhang, Peng Yuan, Colin G Nichols, Grigory Maksaev

2020-Current year OA Pubs

ThermoTRPV1-4 channels are involved in the regulation of multiple physiological processes, including thermo- and pain perception, thermoregulation, itch, and nociception and therefore tight control of their activity is a critical requirement for correct perception of noxious stimuli and pain. We previously reported a voltage-dependent inhibition of TRPV1-4 channels by intracellular polyamines that could be explained by high affinity spermine binding in, and passage through, the permeation path. Here, using electrophysiology and cryo-electron microscopy, we elucidate molecular details of TRPV3 blockade by endogenous spermine and its analog NASPM. We identify a high-affinity polyamine interaction site at the intracellular side of the …

Let-7 Restrains An Epigenetic Circuit In At2 Cells To Prevent Fibrogenic Intermediates In Pulmonary Fibrosis, Matthew J Seasock, Md Shafiquzzaman, Maria E Ruiz-Echartea, Rupa S Kanchi, Brandon T Tran, Lukas M Simon, Matthew D Meyer, Phillip A Erice, Shivani L Lotlikar, Stephanie C Wenlock, Scott A Ochsner, Anton Enright, Alex F Carisey, Freddy Romero, Ivan O Rosas, Katherine Y King, Neil J Mckenna, Cristian Coarfa, Antony Rodriguez

Faculty, Staff and Students Publications

MicroRNA-mediated post-transcriptional regulation of lung alveolar type 2 (AT2) and AT1 cell differentiation remains understudied. Here, we demonstrate that the let-7 miRNA family plays a homeostatic role in AT2 quiescence by preventing the uncontrolled accumulation of AT2 transitional cells and promoting AT1 differentiation. Using mouse and organoid models, we show that genetic ablation of let-7a1/let-7f1/let-7d cluster (let-7afd) in AT2 cells prevents AT1 differentiation and leads to KRT8 transitional cell accumulation in progressive pulmonary fibrosis. Integration of AGO2-eCLIP with RNA-sequencing identified direct let-7 targets within an oncogene feed-forward regulatory network, including BACH1/EZH2/MYC, which drives an aberrant fibrotic cascade. Additional CUT&RUN-sequencing analyses …

Ligand-Activated Egfr/Mapk Signaling But Not Pi3k, Are Key Resistance Mechanisms To Egfr-Therapy In Colorectal Cancer, Xueping Qu, Habib Hamidi, Radia M Johnson, Ethan S Sokol, Eva Lin, Cathy Eng, Tae Won Kim, Johanna Bendell, Smruthy Sivakumar, Benjamin Kaplan, Felipe De Sousa E Melo, Andrew Mancini, Matthew Wongchenko, Yi Shi, David Shames, Yibing Yan, Fortunato Ciardiello, Carlos Bais

Faculty, Staff and Student Publications

Understanding mechanisms of resistance to active therapies is crucial for developing more effective treatments. Here, we investigate resistance to anti-EGFR and anti-VEGF plus chemotherapy treatment in colorectal cancer (CRC) patients from the IMblaze370 trial (NCT02788279). While anti-VEGF does not select for secondary mutations, anti-EGFR leads to simultaneous mutations in EGFR and MAPK, but not PI3K pathway genes. Notably, we observe frequent acquired mutations in the EGFR extracellular but not intracellular domain and that patients with higher baseline expression of EGFR-ligands are prone to acquire resistant mutations. This data reveals a ligand-activated EGFR/MAPK-signaling dependency in CRC. We also observe enrichment for …

Investigating Social Network Peer Effects On Hiv Care Engagement Using A Fuzzy-Like Matching Approach: Cross-Sectional Secondary Analysis Of The N2 Cohort Study, Cho-Hee Shrader, Dustin T Duncan, Redd Driver, Juan G Arroyo-Flores, Makella S Coudray, Raymond Moody, Yen-Tyng Chen, Britt Skaathun, Lindsay Young, Natascha Del Vecchio, Kayo Fujimoto, Justin R Knox, Mariano Kanamori, John A Schneider

Faculty, Staff and Student Publications

BACKGROUND: Social network data are essential and informative for public health research and implementation as they provide details on individuals and their social context. For example, health information and behaviors, such as HIV-related prevention and care, may disseminate within a network or across society. By harmonizing egocentric and digital networks, researchers may construct a sociocentric-like "fuzzy" network based on a subgroup of the population.

