Medical Specialties Commons^™

Spatial Pd-L1, Immune-Cell Microenvironment, And Genomic Copy-Number Alteration Patterns And Drivers Of Invasive-Disease Transition In Prospective Oral Precancer Cohort, William N William, Jianjun Zhang, Xin Zhao, Edwin R Parra, Naohiro Uraoka, Heather Y Lin, S Andrew Peng, Adel K El-Naggar, Jaime Rodriguez-Canales, Jaejoon Song, Ann M Gillenwater, Ignacio I Wistuba, Jeffrey N Myers, Kathryn A Gold, Renata Ferrarotto, Patrick Hwu, Teresa Davoli, J Jack Lee, John V Heymach, Vassiliki A Papadimitrakopoulou, Scott M Lippman

Faculty, Staff and Student Publications

BACKGROUND: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC).

METHODS: The authors evaluated spatial CD3, CD3/8, and CD68 density (cells/mm

RESULTS: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High …

Covariate Adjustment In Continuous Biomarker Assessment, Ziyi Li, Yijian Huang, Dattatraya Patil, Martin G Sanda

Faculty, Staff and Student Publications

Continuous biomarkers are common for disease screening and diagnosis. To reach a dichotomous clinical decision, a threshold would be imposed to distinguish subjects with disease from nondiseased individuals. Among various performance metrics, specificity at a controlled sensitivity level (or vice versa) is often desirable because it directly targets the clinical utility of the intended clinical test. Meanwhile, covariates, such as age, race, as well as sample collection conditions, could impact the biomarker distribution and may also confound the association between biomarker and disease status. Therefore, covariate adjustment is important in such biomarker evaluation. Most existing covariate adjustment methods do not …

Urinary Cd163 Is A Marker Of Active Kidney Disease In Childhood-Onset Lupus Nephritis, Haleigh Inthavong, Kamala Vanarsa, Jessica Castillo, M John Hicks, Chandra Mohan, Scott E Wenderfer

Faculty, Staff and Students Publications

OBJECTIVE: The objective of this study was to evaluate the utility of urine CD163 for detecting disease activity in childhood-onset SLE (cSLE) patients.

METHODS: Sixty consecutive pediatric patients fulfilling four or more ACR criteria for SLE and 20 healthy controls were recruited for testing of urinary CD163 using ELISA. SLE disease activity was assessed using the SLEDAI-2K.

RESULTS: Urine CD163 was significantly higher in patients with active LN than inactive SLE patients and healthy controls, with receiver operating characteristics area under the curve values ranging from 0.93 to 0.96. LN was ascertained by kidney biopsy. Levels of CD163 significantly correlated …

Urine Complement Factor Ba Is Associated With Aki In Critically Ill Children, Erin K Stenson, Charles L Edelstein, Zhiying You, Shinobu Miyazaki-Anzai, Joshua M Thurman, Bradley P Dixon, Michael Zappitelli, Stuart L Goldstein, Ayse Akcan Arikan, Jessica Kendrick

Faculty, Staff and Students Publications

KEY POINTS: Complement activation, specifically factor B, is implicated in AKI pathogenesis in animal models. Urine Ba (an activation fragment of factor B) was significantly higher in critically ill children with stage 3 AKI and sepsis-AKI. If larger studies show similar association between urine Ba and AKI severity, clinical trials of factor B inhibition are warranted.

BACKGROUND:: Critically ill children with AKI have high morbidity and mortality rates and lack treatment options. Complement activation is implicated in AKI pathogenesis, which could be treated with complement-targeted therapeutics. We assessed for an association between urine Ba, an activation fragment of the alternative …

Rational Targets Of Therapy In Extranodal Nk/T-Cell Lymphoma, Ajay Major, Pierluigi Porcu, Bradley M Haverkos

