Analysis of anemia and iron supplementation among glioblastoma patients reveals sex-biased association between anemia and survival
(2024) Scientific Reports, 14 (1), art. no. 2389, .
Shenoy, G.a , Slagle-Webb, B.a , Khunsriraksakul, C.b , Pandya Shesh, B.a , Luo, J.c , Khristov, V.a , Smith, N.a , Mansouri, A.a , Zacharia, B.E.a , Holder, S.d , Lathia, J.D.e , Barnholtz-Sloan, J.S.f g , Connor, J.R.a
a Department of Neurosurgery, Penn State College of Medicine, Hershey, PA, United States
b Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, United States
c Division of Public Health Sciences, Department of Surgery and Siteman Cancer Center Biostatistics Shared Resource, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, United States
e Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
f Trans-Divisional Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
g Center for Biomedical Informatics and Information Technology, National Cancer Institute, Bethesda, MD, United States
Abstract
The association between anemia and outcomes in glioblastoma patients is unclear. We analyzed data from 1346 histologically confirmed adult glioblastoma patients in the TriNetX Research Network. Median hemoglobin and hematocrit levels were quantified for 6 months following diagnosis and used to classify patients as anemic or non-anemic. Associations of anemia and iron supplementation of anemic patients with median overall survival (median-OS) were then studied. Among 1346 glioblastoma patients, 35.9% of male and 40.5% of female patients were classified as anemic using hemoglobin-based WHO guidelines. Among males, anemia was associated with reduced median-OS compared to matched non-anemic males using hemoglobin (HR 1.24; 95% CI 1.00–1.53) or hematocrit-based cutoffs (HR 1.28; 95% CI 1.03–1.59). Among females, anemia was not associated with median-OS using hemoglobin (HR 1.00; 95% CI 0.78–1.27) or hematocrit-based cutoffs (HR: 1.10; 95% CI 0.85–1.41). Iron supplementation of anemic females trended toward increased median-OS (HR 0.61; 95% CI 0.32–1.19) although failing to reach statistical significance whereas no significant association was found in anemic males (HR 0.85; 95% CI 0.41–1.75). Functional transferrin-binding assays confirmed sexually dimorphic binding in resected patient samples indicating underlying differences in iron biology. Anemia among glioblastoma patients exhibits a sex-specific association with survival. © 2024, The Author(s).
Funding details
National Institutes of HealthNIHF30CA250193, P01CA245705
Penn State Clinical and Translational Science InstituteCTSI
Document Type: Article
Publication Stage: Final
Source: Scopus
Cell-specific Systemic Immune Signatures Associated with Treatment Burden in Neovascular Age-related Macular Degeneration
(2024) Ophthalmology Science, 4 (2), art. no. 100410, .
Lin, J.B.a b , Santeford, A.a , Usmani, D.a , Shah, A.V.a , Ruzycki, P.A.a , Apte, R.S.a c d e
a John F. Hardesty, MD, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Neurosciences Graduate Program, Roy & Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
d Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Purpose: Choroidal neovascularization (CNV) accounts for the majority of severe vision loss in neovascular age-related macular degeneration (AMD). Despite therapies that target VEGF, patients are often under-responsive, require frequent eye injections to control disease, and eventually lose some vision despite chronic therapy implicating a multifactorial etiology in treatment response. Genetic studies implicate systemic immunity in AMD and systemic immune cells accumulate within CNV lesions, yet a role for these cells in anti-VEGF response remains undetermined. The purpose of this study was to identify transcriptional signatures of circulating immune cells that are associated with high anti-VEGF treatment burden. Design: Experimental pilot study. Participants: Patients with neovascular AMD seen at Washington University School of Medicine in St. Louis and BJC Health System. Methods: We profiled by single cell RNA sequencing the peripheral blood mononuclear cells of 27 treatment-experienced patients with wet AMD. We stratified this cohort into 2 groups with low and high treatment burden (≤ 5 or ≥ 6 injections in the past 12 months, respectively). Main Outcome Measures: Identification of immune cells associated with high treatment burden. Results: Gene expression signature of CD16+ monocytes may be associated with high treatment burden. Conclusions: These studies delineate potential signatures of circulating immune cells that may be associated with high treatment burden in neovascular AMD, potentially informing the development of diagnostic predictors of anti-VEGF response and new precision medicine-based approaches to complement anti-VEGF therapies. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. © 2023 American Academy of Ophthalmology
Author Keywords
AMD; CNV; Macrophage; Monocyte; VEGF
Funding details
National Institutes of HealthNIHEY02687, R01 EY019287
Research to Prevent BlindnessRPBF30 DK130282
BrightFocus FoundationBFF
Washington University in St. LouisWUSTLT32 GM07200
University of WashingtonUW
Institute of Clinical and Translational SciencesICTSUL1 TR002345
Starr FoundationTSF
Carl Marshall and Mildred Almen Reeves Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
Neurogenetic and multi-omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder
(2024) Addiction Biology, 29 (2), art. no. e13365, .