OBJECTIVE: We aimed to generate a more complete sociocentric-like "fuzzy" network by harmonizing alternative sources of egocentric and digital network data to examine relationships between participants in the Neighborhoods and Networks (N2) cohort study. Further, we …

Empathy And Psychological Outcomes In Informal Caregivers Of Community-Dwelling Older Adults: A Systematic Review And Meta-Analysis, Meng Huo, Thi Vu, Tomiko Yoneda, Jingkai Wei, Bruce Abbott, Joan K Monin

Faculty, Staff and Student Publications

Objectives: Scholars have increasingly recognized the crucial role that empathy plays as informal caregivers provide unpaid care to their older family and friends (i.e., care recipients). Yet, the existing literature exhibits substantial variability in study approaches and results, which limits the extent to which this literature can inform interventions intended to benefit informal caregivers. We sought to address this critical gap by synthesizing research that examined how caregivers' and care recipients' empathy were associated with caregivers' psychological health.

Methods: We conducted a literature search using PubMed, PsycInfo, CINAHL (Cumulative Index to Nursing and Allied Health Literature), EMBASE, and Scopus databases …

Human Genetic Variation Determines 24-Hour Rhythmic Gene Expression And Disease Risk, Ying Chen, Panpan Liu, Aniko Sabo, Dongyin Guan

Faculty, Staff and Students Publications

24-hour biological rhythms are essential to maintain physiological homeostasis. Disruption of these rhythms increases the risks of multiple diseases. Biological rhythms are known to have a genetic basis formed by core clock genes, but how individual genetic variation shapes the oscillating transcriptome and contributes to human chronophysiology and disease risk is largely unknown. Here, we mapped interactions between temporal gene expression and genotype to identify quantitative trait loci (QTLs) contributing to rhythmic gene expression. These newly identified QTLs were termed as rhythmic QTLs (rhyQTLs), which determine previously unappreciated rhythmic genes in human subpopulations with specific genotypes. Functionally, rhyQTLs and their …

Zanidatamab Monotherapy Or Combined With Chemotherapy In Her2-Expressing Gastroesophageal Adenocarcinoma: A Phase 1 Trial, Funda Meric-Bernstam, Sun Young Rha, Erika Hamilton, Yoon-Koo Kang, Diana L Hanna, Syma Iqbal, Keun-Wook Lee, Jeeyun Lee, Muralidhar Beeram, Do-Youn Oh, Jorge Chaves, Rachel A Goodwin, Jaffer A Ajani, Lin Yang, Rajen Oza, Elena Elimova

Faculty, Staff and Student Publications

There is a need for novel therapies for patients with previously treated HER2-positive gastroesophageal adenocarcinoma (GEA). This phase 1 (NCT02892123) dose-escalation and expansion trial evaluated zanidatamab (a dual HER2-targeted bispecific antibody) ± chemotherapy in previously treated patients with HER2-expressing, locally advanced/metastatic cancers. Here, we report the outcomes for GEA cohorts receiving zanidatamab monotherapy or with chemotherapy (paclitaxel or capecitabine). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rate (ORR), disease control rate, progression-free survival, pharmacokinetics, and immunogenicity. Seventy patients were enrolled (n = 29 monotherapy; n = 41 combination therapy); most received prior HER2-targeted agents (monotherapy, …

Characterising Acute And Chronic Care Needs: Insights From The Global Burden Of Disease Study 2019, A. A. Asadi-Pooya