Department of Medical Oncology Faculty Papers

Extranodal NK/T-cell lymphoma (ENKTL) is an aggressive extranodal non-Hodgkin lymphoma (NHL) with poor outcomes, particularly in advanced-stage and relapsed/refractory disease. Emerging research on molecular drivers of ENKTL lymphomagenesis by next-generation and whole genome sequencing has revealed diverse genomic mutations in multiple signaling pathways, with the identification of multiple putative targets for novel therapeutic agents. In this review, we summarize the biological underpinnings of newly-understood therapeutic targets in ENKTL with a focus on translational implications, including epigenetic and histone regulatory aberrations, activation of cell proliferation signaling pathways, suppression of apoptosis and tumor suppressor genes, changes in the tumor microenvironment, and EBV-mediated …

Sakurabonsai: Protocol Design Of A Novel, Prospective Study To Explore Clinical, Imaging, And Biomarker Outcomes In Patients With Aqp4-Igg-Seropositive Neuromyelitis Optica Spectrum Disorder Receiving Open-Label Satralizumab, Jeffrey L Bennett, Kazuo Fujihara, Ho Jin Kim, Romain Marignier, Kevin C O'Connor, Robert C Sergott, Anthony Traboulsee, Heinz Wiendl, Jens Wuerfel, Scott S Zamvil, Veronica G Anania, Regine Buffels, Thomas Künzel, Annemarie N Lekkerkerker, Siân Lennon-Chrimes, Sean J Pittock

Wills Eye Hospital Papers

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a rare, autoimmune disease of the central nervous system that produces acute, unpredictable relapses causing cumulative neurological disability. Satralizumab, a humanized, monoclonal recycling antibody that targets the interleukin-6 receptor, reduced NMOSD relapse risk vs. placebo in two Phase 3 trials: SAkuraSky (satralizumab ± immunosuppressive therapy; NCT02028884) and SAkuraStar (satralizumab monotherapy; NCT02073279). Satralizumab is approved to treat aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD. SAkuraBONSAI (NCT05269667) will explore fluid and imaging biomarkers to better understand the mechanism of action of satralizumab and the neuronal and immunological changes following treatment in AQP4-IgG+ NMOSD.

Objectives: …

Baseline Extracellular Vesicle Tgf-Β Is A Predictive Biomarker For Response To Immune Checkpoint Inhibitors And Survival In Non-Small Cell Lung Cancer, Diego De Miguel-Perez, Alessandro Russo, Muthukumar Gunasekaran, Francesco Buemi, Lisa Hester, Xiaoxuan Fan, Brandon A Carter-Cooper, Rena G Lapidus, Ariel Peleg, Marisol Arroyo-Hernández, Andres F Cardona, Aung Naing, Fred R Hirsch, Philip C Mack, Sunjay Kaushal, Maria Jose Serrano, Vincenzo Adamo, Oscar Arrieta, Christian Rolfo

Faculty, Staff and Student Publications

Background: Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-β (TGF-β), can be found free in …

Inflammatory Biomarkers Differ Among Hospitalized Veterans Infected With Alpha, Delta, And Omicron Sars-Cov-2 Variants, Catherine Park, Shahriar Tavakoli-Tabasi, Amir Sharafkhaneh, Benjamin J Seligman, Bret Hicken, Christopher I Amos, Andrew Chou, Javad Razjouyan

Faculty, Staff and Students Publications

Mortality due to COVID-19 has been correlated with laboratory markers of inflammation, such as C-reactive protein (CRP). The lower mortality during Omicron variant infections could be explained by variant-specific immune responses or host factors, such as vaccination status. We hypothesized that infections due to Omicron variant cause less inflammation compared to Alpha and Delta, correlating with lower mortality. This was a retrospective cohort study of veterans hospitalized for COVID-19 at the Veterans Health Administration. We compared inflammatory markers among patients hospitalized during Omicron infection with those of Alpha and Delta. We reported the adjusted odds ratio (aOR) of the first …

Association Of Circulating Mtdna With Cvd In Hemodialysis Patients And In Vitro Effect Of Exogenous Mtdna On Cardiac Microvascular Inflammation, Zhen Fan, Ya Feng, Li Zang, Yi Guo, Xiao-Yi Zhong

Faculty, Staff and Student Publications

BACKGROUND: Chronic kidney disease (CKD) patients sustain a fairly high prevalence of cardiovascular disease (CVD). Microvascular inflammation is an early manifestation of CVD, and the released mitochondrial DNA (MtDNA) has been proposed to be a crucial integrator of inflammatory signals. Herein, the aim of this study was to determine the relationship between CVD, microvessel, and circulating MtDNA in the settings of uremia.