Miller, A.P.a , Gizer, I.R.b
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
Abstract
Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples, and shared neurobiological and genetic influences may in part explain these associations. Links between sensation seeking and alcohol use disorder (AUD) may primarily manifest via increased alcohol consumption rather than through direct effects on increasing problems and consequences. Here the overlap among sensation seeking, alcohol consumption, and AUD was examined using multivariate modelling approaches for genome-wide association study (GWAS) summary statistics in conjunction with neurobiologically informed analyses at multiple levels of investigation. Meta-analytic and genomic structural equation modelling (GenomicSEM) approaches were used to conduct GWAS of sensation seeking, alcohol consumption, and AUD. Resulting summary statistics were used in downstream analyses to examine shared brain tissue enrichment of heritability and genome-wide evidence of overlap (e.g., stratified GenomicSEM, RRHO, genetic correlations with neuroimaging phenotypes), and to identify genomic regions likely contributing to observed genetic overlap across traits (e.g., H-MAGMA and LAVA). Across approaches, results supported shared neurogenetic architecture between sensation seeking and alcohol consumption characterised by overlapping enrichment of genes expressed in midbrain and striatal tissues and variants associated with increased cortical surface area. Alcohol consumption and AUD evidenced overlap in relation to variants associated with decreased frontocortical thickness. Finally, genetic mediation models provided evidence of alcohol consumption mediating associations between sensation seeking and AUD. This study extends previous research by examining critical sources of neurogenetic and multi-omic overlap among sensation seeking, alcohol consumption, and AUD which may underlie observed phenotypic associations. © 2024 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.
Author Keywords
alcohol consumption; alcohol use disorder; genetics; genomic structural equation modelling; multi-omics; neuroimaging; sensation seeking
Funding details
I01BX003341, I01CX001849
575B
National Science FoundationNSFCNS‐1429294
National Institutes of HealthNIH
National Institute of Mental HealthNIMHMH109532
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAAU01AA008401
National Heart, Lung, and Blood InstituteNHLBI
National Human Genome Research InstituteNHGRI
National Cancer InstituteNCI
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression
(2024) Clinical Pharmacology and Therapeutics, .
Men, X.a b , Taylor, Z.L.c d , Marshe, V.S.e , Blumberger, D.M.b f , Karp, J.F.g , Kennedy, J.L.b f , Lenze, E.J.h , Reynolds, C.F., IIIi , Stefan, C.b j , Mulsant, B.H.b f , Ramsey, L.B.c d k , Müller, D.J.a b f
a Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
b Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
c Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
d Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
e Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
f Department of Psychiatry, University of Toronto, Toronto, ON, Canada
g Department of Psychiatry, The University of Arizona College of Medicine, Tucson, AZ, United States
h Department of Psychiatry, Washington University, St. Louis, MO, United States
i Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
j Clinical Laboratory and Diagnostic Services, Centre for Addiction and Mental Health, Toronto, ON, Canada
k Division of Research in Patient Services, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Abstract
In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine. © 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMH
Brain and Behavior Research FoundationBBRF
American Foundation for Suicide PreventionAFSP
Merck
Centers for Medicare and Medicaid ServicesCMS
Patient-Centered Outcomes Research InstitutePCORI
National Center for Advancing Translational SciencesNCATS
Fondation Brain Canada
Campbell Family Mental Health Research Institute
Centre for Addiction and Mental Health FoundationCAMH
Commonwealth of Pennsylvania
Canadian Institutes of Health ResearchIRSC
Canada Foundation for InnovationCFI
University of TorontoU of T
Université Pierre et Marie CurieUPMC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus