Saint John's Health Center

BackgroundBrain age – an estimate of chronological age‐ derived from structural brain MR neuroimaging may reveal underlying factors driving brain aging. White matter hyperintensities (WMH) are areas of abnormally high signal on FLAIR that frequently reflect chronic small vessel ischemic changes and potentially increased aging.MethodOverall, 1,164 healthy participants from four sites (mean chronological age 55.17 ± 12.37 years, 52% women; 48% men; 39% non‐white) were scanned on 1.5T MR machines with a whole‐body protocol. For each participant, a 2D multi‐slice FLAIR image was obtained. A 2D convolutional neural network, trained on data from 120 individuals across three public datasets (MICCAI 2017, ISLES2015, and ISLES2022), was employed to automatically segment WMH from the FLAIR scans. Deep learning with FastSurfer on MPRAGE trained on 134 participants aged 27‐66 and segmented 96 brain regions. Brain age was computed using a regression‐based 3D Simple Fully Convolutional Network trained on in‐house T1‐weighted MRI scans collected from 5,500 healthy individuals (, aged 18 to 89 years). Brain age gap (BAG) was computed by subtracting chronological age from brain age. Partial correlation and regression models evaluated the relationship between WMH normalized to total brain volume (gray matter and white matter), brain age, brain volumes controlling for age, sex, and total intracranial volume. Chronological age was not adjusted for in the brain age models to avoid collinearity.ResultMean brain age was similar to chronological age (mean brain age = 56.04 ± 12.65, mean BAG = 0.69). The median of WMH were 1.4 mL (0.75‐2.51 mL). Increased WMH were related to lower brain volumes in the i) hippocampus (rp= ‐0.13, p = 1.174e‐05) ii) cerebral white matter (rp= ‐0.08, p = .004) iii) thalamus (rp= ‐0.16, p = 1.634e‐07). Additionally, increased WMH was related to larger cerebral ventricle size (rp= 0.28, p = 6.604e‐21). The regression model showed that increased WMH was related to increased brain age (t= 5.92, rp= .42, p <.001) and increased brain age gap (t= 4.07, rp= .12, p <.001).ConclusionIncreased WMH are related to brain atrophy – in both Alzheimer’s and non‐Alzheimer’s affected regions – and are also related to increased brain age and accelerated brain aging.

BackgroundBrain age – an image derived measure from structural brain images on T1 weighted scans may reveal information on Alzheimer’s risk. We have previously shown that increased abdominal adipose tissue relates to brain atrophy. We evaluated the links between abdominal adipose tissue and brain age.MethodA total of 1,164 healthy participants from four sites (mean chronological age 55.17 ± 12.37 years, 52% women; 48% men; 39% non‐white) were scanned on 1.5T MR machines with a whole‐body protocol. Whole body sequences utilized in the quantitative analyses of abdominal fat were coronal T1 were used to segment visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) segmentation. In this process, a nnU‐Net model was used for fully supervised segmentation and ITK‐SNAP was used for manual annotation. Brain age was computed using a regression‐based 3D Simple Fully Convolutional Network. The model was trained on in‐house T1‐weighted MRI scans collected from 5,500 healthy individuals, aged 18 to 89 years. Brain age gap (BAG) was computed by subtracting chronological age from brain age. Bivariate correlations between VAT and SAT to chronological and brain age were done with partial correlations adjusted for sex with brain age. VAT and SAT were normalized to total abdominal body fat volume. Chronological age was not adjusted for in brain age models to avoid collinearity.ResultMean brain age exceeded chronological age (mean brain age = 56.04 ± 12.65, mean BAG = 0.69) and were highly correlated (r=0.94, p <.001). VAT and SAT were positively related to increased chronological age (VAT: r=0.2780, p = 5.477e‐20; r=0.0924, p = 0.002817) and increased brain age (VAT: r=0.2806, p = 2.42e‐20; SAT: r=0.0947, p = 0.002189) with VAT being more closely linked to age than SAT. This did not change when adjusting for sex in separate partial correlations between VAT and SAT for brain age (VAT: rp = r=0.2948, p = 2.247e‐22; SAT: r=0.1070, p = 0.0005353). No statistically significant link was noted with VAT, SAT, and BAG.ConclusionBoth VAT and SAT are linked to chronological and brain age with VAT being more strongly linked. VAT may be a key target for modifying brain age and Alzheimer’s risk.

Abstract Description Immunotherapy strategies are designed to target immune checkpoint inhibitors (ICIs) such as programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1). ICIs have successfully improved outcomes in metastatic melanoma (MM) patients. The PD-L1 levels in tumor cells are critical in controlling immune responses to ICIs; however, the regulatory mechanisms targeting PD-L1 in the context interferon-gamma (IFN-γ) pathways are not well understood. Here, we showed that the thiol reductase enzyme IFN-γ-inducible factor 30 (IFI30) determines the PD-L1 mRNA and protein levels by modulating the activation IFN-γ pathway. Briefly, IFI30 and PD-L1 levels are stimulated by IFN-γ in MM cell lines. IFI30 knockdown decreased the protein levels of interferon gamma receptor 1 (IFNGR1), which subsequently blocked IFN-γ pathway and decreased PD-L1 levels. We found that IFI30 neutralized cathepsin-L (CTSL) to reduce lysosomal protein degradation of IFNGR1 and PD-L1. Of clinical relevance, MM patients with high IFI30 levels showed: 1) better progression-free survival, 2) better responses to ICIs, and 3) increased infiltration levels of M1 macrophages, CD8+ and CD4+ T cells in MM from three independent datasets. In conclusion, IFI30 regulates the IFN-γ pathway activation and the PD-L1 levels during IFN-γ stimulation by neutralizing CTSL-mediated lysosomal protein degradation. IFI30 may represent a potential biomarker associated with better immune responses in MM patients receiving ICIs. Funding Sources This research program was supported by Dr. Miriam and Sheldon G. Adelson Medical Research Foundation to Dr. DSBH. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