METHODS: Forty-two maintenance hemodialysis (MHD) patients and 36 health controls were enrolled in this study. Plasma cell-free MtDNA was detected by TaqMan-based qPCR assay. CVD risk markers including high-sensitive C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), fibrinogen, and …

Evaluation Of New Potential Inflammatory Markers In Patients With Nonvalvular Atrial Fibrillation, Gabriela Lopes Martins, Rita Carolina Figueiredo Duarte, Érica Leandro Marciano Vieira, Natália Pessoa Rocha, Estêvão Lanna Figueiredo, Francisco Rezende Silveira, José Raymundo Sollero Caiaffa, Rodrigo Pinheiro Lanna, Maria Das Graças Carvalho, András Palotás, Cláudia Natália Ferreira, Helton José Reis

Faculty, Staff and Student Publications

Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = …

The Performance Of Afp, Afp-3, Dcp As Biomarkers For Detection Of Hepatocellular Carcinoma (Hcc): A Phase 3 Biomarker Study In The United States, Nabihah Tayob, Fasiha Kanwal, Abeer Alsarraj, Ruben Hernaez, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND & AIMS: α-fetoprotein (AFP), AFP Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and des-gamma-carboxy prothrombin (DCP) in combination or in GALAD (Gender, Age, AFP-L3, AFP, and DCP) were tested for hepatocellular carcinoma (HCC) surveillance in retrospective cohort and case-control studies. However, there is a paucity of prospective data and no phase III biomarker studies from North American populations.

METHODS: We conducted a prospective specimen collection, retrospective blinded evaluation (PRoBE) cohort study in patients with cirrhosis enrolled in a 6-monthly surveillance with liver imaging and AFP. Blood samples were prospectively collected every 6 months and analyzed in a retrospective blinded …

Serum Biomarkers Correlated With Liver Stiffness Assessed In A Multicenter Study Of Pediatric Cholestatic Liver Disease, Daniel H Leung, Sridevi Devaraj, Nathan P Goodrich, Xinpu Chen, Deepthi Rajapakshe, Wen Ye, Victor Andreev, Charles G Minard, Danielle Guffey, Jean P Molleston, Lee M Bass, Saul J Karpen, Binita M Kamath, Kasper S Wang, Shikha S Sundaram, Philip Rosenthal, Patrick Mckiernan, Kathleen M Loomes, M Kyle Jensen, Simon P Horslen, Jorge A Bezerra, John C Magee, Robert M Merion, Ronald J Sokol, Benjamin L Shneider, Estella Alonso, Lee Bass, Susan Kelly, Mary Riordan, Hector Melin-Aldana, Jorge Bezerra, Kevin Bove, James Heubi, Alexander Miethke, Greg Tiao, Julie Denlinger, Erin Chapman, Ronald Sokol, Amy Feldman, Cara Mack, Michael Narkewicz, Frederick Suchy, Shikha S Sundaram, Johan Van Hove, Benigno Garcia, Mikaela Kauma, Kendra Kocher, Matthew Steinbeiss, Mark Lovell, Kathleen M Loomes, David Piccoli, Elizabeth Rand, Pierre Russo, Nancy Spinner, Jessi Erlichman, Samantha Stalford, Dina Pakstis, Sakya King, Robert Squires, Rakesh Sindhi, Veena Venkat, Kathy Bukauskas, Patrick Mckiernan, Lori Haberstroh, James Squires, Philip Rosenthal, Laura Bull, Joanna Curry, Camille Langlois, Grace Kim, Jeffery Teckman, Vikki Kociela, Rosemary Nagy, Shraddha Patel, Jacqueline Cerkoski, Jean P Molleston, Molly Bozic, Girish Subbarao, Ann Klipsch, Cindy Sawyers, Oscar Cummings, Simon P Horslen, Karen Murray, Evelyn Hsu, Kara Cooper, Melissa Young, Laura Finn, Binita M Kamath, Vicky Ng, Claudia Quammie, Juan Putra, Deepika Sharma, Aishwarya Parmar, Stephen Guthery, Kyle Jensen, Ann Rutherford, Amy Lowichik, Linda Book, Rebecka Meyers, Tyler Hall, Kasper S Wang, Sonia Michail, Danny Thomas, Catherine Goodhue, Rohit Kohli, Larry Wang, Nisreen Soufi, Daniel Thomas, Saul Karpen, Nitika Gupta, Rene Romero, Miriam B Vos, Rita Tory, John-Paul Berauer, Carlos Abramowsky, Jeanette Mcfall, Benjamin L Shneider, Sanjiv Harpavat, Paula Hertel, Daniel Leung, Mary Tessier, Deborah Schady, Laurel Cavallo, Diego Olvera, Christina Banks, Cynthia Tsai, Richard Thompson, Edward Doo, Jay Hoofnagle, Averell Sherker, Rebecca Torrance, Sherry Hall, John Magee, Robert Merion, Cathie Spino, Wen Ye

