Digital Commons Network^™

Persistent Growth-Promoting Effects Of Vosoritide In Children With Achondroplasia Are Accompanied By Improvements In Physical And Social Aspects Of Health-Related Quality Of Life, Ravi Savarirayan, Melita Irving, William R Wilcox, Carlos A Bacino, Julie E Hoover-Fong, Paul Harmatz, Lynda E Polgreen, Klaus Mohnike, Carlos E Prada, Takuo Kubota, Paul Arundel, Antonio Leiva-Gea, Richard Rowell, Andrea Low, Ian Sabir, Alice Huntsman-Labed, Jonathan Day

Faculty, Staff and Students Publications

Purpose: Evaluate the impact of vosoritide on health-related quality of life in children with achondroplasia.

Methods: Participants received vosoritide (15 μg/kg/day) in an extension trial (NCT03424018) after having participated in a placebo-controlled trial (NCT03197766).

Results: The population comprised 119 participants (mean [SD] age 9.7 [2.6] years). Mean treatment duration was 4 (0.78) years. At year 3, the largest mean (SD) changes were observed in the Quality of Life of Short Stature Youth physical score (5.99 [19.41], caregiver reported; 6.32 [20.15], self-reported) and social score (2.85 [8.29] and 6.76 [22.64], respectively). Changes were greatest in participants with …

Association Of Common And Rare Variants With Alzheimer’S Disease In More Than 13,000 Diverse Individuals With Whole-Genome Sequencing From The Alzheimer’S Disease Sequencing Project, Wan-Ping Lee, Seung Hoan Choi, Margaret G Shea, Po-Liang Cheng, Beth A Dombroski, Achilleas N Pitsillides, Nancy L Heard-Costa, Hui Wang, Katia Bulekova, Amanda B Kuzma, Yuk Yee Leung, John J Farrell, Honghuang Lin, Brian W Kunkle, Adam Naj, Elizabeth E Blue, Frederick Nusetor, Dongyu Wang, Eric Boerwinkle, William S Bush, Xiaoling Zhang, Philip L De Jager, Josée Dupuis, Lindsay A Farrer, Myriam Fornage, Eden Martin, Margaret Pericak-Vance, Sudha Seshadri, Ellen M Wijsman, Li-San Wang, Alzheimer's Disease Sequencing Project, Gerard D Schellenberg, Anita L Destefano, Jonathan L Haines, Gina M Peloso

Center for Medical Ethics and Health Policy Staff Publications

Introduction: Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous.

Methods: We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data.

Results: Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10-8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10-9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10-8).

Discussion: We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD.

Highlights: We determine the association of genetic variants with Alzheimer's disease (AD) using …

Association Of Left Atrial Function With Frailty: The Atherosclerosis Risk In Communities (Aric) Study, Daokun Sun, Romil R Parikh, Wendy Wang, Anne Eaton, Pamela L Lutsey, B Gwen Windham, Riccardo M Inciardi, Scott D Solomon, Christie M Ballantyne, Amil M Shah, Lin Yee Chen

Faculty, Staff and Students Publications

Background: Frailty is common in people with cardiovascular disease. Worse left atrial (LA) function is an independent risk factor for cardiovascular disease. However, whether worse LA function is associated with frailty is unclear.

Methods: We included 3292 older adults from the Atherosclerosis Risk in Communities study who were non-frail at baseline (visit 5, 2011-2013) and had LA function (reservoir, conduit, and contractile strain) measured from two-dimensional speckle-tracking echocardiography. LA stiffness index was calculated as a ratio of E/e' to LA reservoir strain. Frailty was defined using the validated Fried frailty phenotype. Incident frailty was assessed between 2016 and 2019 during …

Inflammation, Physical Activity, And Disease-Free Survival In Stage Iii Colon Cancer: Cancer And Leukemia Group B-Southwest Oncology Group 80702 (Alliance), Justin C Brown, Chao Ma, Qian Shi, Felix Couture, Philip Kuebler, Pankaj Kumar, Benjamin Tan, Smitha Krishnamurthi, Victor Chang, Richard M Goldberg, Eileen M O'Reilly, Anthony F Shields, Jeffrey A Meyerhardt

2020-Current year OA Pubs

BACKGROUND: Inflammation and insufficient physical inactivity contribute to individual-level risk of disease recurrence and death in stage III colon cancer. The extent to which increased inflammatory risk can be offset by sufficient physical activity remains unknown.