Department of Neurology Faculty Papers

Chronic care manages long-term, progressive conditions, while acute care addresses short-term conditions. Chronic conditions increasingly strain health systems, which are often unprepared for these demands. This study examines the burden of conditions requiring acute versus chronic care, including sequelae. Conditions and sequelae from the Global Burden of Diseases Study 2019 were classified into acute or chronic care categories. Data were analysed by age, sex, and socio-demographic index, presenting total numbers and contributions to burden metrics such as Disability-Adjusted Life Years (DALYs), Years Lived with Disability (YLD), and Years of Life Lost (YLL). Approximately 68% of DALYs were attributed to chronic …

Genomic Landscape Of Diffuse Glioma Revealed By Whole Genome Sequencing., B Kinnersley, J Jung, Cornish Aj, D Chubb, R Laxton, A Frangou, Gruber Aj, A Sud, G Caravagna, A Sottoriva, Wedge Dc, T Booth, S Al-Sarraj, K Ashkan, Ellie Edlmann

Peninsula Medical School

Diffuse gliomas are the commonest malignant primary brain tumour in adults. Herein, we present analysis of the genomic landscape of adult glioma, by whole genome sequencing of 403 tumours (256 glioblastoma, 89 astrocytoma, 58 oligodendroglioma; 338 primary, 65 recurrence). We identify an extended catalogue of recurrent coding and non-coding genetic mutations that represents a source for future studies and provides a high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and extrachromosomal DNA. Finally, we relate these to clinical outcome. As well as identifying drug targets for treatment of glioma our findings …

A Honduran Prevalence Study On Soil-Transmitted Helminths Highlights Serological Antibodies To Tm-Wap49 As A Diagnostic Marker For Exposure To Human Trichuriasis, Neima Briggs, Leroy Versteeg, Rojelio Mejia, Jeroen Pollet, Maria Jose Villar, Bin Zhan, Graeme Segal, Stephanie Novak, Patricia Lenihan, Paul Musgrave, Viviana Ellis, Carol Florencia Coello, K Jagannadha Sastry, Joe Craft, Peter J Hotez, Maria Elena Bottazzi

Faculty, Staff and Student Publications

Soil-transmitted helminth (STH) infections rank among the most prevalent communicable diseases of humans, yet detection of these parasites is mostly restricted to identifying active infection through fecal examinations. Currently, there are no commercial diagnostic tools to identify a prior whipworm or hookworm exposure, and the few serological assays for roundworm infection have not been well validated for crossreactivity or infections in humans. Such diagnostic restrictions limit the range of scientific and clinical questions that surround STH exposures and their implicated relationship to chronic diseases, such as autoimmunity, allergy, and cancer. The goal of this investigation was to evaluate the diagnostic …

Multilevel Factors Influencing Perceived Barriers To Adjuvant Endocrine Therapy Among Breast Cancer Patients At Medication Onset, Timothy Cocozza, Rita Smith, Ana Maria Lopez, Shari Rudoler, Rachel Slamon, Tingting Zhan, Jazmarie L. Vega, Minal Dhamankar, Aruna Padmanabhan, Suzanne M. Miller, Kuang-Yi Wen

Department of Medical Oncology Faculty Papers

Purpose: Adjuvant endocrine therapy (AET) significantly diminishes recurrence and mortality risks in hormone receptor-positive breast cancer (BCa) patients. Nonetheless, suboptimal adherence and premature discontinuation during the initial year of treatment undermine these positive outcomes. This study aims to understand the potential diverse factors associated with perceived barriers to AET compliance at the onset of medication. Methods: We assessed perceived barriers to AET using the ASK-20 instrument for BCa patients initiating AET within 3 months. Our survey also included demographic variables (e.g., musculoskeletal symptoms) and clinical traits (e.g., medication type). Stepwise regression analyses were employed to elucidate the links between multilevel …