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.

APPROACH AND RESULTS: A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM …

A Method Using Longitudinal Laboratory Data To Predict Future Intestinal Complication In Patients With Crohn's Disease, James Irwin, Anton Lord, Emma Ferguson, Lisa A Simms, Katherine Hanigan, Carlos A Montoya, Graham Radford-Smith

Faculty, Staff and Student Publications

Background

Stenosis, fistulization, and perforation of the bowel are severe outcomes which can occur in patients with Crohn’s disease. Accurate prediction of these events may enable clinicians to alter treatment strategies and avoid these outcomes.

Aims

To study the correlation between longitudinal laboratory testing and subsequent intestinal complications in patients with Crohn’s disease.

Methods

An observational cohort of patients with Crohn’s disease at a single center were analyzed between 01/01/1994 and 06/30/2016. A complication was defined as the development of an intestinal fistula, stenosis, or perforation. Exploratory analysis using Cox regression was performed to select the best statistical method to …

Clinical Features Associated With Outcomes And Biomarker Analysis Of Dabrafenib Plus Trametinib Treatment In Patients With Braf-Mutant Melanoma Brain Metastases, James S Wilmott, Hussein Tawbi, Johnathan A Engh, Nduka M Amankulor, Brindha Shivalingam, Hiya Banerjee, Ismael A Vergara, Hansol Lee, Peter A Johansson, Peter M Ferguson, Philippe Saiag, Caroline Robert, Jean-Jacques Grob, Lisa H Butterfield, Richard A Scolyer, John M Kirkwood, Georgina V Long, Michael A Davies

Faculty, Staff and Student Publications

PURPOSE: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM).

PATIENTS AND METHODS: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate …

Gene Expression Profiling Of Circulating Tumor Cells Captured By Microcavity Array Is Superior To Enumeration In Demonstrating Therapy Response In Patients With Newly Diagnosed Advanced And Locally Advanced Non-Small Cell Lung Cancer, Evan N Cohen, Gitanjali Jayachandran, Hui Gao, Phillip Peabody, Heather B Mcbride, Franklin D Alvarez, Pablo Lopez Bravo, Wei Qiao, Suyu Liu, Luyang Yao, Steven H Lin, James M Reuben

Faculty, Staff and Student Publications

Background: Circulating tumor cells (CTCs) are a promising non-invasive tool for monitoring therapy response. The only Food and Drug Administration (FDA)-approved test is limited to enumeration of epithelial CTC without further characterization and is not approved for the management of non-small cell lung cancer (NSCLC). Here we use a MicroCavity Array (MCA) system to capture CTC agnostic of epithelial markers for further molecular testing in NSCLC.