METHODS: This cohort study was nested within the Cancer and Leukemia Group B (now part of the Alliance for Clinical Trials in Oncology) and Southwest Oncology Group randomized trial. Inflammatory burden was quantified by high-sensitivity C-reactive protein, interleukin-6, and soluble tumor necrosis factor-α receptor 2 after recovery from tumor resection. Physical activity was measured during and after postoperative chemotherapy. The primary endpoint was disease-free …

Dysfunctional Alpha Modulation As A Mechanism Of Working Memory Impairment In Serious Mental Illness, Molly A Erickson, Megan A Boudewyn, Kurt Winsler, Charlotte Li, Deanna M Barch, Cameron S Carter, Michael J Frank, James M Gold, Angus W Macdonald 3rd, John D Ragland, Steven M Silverstein, Andrew Yonelinas, Steven J Luck

2020-Current year OA Pubs

BACKGROUND: People with psychosis and mood disorders experience disruptions in working memory; however, the underlying mechanism remains unknown. We focused on 2 potential mechanisms: poor attentional engagement should be associated with elevated levels of prestimulus alpha-band activity within the electroencephalogram (EEG), whereas impaired working memory encoding should be associated with reduced poststimulus alpha suppression.

METHODS: We collected EEG data from 68 people with schizophrenia, 43 people with bipolar disorder with a history of psychosis, 53 people with major depressive disorder, and 90 healthy comparison subjects while they completed a spatial working memory task. We quantified attention lapsing, memory precision, and …

The Effects Of Mosaicism On Biological And Clinical Markers Of Alzheimer's Disease In Adults With Down Syndrome, Laura Xicota, Rachel L Henson, Beau Ances, Et Al.

2020-Current year OA Pubs

BACKGROUND: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.

METHODS: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma …

Quantifying Brain Development In The Healthy Brain And Child Development (Hbcd) Study: The Magnetic Resonance Imaging And Spectroscopy Protocol, Douglas C Dean 3rd, Chad M Sylvester, Michael P Harms, Christopher D Smyser, Et Al.

2020-Current year OA Pubs

The HEALthy Brain and Child Development (HBCD) Study, a multi-site prospective longitudinal cohort study, will examine human brain, cognitive, behavioral, social, and emotional development beginning prenatally and planned through early childhood. The acquisition of multimodal magnetic resonance-based brain development data is central to the study's core protocol. However, application of Magnetic Resonance Imaging (MRI) methods in this population is complicated by technical challenges and difficulties of imaging in early life. Overcoming these challenges requires an innovative and harmonized approach, combining age-appropriate acquisition protocols together with specialized pediatric neuroimaging strategies. The HBCD MRI Working Group aimed to establish a core acquisition …

Hypertonic Saline Induces Host Protective Immune Responses Against, Tran Xuan Ngoc Huy, Trang Thi Nguyen, Said Abdi Salad, Ched Nicole Turbela Aguilar, Alisha Wehdnesday Bernardo Reyes, Lauren Togonon Arayan, Wongi Min, Hu Jang Lee, Huynh Tan Hop, Suk Kim

Faculty Research 2024

Hypertonic saline (HTS) resuscitation can enhance immune responses against various pathogens, however, the effect of HTS on brucellosis is yet to be defined. In this study, we found that HTS inhibited Brucella infection in mice by augmenting Th1 immunity. HTS treatment enhanced the serum cytokines production and the expression of nitric oxide synthase (NOS2) and nuclear factor kappa B (NF-ĸB) p50 and p65, crucial anti-Brucella effectors in splenocytes. In addition, HTS treatment also inhibited the phosphorylation of MAPK signaling, accompanied by the down-regulation of the autophagy marker LC3B-II. Due to directing an appropriate immune response, HTS treatment substantially decreased bacterial …

