Citations

Abstract Glioblastoma (GBM) remains the most aggressive primary adult brain cancer with limited therapeutic options. Our prior research demonstrated that androgen receptor antagonists (ARAs) enhance survival in GBM mouse models by preferentially suppressing glioma stem cells. This study investigates the potential of ARAs as radiosensitizers in combination with radiotherapy (RT). Combined effects of ARAs and RT were evaluated using an orthotopic GBM mouse model. RNA-Seq and TCGA analyses delineated AR-associated regulatory networks, while integrated cellular and molecular approaches utilizing human and mouse GBM cell lines, as well as in patient-derived primary high-grade glioma cultures, interrogated signaling and immune paradigms. ARA treatment induced G2/M cell cycle arrest, apoptosis, and downregulated DNA repair genes, with AR expression correlating with the DNA repair and TGF-β pathway. In both immortalized GBM cell lines and primary high-grade glioma cultured cells, ARAs in combination with RT showed only a modest enhancement of radiosensitivity. However, in an orthotopic GBM mouse model, ARA + RT demonstrated a strong synergy, achieving 100% long-term survival, compared to less than 50% with ARA alone and 0% with RT alone. Mechanistically, ARA modulated the TGF-β pathway, durably switching from Smad3 linker to c-terminal phosphorylation (pSmad3C) and inhibiting LIF/STAT3 axis. Distinct TGF-βs ligand expression patterns were observed in ARA-treated GBM cells. A protein–protein interaction noted between AR and Smad3, which was disrupted following ARA treatment, leading to elevated protein levels and nuclear localization of pSmad3C (S423/425), indicating normalization/activation of the TGF-β/pSmad3C-dependent anti-tumorigenic cascade. Comprehensive analyses in GBM cell lines and mouse model tissues demonstrated pathway reprogramming characterized by elevated TGF-β2 and increased pSmad3C. Tissue analysis revealed immune activation in the tumor microenvironment, while peripheral blood and spleen showed systemic immune responses following ARA + RT. Our study provides novel insights into how ARAs enhance RT efficacy through immunomodulation involving TGF-β/pSmad3C cascade, offering therapeutic implications in GBM.

Abstract Cerebrospinal fluid (CSF) proteomics offers insights into molecular changes in aging and Alzheimer’s disease (AD). Key AD biomarkers, in particular amyloid-β (Aβ) and tau, in CSF are strongly associated with APOE genotype, the strongest genetic risk determinant of AD. To investigate how APOE genotype influences CSF proteome across AD pathology and age, we analyzed 362 neurology-related proteins and established AD biomarkers in CSF from 145 cognitively unimpaired participants in the Mayo Clinic Study of Aging. Importantly, our cohort is uniquely balanced across APOE genotypes, with similar representation of APOE2 carriers, APOE3/3 genotype, and APOE4 carriers. We identified several proteins, including lipid metabolism-related Lp-PLA2 and immune-related ITGAM, with strong APOE genotype-specific association. Notably, meta-analysis confirmed that ITGAM levels were consistently higher in APOE4 compared to APOE2 carriers across multiple cohorts and proteomic platforms. In addition, with increasing amyloid deposition, APOE4 carriers exhibited stronger immune responses, reflected by elevated ITGAM, TNF-α receptors, and IL-6, whereas APOE2 carriers showed attenuated responses. We further observed sex-specific effects among APOE2 carriers, characterized by distinct patterns in amyloid and CXCL11 levels. These findings suggest distinct mechanisms underlying APOE2’s protective and APOE4’s detrimental effects in brain aging and AD, paving for personalized diagnostics and interventions.

Abstract Background Relapsed medulloblastoma remains a significant therapeutic challenge as it is near universally fatal. The tumor microenvironment of medulloblastoma plays a critical role in tumor progression, influencing tumor growth, immune evasion, and therapeutic resistance. We hypothesized that defining tumor-immune interactions in diagnostic and relapsed medulloblastoma may uncover mechanisms of immune evasion and identify novel therapeutic targets. Methods We analyzed paired primary and recurrent RNA-sequencing data from 140 medulloblastoma patients to profile immune cell composition and validate spatial relationships within the TME. To identify key tumor-immune interactions, we developed a novel algorithm to detect receptor-ligand pairs using single-cell RNA-sequencing data. These interactions were validated across RNA and proteomic datasets. Their functional significance was empirically demonstrated in newly developed immunocompetent models of recurrent medulloblastoma that closely recapitulate the human disease. Results We observed a shift toward a heightened immunosuppressive TME at relapse. Using our algorithm, we identified biologically significant receptor-ligand interactions, most notably MIF-CD74, constitutively expressed at RNA and protein levels across medulloblastoma subgroups, at diagnosis and relapse. Disrupting MIF-CD74 interactions led to significant alterations in the tumor microenvironment, highlighting its functional significance. Conclusions Our multifaceted approach identified key tumor-immune interactions in medulloblastoma. Among these, MIF-CD74 was validated as a targetable interaction, demonstrating the utility of our integrative approach for identifying novel therapeutic targets across multiple tumor types.