Methods: CTCs were enumerated by fluorescent microscopy as longitudinal sampling throughout disease management from 213 NSCLC patients. CTC-enriched samples from a subset of 127 patients were interrogated for gene expression by reverse transcription polymerase …

Effect Of Intensive Blood Pressure Control On Troponin And Natriuretic Peptide Levels: Findings From Sprint, Jarett D Berry, Haiying Chen, Vijay Nambi, Walter T Ambrosius, Simon B Ascher, Michael G Shlipak, Joachim H Ix, Rajesh Gupta, Anthony Killeen, Robert D Toto, Dalane W Kitzman, Christie M Ballantyne, James A De Lemos

Faculty, Staff and Students Publications

Background: Given the important role of cardiac injury and neurohormonal activation in the pathways leading from hypertension to heart failure and strong associations observed between hypertension and its sequelae on hs-cTnT (high-sensitivity cardiac troponin T) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, we hypothesized that intensive systolic blood pressure (SBP) lowering would decrease levels of hs-cTnT and NT-proBNP.

Methods: hs-cTnT and NT-proBNP were measured at baseline and 1 year from stored specimens in SPRINT (Systolic Blood Pressure Intervention Trial). Changes in biomarkers were evaluated continuously on the log scale and according to categories (≥50% increase, ≥50% decrease, or < 50% change). The effect of intensive SBP lowering on continuous and categorical changes in biomarker levels were assessed using linear and multinomial logistic regression models, respectively. The association between changes in biomarkers on heart failure and death was assessed using multivariable-adjusted Cox proportional hazards models.

Results: Randomization …

Plasma Cytokines/Chemokines As Predictive Biomarkers For Lymphedema In Breast Cancer Patients, Anna R Vang, Simona F Shaitelman, John C Rasmussen, Wenyaw Chan, Eva M Sevick-Muraca, Melissa B Aldrich

Faculty, Staff and Student Publications

Breast cancer-related lymphedema (BCRL) occurs in ~ 40% of patients after axillary lymph node dissection (ALND), radiation therapy (RT), or chemotherapy. First-line palliative treatment utilizes compression garments and specialized massage. Reparative microsurgeries have emerged as a second-line treatment, yet both compression and surgical therapy are most effective at early stages of LE development. Identifying patients at the highest risk for BCRL would allow earlier, more effective treatment. Perometric arm volume measurements, near-infrared fluorescent lymphatic imaging (NIRF-LI) data, and blood were collected between 2016 and 2021 for 40 study subjects undergoing treatment for breast cancer. Plasma samples were evaluated using MILLIPLEX …

Impact Of Adherence To Procalcitonin Antibiotic Prescribing Guideline Recommendations For Low Procalcitonin Levels On Antibiotic Use, Brian E Malley, Jonathan G Yabes, Elizabeth Gimbel, Chung-Chou H Chang, Donald M Yealy, Michael J Fine, Derek C Angus, David T Huang, Proact Investigators

Faculty, Staff and Student Publications

BACKGROUND: The Procalcitonin Antibiotic Consensus Trial (ProACT) found provision of a procalcitonin antibiotic prescribing guideline to hospital-based clinicians did not reduce antibiotic use. Possible reasons include clinician reluctance to follow the guideline, with an observed 64.8% adherence rate. In this study we sought to determine the threshold adherence rate for reduction in antibiotic use, and to explore opportunities to increase adherence.

METHODS: This study is a retrospective analysis of ProACT data. ProACT randomized 1656 patients presenting to 14 U.S. hospitals with suspected lower respiratory tract infection to usual care or provision of procalcitonin assay results and an antibiotic prescribing guideline …

Noninvasive Reflection Spectroscopy Measurement Of Skin Carotenoid Score In Infants Is Feasible And Reliable, Nancy E Moran, Jocelyn Chang, Rachel Stroh, Yusuf Zaidi, Noor Hason, Salma Musaad, Teresia O'Connor

Children’s Nutrition Research Center Staff Publications

Background: Skin carotenoid measurement by reflection spectroscopy (RS) offers a noninvasive biomarker of carotenoid intake, but feasibility, reliability, and validity are not established in infants.