Genomic, Transcriptomic, And Immunogenomic Landscape Of Over 1300 Sarcomas Of Diverse Histology Subtypes., Alex Soupir, Oscar E. Ospina, Oliver Hampton, Michelle Churchman, Michael Radmacher, Dale Hedges, David Mckean, Phaedra Agius, Saman Zeeshan, Nathan D. Seligson, Raphael Pollock, David Liebner, James L. Chen, Gabriel Tinoco, Bodour Salhia, Martin Mccarter, Breelyn A. Wilky, Benjamin J. Miller, Michael J. Cavnar, John S. Groundland, Bryan P. Schneider, Gregory Riedlinger, Stephen B. Edge, Christopher A. Moskaluk, Kenneth Cardona, Abdul Rafeh Naqash, Ricardo J. Gonzalez, John E. Mullinax, David M. Joyce, Odion Binitie, G Douglas Letson, Arash O. Naghavi, Mihaela Druta, Damon R. Reed, Erin M. Siegel, Jamie K. Teer, Brooke L. Fridley, Andrew S. Brohl

Manuscripts, Articles, Book Chapters and Other Papers

Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p <  0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p <  0.01). Interestingly, GIST predominantly form a distinct "immune intermediate" cluster that is marked by a specific enrichment for NK cells (FDR <  0.01).

Genome Announcement Of Four Parechovirus A3 Isolates From The United States Of America., Debarpan Dhar, Terry Fei Fan Ng, Christopher J. Harrison, Eric Rhoden, Bernardo A Mainou, Anjana Sasidharan, Katelyn E. Vandonge, Varun Chandra Boinpelly, Rangaraj Selvarangan

Manuscripts, Articles, Book Chapters and Other Papers

We report the complete genome sequences of four parechovirus-A3 (PeV-A3) isolates from Children's Mercy Kansas City (CMKC), United States of America (USA): PeV-A3-MO-12-CMKC/CSF/MO/USA/2012 (isolated in 2012 from cerebrospinal fluid), PeV-A3-8C-CMKC/CSF/MO/USA/2022/ (isolated in 2022 from cerebrospinal fluid), PeV-A3-9C-CMKC/CSF/MO/USA/2022 (isolated in 2022 from cerebrospinal fluid), and PeV-A3-11B-CMKC/Blood/MO/USA/2022 (isolated in 2022 from blood). Sequence analysis revealed multiple mutations throughout the genome of the PeV-A3 isolates in comparison to the prototypic PeV-A3 A308/99 reference sequence (AB084913). Several unique amino acid changes were observed in the PeV-A3 isolates from 2022 that were absent in the PeV-A3 isolate from 2012. Phylogenetic analysis comparison determined that the …

Alzheimer’S Disease Protective Allele Of Clusterin Modulates Neuronal Excitability Through Lipid-Droplet-Mediated Neuron-Glia Communication, Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J Moulton, Lindsey D Goodman, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan

Duncan NRI Faculty and Staff Publications

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.

Methods: Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.

Results: We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with …

The Association Of Discrimination, Inflammation, And Coping Style On Self-Rated Health Among South Asian Individuals In The Masala Study, Raji Pillai, Sahiti Myneni, Constance M Johnson, Nilay S Shah, Alka M Kanaya, Jennifer E S Beauchamp

Faculty, Staff and Student Publications

Objectives: South Asian individuals (SAs) may have heightened levels of inflammatory markers, such as C reactive protein (CRP), Tumor Necrosis Factor-α (TNF-α), leptin, and resistin, and decreased levels of anti-inflammatory adiponectin, contributing to higher cardiovascular disease (CVD) incidence. Social determinants of health, like discrimination, are also associated with risks for CVD in SAs. This study examined the associations between discrimination and inflammation and whether coping styles moderated the association between discrimination and self-rated health (SRH) among SAs in the United States.