This study uncovers a previously unrecognized role for NAV3 in TGF-β1-driven cardiac fibroblast activation. We show that NAV3 facilitates profibrotic remodeling through noncanonical signaling and cell cycle arrest, independently of SMAD2/3. These findings position NAV3 as a novel regulator of fibroblast phenotype and a potential modulator of cardiac fibrosis.

Background While SARS-CoV-2 vaccines are highly effective in healthy individuals, the magnitude and durability of humoral and cellular responses in patients with solid malignancies receiving chemotherapy remain understudied. Previous reports suggest that patients with cancer may not mount adequate immune response after SARS-CoV-2 vaccination. Additionally, most studies focused on humoral responses, while data regarding cellular immune responses are scarce. In this study, we evaluated humoral and cellular responses in patients with solid tumors receiving chemotherapy compared to healthy individuals up to one year after vaccinations. Methods Patients aged ≥18 who were willing to receive the SARS-CoV-2 vaccine were enrolled. Anti-SARS-CoV-2 immunoassays were used to detect antibodies against nucleocapsid and spike proteins. Human IFN-γ Fluorospot assay was used to determine antigen−specific T-cell responses. Data were compared between groups using Mann−Whitney test for continuous variables and Fisher’s exact test for categorical variables. Results A total of 67 subjects (47 patients with cancer and 20 healthy individuals) were included. 1–3 months following the second vaccine doses, 96% of patients with cancer and 100% of healthy individuals demonstrated a positive humoral response. While the positivity rate was not significantly different, patients with cancer had significantly lower spike IgG antibodies than healthy individuals. However, this difference diminished at 6 months when patients with cancer had increased antibodies compared to decreased antibodies in the healthy cohort and no difference was noticed at 12-month. Patients with cancer developed a similar antigen-specific T-cell response as healthy individuals at 1–3 months, 6 months and 12 months. There were no significant differences when comparing patients aged ≤ 55 years vs. >55 years, stages I-III vs. IV, single vs. multiple chemotherapy, and BNT162b2 vs. mRNA-1273 vaccines. There was a significant moderate correlation between neutralization and antibody levels at 12 months. However, despite patients with cancer having a significantly higher COVID risk score, there were no significant differences in COVID-19 infection and hospitalization between patients with cancer and healthy individuals. Conclusion Despite initial impaired antibody responses to SARS-CoV-2 vaccinations, patients with solid malignancies receiving chemotherapy effectively generated long-term cellular and humoral responses by 6 and 12 months, leading to similar infection and hospitalization rates compared to healthy individuals.

INTRODUCTION: This study used the novel C-reactive protein-albumin-lymphocyte (CALLY) index to explore its relationship with the risk of developing gallstones. METHODS: This study conducted a cross-sectional analysis of the National Health and Nutrition Examination Survey data from 2017 to 2020; multivariable logistic regression examined the CALLY-gallstone association. Restricted cubic splines tested nonlinearity. Subgroup and mediation analyses explored population variations and mediating effects (Conicity, lipid accumulation product, and a body shape index). Receiver operating characteristic curves compared CALLY, systemic immune inflammation index, systemic inflammatory response index, and aggregate index of systemic inflammation predictive performance. RESULTS: After comprehensive adjustments, the highest CALLY quartile had significantly lower gallstone risk vs the lowest (odds ratio 0.56, 95% confidence interval 0.34–0.94). Restricted cubic splines revealed a linear inverse correlation. Subgroup analyses generally supported this inverse relationship. Mediation analysis identified the Conicity index as the strongest mediator (21.47%, P < 0.001), followed by lipid accumulation product and a body shape index (10.72% each, P < 0.001). Receiver operating characteristic analysis showed CALLY (area under the curve = 0.604) outperformed systemic immune inflammation index (0.540), systemic inflammatory response index (0.550), and aggregate index of systemic inflammation (0.546). DISCUSSION: A significant inverse association exists between the CALLY index and gallstone prevalence. The CALLY index demonstrates superior predictive ability compared with other indices, suggesting its potential utility as an objective biomarker for early gallstone risk identification.