Objectives: In this study we aimed to determine the feasibility and reliability of 4-mo-old infant skin carotenoid score (SCS) measurement and its correlation with total carotenoid intake and plasma concentrations.

Methods: SCSs were measured in a prospective, observational study with a modified, portable RS device at the index finger and heel of the foot in 4-mo-olds (n = 21). Infant plasma, human milk, and formula carotenoid concentrations were measured by HPLC-photodiode array, and carotenoid intake …

Impact Of Enteropathogens On Faltering Growth In A Resource-Limited Setting, Furqan Kabir, Junaid Iqbal, Zehra Jamil, Najeeha Talat Iqbal, Fatima Aziz, Adil Kalam, Sahrish Muneer, Aneeta Hotwani, Sheraz Ahmed, Fayyaz Umrani, Sana Syed, Kamran Sadiq, Syed Asad Ali

Department of Paediatrics and Child Health

Introduction: Environmental enteropathy is an important contributor to childhood malnutrition in the developing world. Chronic exposure to fecal pathogens leads to alteration in intestinal structure and function, resulting in impaired gut immune function, malabsorption, and growth faltering leading to environmental enteropathy.
Methods: A community-based intervention study was carried out on children till 24 months of age in Matiari district, Pakistan. Blood and fecal specimens were collected from the enrolled children aged 3-6 and 9 months. A real-time PCR-based TaqMan array card (TAC) was used to detect enteropathogens.
Results: Giardia, Campylobacter spp., enteroaggregative Escherichia coli (EAEC), Enteropathogenic Escherichia coli (EPEC), …

Differential Co-Expression Networks Of The Gut Microbiota Are Associated With Depression And Anxiety Treatment Resistance Among Psychiatric Inpatients, Dominique S Thompson, Chenlian Fu, Tanmay Gandhi, J Christopher Fowler, B Christopher Frueh, Benjamin L Weinstein, Joseph Petrosino, Julia K Hadden, Marianne Carlson, Cristian Coarfa, Alok Madan

Faculty, Staff and Students Publications

BACKGROUND: Comorbid anxiety and depression are common and are associated with greater disease burden than either alone. Our recent efforts have identified an association between gut microbiota dysfunction and severity of anxiety and depression. In this follow-up, we applied Differential Co-Expression Analysis (DiffCoEx) to identify potential gut microbiota biomarker(s) candidates of treatment resistance among psychiatric inpatients.

METHODS: In a sample of convenience, 100 psychiatric inpatients provided clinical data at admission and discharge; fecal samples were collected early during the hospitalization. Whole genome shotgun sequencing methods were used to process samples. DiffCoEx was used to identify clusters of microbial features significantly …

Histopathologic And Proteogenomic Heterogeneity Reveals Features Of Clear Cell Renal Cell Carcinoma Aggressiveness, Yize Li, Tung-Shing M Lih, Saravana M Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A Wyczalkowski, Michael C Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe Da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A Reimers, Russell Pachynski, Alexander J Lazar, Arul M Chinnaiyan, Brian A Van Tine, Bing Zhang, Karin D Rodland, Gad Getz, D R Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W Marston Linehan, David Fenyö, Scott D Jewell, Gilbert S Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W Chan, Christopher J Ricketts, Alexey I Nesvizhskii, Hui Zhang, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 …

Psychotic Symptom, Mood, And Cognition-Associated Multimodal Mri Reveal Shared Links To The Salience Network Within The Psychosis Spectrum Disorders, Chuang Liang, Godfrey Pearlson, Juan Bustillo, Peter Kochunov, Jessica A Turner, Xuyun Wen, Rongtao Jiang, Zening Fu, Xiao Zhang, Kaicheng Li, Xijia Xu, Daoqiang Zhang, Shile Qi, Vince D Calhoun

