Biology subjects

Quan, R.

Publications and source records attributed to Quan, R..

4 recordsLinked to original sources

bioRxiv2026

BNCT Triggers Immunogenic Cell Death in B16 Melanoma Without Accompanying T-Cell Infiltration--Implications for Combination Immunotherapy

Objective: Boron neutron capture therapy (BNCT) is a targeted radiotherapy with highly selective tumor killing; its potential to induce immunogenic cell death (ICD) and modulate the tumor immune microenvironment has attracted attention. However, whether BNCT-induced immune activation can overcome the T-cell exclusion barrier of immunologically "cold" tumors and translate into intratumoral effector T-cell infiltration remains unclear. Methods: A B16 melanoma model was established in C57BL/6 mice. Mice were assigned to CK, N10/N20 (neutron irradiation alone for 10 or 20 min), BPA, and BNCTN10/BNCTN20 groups (BPA 500 mg/kg plus 10 or 20 min irradiation) to evaluate tumor suppression and survival. In a separate cohort (CK, N20, and BNCTN20), the most efficacious regimen (BNCTN20) was compared with CK on days 3 and 7: H&E staining; immunohistochemistry/immunofluorescence for gamma-H2AX, HMGB1, cleaved caspase-3, PD-L1, CD8+, and granzyme B; ELISA for cytokines and chemokines; and ICP-OES for 10B distribution. Results: BNCT significantly suppressed tumor growth. When CK tumors reached the humane endpoint (~2000 mm3), N20 tumor volume was half that of CK (TGI ~ 49.8%), whereas BNCTN20 reached only one tenth (TGI ~ 88.9%, p < 0.001), with prolonged survival (p < 0.001). BNCT induced gamma-H2AX-associated DNA damage, HMGB1 release, and cleaved caspase-3-mediated apoptosis; upregulated PD-L1; induced a Th1-type response (elevated IFN-gamma/TNF-alpha, reduced IL-10); and enhanced CXCL9/10 signaling. However, intratumoral CD8+ T-cell infiltration and granzyme B expression did not increase, indicating that this activation was not translated into a local effector T-cell response. Conclusions: BNCT inhibited tumor growth and prolonged survival while inducing ICD and a systemic Th1 response; nevertheless, systemic activation failed to translate into local CD8+ T-cell infiltration, while PD-L1 was upregulated, a "strong direct killing but blocked immune translation" profile in the B16 cold tumor. PD-L1-associated adaptive immune resistance may limit this conversion, providing rationale for combining BNCT with immune checkpoint blockade.

cancer biology↗

bioRxiv2024

Maternal n-3 enriched diet reprograms neurovascular transcriptome and blunts inflammation in neonate

Infection during perinatal period can adversely affect brain development, predispose infants to ischemic stroke and have lifelong consequences. We previously demonstrated that diet enriched in n-3 polyunsaturated fatty acids (PUFA) transforms brain lipid composition and protects from neonatal stroke. Vasculature is a critical interface between blood and brain providing a barrier to systemic infection. Here we examined whether maternal PUFA-enriched diets exert reprograming of endothelial cell signalling in 9-day old mice after endotoxin (LPS)-induced infection. Transcriptome analysis was performed on brain microvessels from pups born to dams maintained on 3 diets: standard, n-3 or n-6 enriched. N-3 diet enabled higher immune reactivity in brain vasculature, while preventing imbalance of cell cycle regulation and extracellular matrix cascades that accompanied inflammatory response in standard diet. LPS response in blood and brain was blunted in n-3 offspring. Cerebral angioarchitecture analysis revealed modified vessel complexity after LPS. Thus, n-3-enriched maternal diet partially prevents imbalance in homeostatic processes and alters inflammation rather than affects brain vascularization during early life. Importantly, maternal diet may presage offspring neurovascular outcomes later in life.

neuroscience↗

bioRxiv2023

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease

The 5xFAD mouse model is a popular model of familial Alzheimers Disease (AD) that is characterized by early beta-amyloid (A{beta}) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Male and female 5xFAD and WT littermates underwent in vivo 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter. With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan. While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing A{beta} deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of the motor and visual cortex and increased vessel lengths alongside decreased collaterals coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing A{beta} deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

neuroscience↗

bioRxiv2019

Fibroblast Protection of Borrelia burgdorferi from Doxycycline, Cefuroxime and Daptomycin Combination is Eliminated by Oregano or Carvacrol Essential Oil

Borrelia burgdorferi could be occasionally recovered from patients after antibiotic treatment, which indicates it may resist eradication by antibiotic and host defense mechanisms. Skin fibroblast cells have previously been shown to protect the killing of B. burgdorferi by ceftriaxone, a powerful antibiotic commonly used to treat Lyme disease. In this study, we evaluated if fibroblast cells could also protect against the doxycycline+ cefuroxime+ daptomycin drug combination which has previously been shown to completely eradicate highly persistent biofilm-like microcolonies of B. burgdorferi. To do so, we utilized a GFP-labeled B. burgdorferi for infection of murine fibroblast cells and assessed the effect of the drug combination on killing the bacteria in the presence or absence of the fibroblast cells. Surprisingly, we found that fibroblasts could protect B. burgdorferi from being completely killed by the drug combination doxycycline, cefuroxime and daptomycin, which eradicated B. burgdorferi completely in the absence of fibroblast cells. Interestingly, addition of essential oil carvacrol or oregano at 0.1% could enhance the activity of the doxycycline+ cefuroxime+ daptomycin drug combination and led to complete eradication of B. burgdorferi even in the presence of fibroblast cells. Further studies are needed to determine if the essential oil drug combinations could eradicate persistent B. burgdorferi infection in vivo in animal models. Our study provides a useful and convenient ex vivo model for evaluating different drug regimens needed for developing more effective treatment of persistent Lyme disease in the future.

microbiology↗