Design: Secondary analysis of data obtained from 1164 SAs (mean age = 57 years, SD = 9.4, 48% women) …

Deciphering The Longitudinal Trajectories Of Glioblastoma Ecosystems By Integrative Single-Cell Genomics., Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà

Faculty Research 2025

The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there …

An Intranasal Subunit Vaccine Induces Protective Systemic And Mucosal Antibody Immunity Against Respiratory Viruses In Mouse Models., Aina Karen Anthi, Anette Kolderup, Eline Benno Vaage, Malin Bern, Sopisa Benjakul, Elias Tjärnhage, Fulgencio Ruso-Julve, Kjell-Rune Jensen, Heidrun Elisabeth Lode, Marina Vaysburd, Jeannette Nilsen, Marie Leangen Herigstad, Siri Aastedatter Sakya, Lisa Tietze, Diego Pilati, Mari Nyquist-Andersen, Mirjam Dürkoop, Torleif Tollefsrud Gjølberg, Linghang Peng, Stian Foss, Morten C Moe, Benjamin E. Low, Michael V. Wiles, David Nemazee, Frode L Jahnsen, John Torgils Vaage, Kenneth A Howard, Inger Sandlie, Leo C James, Gunnveig Grødeland, Fridtjof Lund-Johansen, Jan Terje Andersen

Faculty Research 2025

Although vaccines are usually given intramuscularly, the intranasal delivery route may lead to better mucosal protection and limit the spread of respiratory virus while easing administration and improving vaccine acceptance. The challenge, however, is to achieve delivery across the selective epithelial cell barrier. Here we report on a subunit vaccine platform, in which the antigen is genetically fused to albumin to facilitate FcRn-mediated transport across the mucosal barrier in the presence of adjuvant. Intranasal delivery in conventional and transgenic mouse models induces both systemic and mucosal antigen-specific antibody responses that protect against challenge with SARS-CoV-2 or influenza A. When benchmarked …

Cord Blood Treatment For Children With Cerebral Palsy: Individual Participant Data Meta-Analysis, Megan Finch-Edmondson, Madison C B Paton, Annabel Webb, Mahmoud Reza Ashrafi, Remy K Blatch-Williams, Charles S Cox, Kylie Crompton, Alexandra R Griffin, Minyoung Kim, Steven Kosmach, Joanne Kurtzberg, Masoumeh Nouri, Mi Ri Suh, Jessica Sun, Morteza Zarrabi, Iona Novak

The Brown Foundation: Institute of Molecular Medicine

Context: Umbilical cord blood (UCB) is a novel treatment for cerebral palsy (CP), with trials indicating UCB can improve gross motor function. However, heterogeneity has limited the ability to interpret findings.

Objective: Assess the safety and efficacy of UCB for improving gross motor function in children with CP, including exploring cell dose effect and responder subgroups.

Data sources: Individual participant data from published reports and registered trials identified via systematic searches.

Study selection: Studies administering UCB to individuals with CP collecting Gross Motor Function Measure (GMFM) scores.

Data extraction: A 1-stage individual participant data meta-analysis was conducted in R to …

An Agrin-Yap/Taz Rigidity Sensing Module Drives Egfr-Addicted Lung Tumorigenesis., Reza Bayat Mokhtari, Divyaleka Sampath, Paige Eversole, Melissa Ong Yu Lin, Dmitriy A. Bosykh, Gandhi T. K. Boopathy, Aravind Sivakumar, Cheng-Chun Wang, Ramesh Kumar, Joe Yeong Poh Sheng, Ellen Karasik, Barbara A. Foster, Han Yu, Xiang Ling, Wenjie Wu, Fengzhi Li, Zoë Weaver Ohler, Christine Fillmore Brainson, David W. Goodrich, Wanjin Hong, Sayan Chakraborty