Blood Matters: The Hematological Signatures Of Coronavirus Infection, Ayelen Toro, Ana P Arévalo, Marianoel Pereira-Gómez, Agustina Sabater, Eric A Zizzi, Paula Perbolianachis, Gaston Pascual, Sofia Lage-Vickers, Jorge L Pórfido, Ines Achinelli, Rocio Seniuk, Juan Bizzotto, Pablo Sanchis, Alvaro Olivera, Alejandro Leyva, Pilar Moreno, Alicia Costábile, Alvaro Fajardo, Federico Carrión, Martín Fló, Natalia Olivero-Deibe, Fernando Rodriguez, Nicolas Nin, Nicolas Anselmino, Estefania Labanca, Elba Vazquez, Javier Cotignola, Daniel F Alonso, Maria P Valacco, Marcelo Marti, Francesco Gentile, Artem Cherkasov, Martina Crispo, Gonzalo Moratorio, Geraldine Gueron

Faculty, Staff and Student Publications

Recent developments have broadened our perception of SARS-CoV-2, indicating its capability to affect the body systemically beyond its initial recognition as a mere respiratory pathogen. However, the pathways of its widespread are not well understood. Employing a dual-modality approach, we integrated findings from a Murine Hepatitis Virus (MHV) infection model with corroborative clinical data to investigate the pervasive reach of Coronaviruses. The novel presence of viral particles within red blood cells (RBCs) was demonstrated via high-resolution transmission electron microscopy, with computational modeling elucidating a potential heme-mediated viral entry mechanism via Spike protein affinity. Our data affirm viral localization in RBCs, …

Host Dna Depletion On Frozen Human Respiratory Samples Enables Successful Metagenomic Sequencing For Microbiome Studies, Minsik Kim, Raymond C Parrish, Michael J Tisza, Viral S Shah, Thi Tran, Matthew Ross, Juwan Cormier, Aribah Baig, Ching-Ying Huang, Laura Brenner, Isabel Neuringer, Katrine Whiteson, J Kirk Harris, Amy D Willis, Peggy S Lai

Faculty, Staff and Students Publications

Most respiratory microbiome studies use amplicon sequencing due to high host DNA. Metagenomics sequencing offers finer taxonomic resolution, phage assessment, and functional characterization. We evaluated five host DNA depletion methods on frozen nasal swabs from healthy adults, sputum from people with cystic fibrosis (pwCF), and bronchoalveolar lavage (BAL) from critically ill patients. Median sequencing depth was 76.4 million reads per sample. Untreated nasal, sputum, and BAL had 94.1%, 99.2%, and 99.7% host reads, respectively. Host depletion effects varied by sample type, generally increasing microbial reads, species and functional richness; this was mediated by higher effective sequencing depth. Rarefaction curves showed …

Characterising The Anxiogenic Network From Functional Connectivity Analysis Of The Co2 Challenge Model, Daniel Graham, Santra Mathew, Jonathan Marsden, Alastair D Smith, Gary Smerdon, Stephen D Hall

School of Psychology

The CO2 challenge model (CCM) is a gas inhalation paradigm that provides precisely controlled anxiety induction in experimental settings. Despite its potential as an experimental model of anxiety, our understanding of the neural effects of the CCM is incomplete. This study employs resting-state functional magnetic resonance imaging (rs-fMRI) to explore functional connectivity (FC) changes underlying the CCM. Following a preliminary CO2 tolerance assessment, participants completed an MRI session that included three rs-fMRI scans: during inhalation of control air (pre and post), and during a 6% CCM exposure. Here, we confirm that 6% CCM is a tolerable anxiogenic model in the …