Faculty, Staff and Student Publications

Schizophrenia (SZ), schizoaffective disorder (SAD), and psychotic bipolar disorder share substantial overlap in clinical phenotypes, associated brain abnormalities and risk genes, making reliable diagnosis among the three illness challenging, especially in the absence of distinguishing biomarkers. This investigation aims to identify multimodal brain networks related to psychotic symptom, mood, and cognition through reference-guided fusion to discriminate among SZ, SAD, and BP. Psychotic symptom, mood, and cognition were used as references to supervise functional and structural magnetic resonance imaging (MRI) fusion to identify multimodal brain networks for SZ, SAD, and BP individually. These features were then used to assess the ability …

Multi-Model Order Spatially Constrained Ica Reveals Highly Replicable Group Differences And Consistent Predictive Results From Resting Data: A Large N Fmri Schizophrenia Study, Xing Meng, Armin Iraji, Zening Fu, Peter Kochunov, Aysenil Belger, Judy M Ford, Sara Mcewen, Daniel H Mathalon, Bryon A Mueller, Godfrey Pearlson, Steven G Potkin, Adrian Preda, Jessica Turner, Theo G M Van Erp, Jing Sui, Vince D Calhoun

Faculty, Staff and Student Publications

Brain functional networks identified from resting functional magnetic resonance imaging (fMRI) data have the potential to reveal biomarkers for brain disorders, but studies of complex mental illnesses such as schizophrenia (SZ) often yield mixed results across replication studies. This is likely due in part to the complexity of the disorder, the short data acquisition time, and the limited ability of the approaches for brain imaging data mining. Therefore, the use of analytic approaches which can both capture individual variability while offering comparability across analyses is highly preferred. Fully blind data-driven approaches such as independent component analysis (ICA) are hard to …

Associations Of Snfl With Clinico-Radiological Measures In A Large Ms Population., Elias S Sotirchos, Kathryn C Fitzgerald, Carol M Singh, Matthew D Smith, Maria Reyes-Mantilla, Carrie M Hersh, Megan H Hyland, Ryan Canissario, Sarah B Simmons, Georgina Arrambide, Xavier Montalban, Manuel Comabella, Robert T Naismith, Min Qiao, Lauren B Krupp, Jacqueline A Nicholas, Katja Akgün, Tjalf Ziemssen, Richard Rudick, Elizabeth Fisher, Robert A Bermel, Ellen M Mowry, Peter A Calabresi

Neuroscience Articles

OBJECTIVE: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice.

METHODS: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay.

RESULTS: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with …

Serum Neurofilament Light-Chain Levels And Long-Term Treatment Outcomes In Relapsing-Remitting Multiple Sclerosis Patients: A Post Hoc Analysis Of The Randomized Combirx Trial, Gary Cutter, Richard A Rudick, Carl De Moor, Carol M Singh, Elizabeth Fisher, Thijs Koster, Fred D Lublin, Jerry S Wolinsky, Henry Mcfarland, Steven Jacobson, Maria L Naylor

Faculty, Staff and Student Publications

BACKGROUND: CombiRx was a randomized, double-blind, placebo-controlled phase 3 trial in treatment-naive relapsing-remitting multiple sclerosis (RRMS) patients randomized to intramuscular interferon beta-1a (IM IFN beta-1a), glatiramer acetate (GA), or both therapies.

OBJECTIVE: This analysis investigated changes in serum neurofilament light-chain (sNfL) levels in response to treatment and assessed baseline sNfL as a predictor of relapse.

METHODS: RRMS patients treated with IM IFN beta-1a 30 µg weekly + placebo (n = 159), GA 20 mg/mL daily + placebo (n = 172), or IM IFN beta-1a + GA (n = 344) were included. A linear mixed model compared sNfL values over time. …

Trem-1, Trem-2 And Their Association With Disease Severity In Patients With Covid-19, Ruyue Fan, Zuowang Cheng, Zhisheng Huang, Ying Yang, Na Sun, Bin Hu, Peibin Hou, Bo Liu, Chuanjun Huang, Shuai Liu

Faculty, Staff and Student Publications

BACKGROUND: Delayed diagnosis and inadequate treatment caused by limited biomarkers are associated with the outcomes of COVID-19 patients. It is necessary to identify other promising biomarkers and candidate targets for defining dysregulated inflammatory states.