Markey Cancer Center Faculty Publications

Despite epidermal growth factor receptor (EGFR) is a pivotal oncogene for several cancers, including lung adenocarcinoma (LUAD), how it senses extracellular matrix (ECM) rigidity remain elusive in the context of the increasing role of tissue rigidity on various hallmarks of cancer development. Here it is shown that EGFR dictates tumorigenic agrin expression in lung cancer cell lines, genetically engineered EGFR-driven mouse models, and human specimens. Agrin expression confers substrate stiffness-dependent oncogenic attributes to EGFR-reliant cancer cells. Mechanistically, agrin mechanoactivates EGFR through epidermal growth factor (EGF)-dependent and independent modes, thereby sensitizing its activity toward localized cancer cell-ECM adherence and bulk rigidity …

An Updated Systematic Review And Consensus Definitions For Standardised Endpoints In Perioperative Medicine: Patient Comfort And Pain Relief, Paul S Myles, Sophie Wallace, Oliver Boney, Mari Botti, Frances Chung, Allan M Cyna, Tong J Gan, Michael P W Grocott, Mark P Jensen, Henrik Kehlet, Andrea Kurz, Maxime Leger, Ulrica Nilsson, Phillip Peyton, Daniel I Sessler, Martin R Tramèr, Christopher L Wu, Alfred Health Patient Experience And Consumer Engagement Group

Faculty, Staff and Student Publications

Background: Improving comfort during and after surgery is a key concern for anaesthetists and other clinicians. With the inclusion of patient and public involvement, we undertook a Delphi consensus process to update previously recommended endpoints to be used in clinical trials evaluating treatments aiming to improve patient comfort after surgery.

Methods: We undertook a systematic review to identify domains and outcome measures of patient comfort used in perioperative studies. Focus groups, workshops, and a multi-round Delphi consensus process that included clinician-researchers and a patient experience and consumer group updated a recommended list of standardised endpoints focused on patient comfort. Consensus …

Metastatic Medulloblastoma Remodels The Local Leptomeningeal Microenvironment To Promote Further Metastatic Colonization And Growth, Namal Abeysundara, Alexandra Rasnitsyn, Vernon Fong, Alexander Bahcheli, Randy Van Ommeren, Kyle Juraschka, Maria Vladoiu, Winnie Ong, Bryn Livingston, Pasqualino De Antonellis, Michelle Ly, Borja López Holgado, Olga Sirbu, Shahrzad Bahrampour, Hyun-Kee Min, Jerry Fan, Carolina Nor, Abhirami Visvanathan, Jiao Zhang, Hao Wang, Lei Qin, Ning Huang, Jonelle Pallotta, Tajana Douglas, Esta Mak, Haipeng Su, Karen Ng, Kevin Yang Zhang, Craig Daniels, Calixto-Hope G Lucas, Charles G Eberhart, Hailong Liu, Tao Jiang, Faiyaz Notta, Vijay Ramaswamy, Jüri Reimand, Marco Gallo, Jeremy N Rich, Xiaochong Wu, Xi Huang, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the major source of morbidity and mortality for patients with medulloblastoma. The biology of the leptomeningeal metastases and the local tumour microenvironment are poorly characterized. Here we show that metastasis-associated meningeal fibroblasts (MB-MAFs) are transcriptionally distinct and signal extensively to tumour cells and the tumour microenvironment. Metastatic cells secrete platelet-derived growth factor (PDGF) ligands into the local microenvironment to chemotactically recruit meningeal fibroblasts. Meningeal fibroblasts are reprogrammed to become MB-MAFs, expressing distinct transcriptomes and secretomes, including bone morphogenetic proteins. Active bone morphogenetic protein signalling and co-implantation of tumour cells with MB-MAFs enhances the colonization of the leptomeninges …

Igtp: Learning Interpretable Cellular Embedding For Inferring Biological Mechanisms Underlying Single-Cell Transcriptomics, Kang-Lin Hsieh, Kai Zhang, Yan Chu, Lishan Yu, Xiaoyang Li, Nuo Hu, Isha Kawosa, Patrick G Pilié, Pratip K Bhattacharya, Degui Zhi, Xiaoqian Jiang, Zhongming Zhao, Yulin Dai