Comparing Neoantigen Cancer Vaccines And Immune Checkpoint Therapy Unveils An Effective Vaccine And Anti-Trem2 Macrophage-Targeting Dual Therapy, Sunita Keshari, Alexander S Shavkunov, Qi Miao, Akata Saha, Tomoyuki Minowa, Martina Molgora, Charmelle D Williams, Mehdi Chaib, Anna M Highsmith, Josué E Pineda, Sayan Alekseev, Elise Alspach, Kenneth H Hu, Marco Colonna, Kristen E Pauken, Ken Chen, Matthew M Gubin

Faculty, Staff and Student Publications

The goal of therapeutic cancer vaccines and immune checkpoint therapy (ICT) is to promote T cells with anti-tumor capabilities. Here, we compared mutant neoantigen (neoAg) peptide-based vaccines with ICT in preclinical models. NeoAg vaccines induce the most robust expansion of proliferating and stem-like PD-1+TCF-1+ neoAg-specific CD8 T cells in tumors. Anti-CTLA-4 and/or anti-PD-1 ICT promotes intratumoral TCF-1- neoAg-specific CD8 T cells, although their phenotype depends in part on the specific ICT used. Anti-CTLA-4 also prompts substantial changes to CD4 T cells, including induction of ICOS+Bhlhe40+ T helper 1 (Th1)-like cells. Although neoAg vaccines or ICTs expand iNOS+ macrophages, neoAg vaccines …

Metabolite Signatures Of Chronological Age, Aging, Survival, And Longevity, Paola Sebastiani, Mary F Feitosa, Mary K Wojczynski, Gary J Patti, Et Al.

2020-Current year OA Pubs

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we differentiate between metabolites that may mark aging-associated compensatory mechanisms from metabolites that mark cumulative damage of aging and from metabolites that characterize extreme longevity. We generate and validate a metabolomic …

Impact Of Vitamin D On Hyperoxic Acute Lung Injury In Neonatal Mice, Thu T Tran, Jonathan Davies, Richard A Johnston, Harry Karmouty-Quintana, Huiling Li, Caroline E Crocker, Amir M Khan, Joseph L Alcorn

Faculty, Staff and Students Publications

BACKGROUND: Prolonged exposure to hyperoxia can lead to hyperoxic acute lung injury (HALI) in preterm neonates. Vitamin D (VitD) stimulates lung maturation and acts as an anti-inflammatory agent. Our objective was to determine if VitD provides a dose-dependent protective effect against HALI by reducing inflammatory cytokine expression and improving alveolarization and lung function in neonatal mice.

METHODS: C57BL/6 mouse neonates were randomized and placed in room air or hyperoxic (85% O

RESULTS: Neonatal mice treated with VitD in hyperoxic conditions had improved weight gain, reduced pulmonary edema and increased alveolar surface area compared to untreated pups in hyperoxia. No significant …

Clc-Kb Pore Mutation Disrupts Glycosylation And Triggers Distal Tubular Remodeling, Yogita Sharma, Robin Lo, Viktor N Tomilin, Kotdaji Ha, Holly Deremo, Aishwarya V Pareek, Wuxing Dong, Xiaohui Liao, Svetlana Lebedeva, Vivek Charu, Neeraja Kambham, Kerim Mutig, Oleh Pochynyuk, Vivek Bhalla

Faculty, Staff and Student Publications

Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, cause type 3 Bartter syndrome. We identified a family with a mixed Bartter/Gitelman phenotype and early-onset kidney failure and by employing a candidate gene approach, identified what we believe is a novel homozygous mutation (CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole-exome sequencing. Compared with wild-type ClC-Kb, the Gly167Cys mutant conducted less current and exhibited impaired complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, …

Identification Of Lrp1+Cd13+ Human Periosteal Stem Cells That Require Lrp1 For Bone Repair, Youngjae Jeong, Lorenzo Deveza, Laura Ortinau, Kevin Lei, John R Dawson, Dongsu Park