METHODS: The triggering receptors expressed on myeloid cell (TREM)-1 and TREM-2 expression from hospitalized COVID-19 patients were characterized using ELISA and flow cytometry, respectively. Their correlation with disease severity and contrast with the main clinical indicators were evaluated.

RESULTS: Increased expression of soluble TREM-1 and TREM-2 in the plasma of COVID-19 patients was found compared to the control group. Moreover, membrane-bound TREM-1 and TREM-2 expression was …

Circulating Long Non-Coding Rnas As Novel Diagnostic Biomarkers For Alzheimer’S Disease (Ad): A Systematic Review And Meta-Analysis, Parnian Shobeiri, Sanam Alilou, Mehran Jaberinezhad, Farshad Zare, Nastaran Karimi, Saba Maleki, Antonio L Teixeira, George Perry, Nima Rezaei

Faculty, Staff and Student Publications

BACKGROUND: Long non-coding RNAs (lncRNAs) have been reported to be involved in the pathogenesis of neurodegenerative diseases. It has also been hypothesized that plasma exosomal lncRNAs may be used as Alzheimer's disease (AD) biomarkers. In this systematic review, we compiled all studies on the subject to evaluate the accuracy of lncRNAs in identifying AD cases through meta-analysis.

METHODS: A PRISMA-compliant systematic search was conducted in PubMed/MEDLINE, EMBASE, and Web of Science databases for English publications till September 2022. We included all observational studies published which investigated the sensitivity and specificity of various lncRNAs in plasma samples of AD diagnosis. Our …

Brain-Derived Neurotrophic Factor In Fibromyalgia: A Systematic Review And Meta-Analysis Of Its Role As A Potential Biomarker, Amir Hossein Behnoush, Amirmohammad Khalaji, Shaghayegh Khanmohammadi, Parsa Alehossein, Behrad Saeedian, Parnian Shobeiri, Antonio L Teixeira, Nima Rezaei

Faculty, Staff and Student Publications

BACKGROUND: Fibromyalgia (FM) is a form of chronic pain disorder accompanied by several tender points, fatigue, sleeping and mood disturbances, cognitive dysfunction, and memory problems. Brain-derived neurotrophic factor (BDNF) is also a mediator of neurotrophin for many activity-dependent processes in the brain. Despite numerous research studies investigating BDNF in FM, contradictory results have been reported. Thus, we investigated the overall effect shown by studies to find the association between peripheral BDNF concentrations and its gene polymorphisms with FM.

METHODS: A systematic search in online international databases, including PubMed, Cochrane Library, Embase, the Web of Science, and Scopus was performed. Relevant …

Circulating Tumor Dna Sequencing Of Pediatric Solid And Brain Tumor Patients: An Institutional Feasibility Study, Ross Mangum, Jacquelyn Reuther, Koel Sen Baksi, Ilavarasi Gandhi, Ryan C Zabriskie, Alva Recinos, Robin Raesz-Martinez, Frank Y Lin, Samara L Potter, Andrew C Sher, Stephen F Kralik, Carrie A Mohila, Murali M Chintagumpala, Donna Muzny, Jianhong Hu, Richard A Gibbs, Kevin E Fisher, Juan Carlos Bernini, Jonathan Gill, Timothy C Griffin, Gail E Tomlinson, Kelly L Vallance, Sharon E Plon, Angshumoy Roy, D Williams Parsons

Faculty, Staff and Students Publications

The potential of circulating tumor DNA (ctDNA) analysis to serve as a real-time "liquid biopsy" for children with central nervous system (CNS) and non-CNS solid tumors remains to be fully elucidated. We conducted a study to investigate the feasibility and potential clinical utility of ctDNA sequencing in pediatric patients enrolled on an institutional clinical genomics trial. A total of 240 patients had tumor DNA profiling performed during the study period. Plasma samples were collected at study enrollment from 217 patients and then longitudinally from a subset of patients. Successful cell-free DNA extraction and quantification occurred in 216 of 217 (99.5%) …