Faculty, Staff and Student Publications

Deep-learning models like Variational AutoEncoder have enabled low dimensional cellular embedding representation for large-scale single-cell transcriptomes and shown great flexibility in downstream tasks. However, biologically meaningful latent space is usually missing if no specific structure is designed. Here, we engineered a novel interpretable generative transcriptional program (iGTP) framework that could model the importance of transcriptional program (TP) space and protein-protein interactions (PPI) between different biological states. We demonstrated the performance of iGTP in a diverse biological context using gene ontology, canonical pathway, and different PPI curation. iGTP not only elucidated the ground truth of cellular responses but also surpassed other …

Glim Consensus Approach To Diagnosis Of Malnutrition: A 5-Year Update., Gordon L Jensen, Tommy Cederholm, M Isabel T D Correia, M Cristina Gonzalez, Ryoji Fukushima, Veeradej Pisprasert, Renee Blaauw, Diana Cardenas Braz, Fernando Carrasco, Alfonso J Cruz Jentoft, Cristina Cuerda, David C Evans, Vanessa Fuchs-Tarlovsky, Leah Gramlich, Han Ping Shi, Jeanette M Hasse, Michael Hiesmayr, Naoki Hiki, Harriët Jager-Wittenaar, Shukri Jahit, Anayanet Jáquez, Heather Keller, Stanislaw Klek, Ainsley Malone, Kris M Mogensen, Naoharu Mori, Manpreet Mundi, Maurizio Muscaritoli, Doris Ng, Ibolya Nyulasi, Matthias Pirlich, Stephane Schneider, Marian De Van Der Schueren, Soranit Siltharm, Pierre Singer, Alison Steiber, Kelly A Tappenden, Jianchun Yu, André Van Gossum, Jaw-Yuan Wang, Marion F Winkler, Charlene Compher, Rocco Barazzoni

Ambulatory and Primary Care Articles

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) introduced an approach for malnutrition diagnosis in 2019 that comprised screening followed by assessment of three phenotypic criteria (weight loss, low body mass index [BMI], and low muscle mass) and two etiologic criteria (reduced food intake/assimilation and inflammation/disease burden). This planned update reconsiders the GLIM framework based on published knowledge and experience over the past 5 years.

METHODS: A working group (n = 43 members) conducted a literature search spanning 2019-2024 using the keywords "Global Leadership Initiative on Malnutrition or GLIM." Prior GLIM guidance activities for using the criteria on muscle mass …

Longevity Humans Have Youthful Erythrocyte Function And Metabolic Signatures, Fang Yu, Changhan Chen, Wuping Liu, Zhixiang Zhao, Yuhua Fan, Zhenjiang Li, Weilun Huang, Tingting Xie, Cheng Luo, Zhouzhou Yao, Qi Guo, Zhiyu Yang, Juan Liu, Yujin Zhang, Rodney E Kellems, Jian Xia, Ji Li, Yang Xia

Faculty, Staff and Student Publications

Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, …

Targeting Discrepancies In Linear Growth Measurements In The Neonatal Intensive Care Unit Through Nursing Interventions: A Quality Improvement Initiative, Gail Snyder, Rebekah Wilkinson, Raina Evans, Meagan Owen, Akram Yazdani, Covi Tibe, Catherine Perez, Lindsay F Holzapfel

Faculty, Staff and Student Publications

Objective: Accurate length measurements are essential for infants to identify growth deficiencies and adjust nutrition accordingly. The gold standard for length measurement in infants is using a length board with two people to obtain an accurate clinical assessment. We aimed to improve the number of measurements with the desired minimal difference, defined as a discrepancy ≤1 cm between nurse and audit measurements, in our center. Our secondary aim was to increase and maintain the number of length boards available.

Methods: This quality improvement (QI) study used a before-and-after intervention comparison design in a single-level IV neonatal intensive care unit between …