Faculty, Staff and Students Publications

Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, podoplanin (PDPN) and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs, selectively expressed identified markers low density lipoprotein receptor-related protein 1 (LRP1) and CD13. These LRP1+CD13+ human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. Upon transplantation into bone injuries in mice, they preserved self-renewal capability in vivo. Single-cell analysis of mouse periosteum further supported the preferential …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Xiuqi Gui, Yunhao Zou, Qian Liu, Zhicheng Yang, Jusheng An, Xuan Guo, Kaihua Wang, Jiaming Guo, Manni Huang, Shuhan Zhou, Jing Zuo, Yimin Chen, Lu Deng, Guangwen Yuan, Ning Li, Yan Song, Jia Jia, Jia Zeng, Yuxi Zhao, Xianming Liu, Xiaoxian Du, Yansheng Liu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Hu Zhou, Zhen Shao, Lingying Wu, Daming Gao

Faculty, Staff and Students Publications

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Li Ding, Et Al.

2020-Current year OA Pubs

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Genotype-Specific Effects Of Elamipretide In Patients With Primary Mitochondrial Myopathy: A Post Hoc Analysis Of The Mmpower-3 Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce Cohen, Gregory M Ennes, Marni J Falk, Amy Goldstein, Gráinne Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russekk Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, Anthony Abbruscato, David A Brown, Alana Sullivan, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Students Publications

BACKGROUND: As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those …

Comparison Of The Bristol Stool Scale And Modified Version For Children: Use By Providers Vs Children, James Orozco, Mariella M Self, Sara Grisales, Bruno P Chumpitazi, Danita I Czyzewski, Meagan S Mcmullen, Rebecca Berger, Clarissa A Gonzalez, Amber L Cunha, Robert J Shulman

Faculty, Staff and Students Publications

Introduction: Accurate report of stool form is essential to diagnosis and assessment of treatment response. The modified Bristol Stool Form Scale for Children (mBSFS-C) classifies stool form into 5 types and is reliable and valid. However, a direct comparison of provider's and children's ratings using the mBSFS-C vs the traditional BSFS that uses 7 stool form types has not been done.

Methods: Pediatric gastroenterology providers and children rated the same 35 stool photographs, reflecting diverse stool forms, using both scales. The order of photograph presentation and scale use were randomized. For each photograph, the most common rating (modal rating) was …

Does Muscle Pain Induce Alterations In The Pelvic Floor Motor Unit Activity Properties In Interstitial Cystitis/Bladder Pain Syndrome? A High-Density Semg-Based Study, Monica Albaladejo-Belmonte, Michael Houston, Nicholas Dias, Theresa Spitznagle, Henry Lai, Yingchun Zhang, Javier Garcia-Casado

2020-Current year OA Pubs

Several studies have shown interstitial cystitis/bladder pain syndrome (IC/BPS), a chronic condition that poses challenges in both diagnosis and treatment, is associated with painful pelvic floor muscles (PFM) and altered neural drive to these muscles. However, its pathophysiology could also involve other alterations in the electrical activity of PFM motor units (MUs). Studying these alterations could provide novel insights into IC/BPS and help its clinical management. This study aimed to characterize PFM activity at the MU level in women with IC/BPS and pelvic floor myalgia using high-density surface electromyography (HD-sEMG). Signals were recorded from 15 patients and 15 healthy controls …

Phase I Dose Escalation Study Of Io-108, An Anti-Lilrb2 Antibody, In Patients With Advanced Solid Tumors, Matthew H Taylor, Aung Naing, John Powderly, Paul Woodard, Luke Chung, Wen Hong Lin, Hongyu Tian, Nathan Siemers, Hong Xiang, Rong Deng, Kyu Hong, Donna Valencia, Tao Huang, Ying Zhu, X Charlene Liao, Xiao Min Schebye, Manish R Patel

Faculty, Staff and Student Publications

Purpose: In this first-in-human dose escalation study, the safety and efficacy of IO-108, a fully human monoclonal antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2), was investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody.