PURPOSE: Explore the relationships among subjective social status, physician trust, and sensation seeking in young adults. METHODS: This cross-sectional study included 69 young adults (83% female, age = 22.34 ± 3.5) who were part of a larger parent study. Assessments in the current study included demographics (sex, concussion history, age), Trust in Physician Scale (TPS, individual items referencing primary care physician) an 11 item Likert scale, MacArthur Subjective Social Status (subscales: MacArthur SES- perceived societal social standing, range = 1-10, MacArthur Community- perceived community social standing, range = 1-10), and the Brief Sensation Seeking Scale (BSSS, range = 1-5, higher scores indicate greater sensation seeking). Demographics were analyzed via descriptive statistics and Spearman correlations examined the relationship among individual TPS items, MacArthur Subjective Social Status, and BSSS. Alpha level was set to 0.05 a priori. RESULTS: Mean BSSS scores skewed towards greater sensation seeking (3 ± 0.77; range: 1.5-5.0) and mean MacArthur SES (6.7 ± 1.4; range: 2-9) and Community scores (5.9 ± 1.7; range: 2-9) identified higher subjective social status within this population. Physician trust was generally strong across the scale. No relationships were identified among MacArthur SES or Community and BSSS score (p > 0.05). Significant negative relationships were identified between MacArthur Community and TPS including doubt in physician caring (r = -0.42, p = .0004), distrust of physician opinion (r = -0.33, p = .007), and patient privacy concerns (r = -0.41, p = .0005). Significant positive relationships between MacArthur Community and physician judgement (r = 0.33, p = .006), physician expertise (r = 0.45, p = .0001), and physician mistake reporting (r = 0.32, p = .009) were observed. No significant relationships were identified among MacArthur SES and TPS responses. CONCLUSIONS: Higher levels of community social status were associated with lower levels of doubt regarding physician caring, competency, and patient privacy, and higher levels of trust in physician judgement, mistake reporting, and expertise. These findings highlight areas of health equity (e.g., patient education, compliance, follow-up care) that could require future attention by providers.

ABSTRACT Survival of glioblastoma (GBM) patients is unsatisfactory. Adding patient-specific vaccines to standard therapy may improve outcomes. Autologous dendritic cells (DC) loaded with autologous tumor antigens (ATA) from short-term cell lines established from autologous tumor are a promising therapeutic vaccine strategy. DC-ATA vaccines were tested in a single-arm phase 2 trial in newly diagnosed GBM patients. Tumor tissue was collected during surgical resection. DC were differentiated from peripheral blood monocytes. Intent-to-treat enrollment took place before standard concurrent radiation therapy and temozolomide (RT/TMZ). DC-ATA was manufactured during RT/TMZ, then injected subcutaneously over 6 months concurrently with adjuvant TMZ. DC-ATA was reliably manufactured; treatment was well tolerated. Fifty-seven patients started vaccine therapy; 69% received all eight vaccine doses. The 10.7-month median progression-free survival (PFS) is 57% greater than the average of medians from standard treatment arms in six randomized trials that also enrolled patients before RT/TMZ. Disease control and overall survival (OS) dropped precipitously once DC-ATA was completed. Survival curves stratified by prognostic variables did not separate until after DC-ATA was discontinued. Multivariate analysis identified receipt of all eight planned vaccine injections, MGMT promoter methylation, concurrent dexamethasone dose ≤2 mg, and receipt of six or more TMZ cycles as independent variables. Common features among the seven patients who were progression-free after 3 years were eight vaccine injections, ≤2 mg dexamethasone, age <60 years, and adjuvant TMZ given without concurrent bevacizumab. PFS was encouraging, and the data suggest that OS may be increased by extending vaccine treatment.

Glioblastoma (GBM) is a lethal brain cancer with no effective treatment; understanding how GBM cells respond to tumor microenvironment remains challenging as conventional cell cultures lack proper cytoarchitecture while in vivo animal models present complexity all at once. Developing a culture system to bridge the gap is thus crucial. Here, a multicellular approach is employed using human glia and vascular cells to optimize a 3D brain vascular niche model that enabled not only long‐term culture of patient derived GBM cells but also recapitulation of key features of GBM heterogeneity, in particular invasion behavior and vascular association. Comparative transcriptomics of identical patient derived GBM cells in 3D and in vivo xenotransplants models revealed that glia‐vascular contact induced genes concerning neural/glia development, synaptic regulation, as well as immune suppression. This gene signature displayed region specific enrichment in the leading edge and microvascular proliferation zones in human GBM and predicted poor prognosis. Gene variance analysis also uncovered histone demethylation and xylosyltransferase activity as main themes for gene adaption of GBM cells in vivo. Furthermore, the 3D model also demonstrated the capacity to provide a quiescence and a protective niche against chemotherapy.