Methods: The study included patients with histologically or cytologically confirmed advanced and relapsed solid tumors, with measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Patients were treated with escalating doses of IO-108 every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. Safety and tolerability were the primary objectives. …

Il-37 Suppresses Cns Autoimmunity By Increasing The Frequency Of Treg Cells And Reducing Cd4 + T Cell-Derived Il-10 Production, Reza Yazdani, Hamed Naziri, Gholamreza Azizi, Bogoljub Ciric, Mozhde Askari, Amir Moghadam-Ahmadi, Jaya Aseervatham, Guang-Xian Zhang, Mohamad Rostami

Department of Neurology Faculty Papers

BACKGROUND: Interleukin-37 (IL-37) has anti-inflammatory properties in innate and adaptive immunity. Patients with multiple sclerosis (MS), an autoimmune inflammatory demyelinating disease of the central nervous system (CNS), have increased serum levels of IL-37. However, it is unknown whether IL-37 has an inhibitory effect on ongoing autoimmune neuroinflammation, thus offering a potential MS therapy.

AIM: Here, we examined the effect of IL-37 in an experimental autoimmune encephalomyelitis (EAE) model after disease onset to determine if it was protective.

FINDINGS: IL-37-treated mice developed a less severe disease than control mice, with reduced demyelination as determined by increased expression of myelin basic protein. …

Long-Term Outcomes Following Posterior Fossa Decompression In Pediatric Patients With Chiari Malformation Type 1, A Population-Based Cohort Study, Victor Gabriel El-Hajj, Erik Öhlén, Ulrika Sandvik, Jenny Pettersson-Segerlind, Elias Atallah, Pascal Jabbour, Mohamad Bydon, David J. Daniels, Adrian Elmi-Terander, Erik Edström

Department of Neurosurgery Faculty Papers

OBJECTIVE: Posterior fossa decompression for Chiari malformation type I (Chiari 1) is effective and associated with a low risk of complication. However, up to 20% of patients may experience continued deficits or recurring symptoms after surgical intervention. For pediatric patients, there are no established tools to predict outcomes, and the risk factors for unfavorable postoperative outcomes are poorly understood. Hence, our aim was to investigate baseline data and early postoperative predictors of poor outcomes as determined by the Chicago Chiari outcome scale (CCOS).

METHODS: All pediatric patients (< 18 years) receiving a posterior fossa decompression for Chiari 1 between the years of 2005 and 2020 at the study center were eligible for inclusion. Patients with congenital anomalies were excluded.

RESULTS: Seventy-one pediatric patients with a median age of 9 years were …

Lung Tissue Multilayer Network Analysis Uncovers The Molecular Heterogeneity Of Chronic Obstructive Pulmonary Disease, Nuria Olvera, Jon Sánchez-Valle, Iker Núñez-Carpintero, Joselyn Rojas-Quintero, Guillaume Noell, Sandra Casas-Recasens, Alen Faiz, Philip Hansbro, Angela Guirao, Rosalba Lepore, Davide Cirillo, Alvar Agustí, Francesca Polverino, Alfonso Valencia, Rosa Faner

Faculty, Staff and Students Publications

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition. Objectives: We hypothesized that the unbiased integration of different COPD lung omics using a novel multilayer approach might unravel mechanisms associated with clinical characteristics.

Methods: We profiled mRNA, microRNA and methylome in lung tissue samples from 135 former smokers with COPD. For each omic (layer), we built a patient network on the basis of molecular similarity. The three networks were used to build a multilayer network, and optimization of multiplex modularity was used to identify patient communities across the three distinct layers. Uncovered communities were related to clinical features.

Measurements …

Association Of Clonal Hematopoiesis And Mosaic Chromosomal Alterations With Solid Malignancy Incidence And Mortality, Pinkal Desai, Ying Zhou, Justin Grenet, Samuel K Handelman, Cynthia M Crispino, Laura N Tarbay, Eric A Whitsel, Gail Roboz, Ana Barac, Michael Honigberg, Alexander Bick, Garnet Anderson, Jean Wactawski-Wende, Yasminka A Jakubek Swartzlander, Jason Bacon, Justin Wong, Xiaolong Ma, Paul Scheet, Zichan Li, Pashtoon Kasi, Ross Prentice, Paul Auer, Joann E Manson, Alexander Reiner, Michael Simon

Faculty, Staff and Student Publications

Background: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways.

Methods: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers.

Results: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or …

Disease Site Specialization In The Academic Radiation Oncology Workforce: Evidence Of Gender Differences, Kelsey L Corrigan, Mikaela E Bankston, Emma B Holliday, Simona F Shaitelman, Anna Lee, Chelain R Goodman, C David Fuller, Fumiko L Chino, Charles R Thomas, Reshma Jagsi, Ethan B Ludmir

Faculty, Staff and Student Publications

Purpose: Because some stakeholders within medicine seek to diversify and attain greater workforce equity, it is critical to understand gender-based divisions within specialization. Radiation oncology (RO) has one of the smallest proportions of women representation of all specialties, and to our knowledge, no prior studies have investigated gender differences in all the disease site specializations within RO. Thus, we analyzed the relationship between gender and disease site(s) treated in academic RO (ARO).

Methods and materials: Faculty gender and disease site(s) treated by faculty from ARO departments were collected via publicly available department websites in January 2020. X2 analyses were conducted …

Low-Molecular Weight Cyclin E Confers A Vulnerability To Pkmyt1 Inhibition In Triple-Negative Breast Cancer, Mi Li, Amriti R Lulla, Yan Wang, Spyros Tsavaschidis, Fuchenchu Wang, Cansu Karakas, Tuyen D T Nguyen, Tuyen N Bui, Marc A Pina, Mei-Kuang Chen, Sofia Mastoraki, Asha S Multani, Natalie W Fowlkes, Aysegul Sahin, C Gary Marshall, Kelly K Hunt, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. The cleavage of full-length cyclin E (FL-cycE) to low-molecular weight isoforms (LMW-E) dramatically alters substrate specificity, promoting G1-S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. In this study, analysis of tumor samples of patients with TNBC revealed that coexpression of LMW-E and PKMYT1-catalyzed CDK1 …

Personalized Composite Dosimetric Score-Based Machine Learning Model Of Severe Radiation-Induced Lymphopenia Among Patients With Esophageal Cancer, Yan Chu, Cong Zhu, Brian P Hobbs, Yiqing Chen, Peter S N Van Rossum, Clemens Grassberger, Degui Zhi, Steven H Lin, Radhe Mohan

Faculty, Staff and Student Publications

Purpose: Radiation-induced lymphopenia (RIL) is common among patients undergoing radiation therapy (RT)' Severe RIL has been linked to adverse outcomes. The severity and risk of RIL can be predicted from baseline clinical characteristics and dosimetric parameters. However, dosimetric parameters, e.g. dose-volume (DV) indices, are highly correlated with one another and are only weakly associated with RIL. Here we introduce the novel concept of "composite dosimetric score" (CDS) as the index that condenses the dose distribution in immune tissues of interest to study the dosimetric dependence of RIL. We derived an improved multivariate classification scheme for risk of grade 4 RIL …

Isolation, Discrimination, And Feeling “Constant Guilt”: A Mixed-Methods Analysis Of Female Physicians’ Experience With Fertility, Family Planning, And Oncology Careers, Sarah Marion, Shraddha M Dalwadi, Aleksandra Kuczmarska-Haas, Erin F Gillespie, Michelle S Ludwig, Emma B Holliday, Bridgette Thom, Fumiko Chino, Anna Lee

Faculty, Staff and Students Publications

Introduction: Family planning among female physicians is harmed by high risks of infertility, workload burden, poor family leave policies, and gender discrimination. Many women report feeling unsupported in the workplace, despite national policies to protect against unfair treatment.

Methods: This secondary analysis applied a modified version of the rigorous and accelerated data reduction technique to conduct a thematic analysis of comments to an open-ended prompt. Comments were coded by multiple trained researchers then grouped and merged into illustrative themes via qualitative techniques.

Results: Of 1004 responses to the quantitative survey, 162 physicians completed the open-ended prompt. Initial codes (n = …