Biology subjects

Bilker, W. B.

Publications and source records attributed to Bilker, W. B..

3 recordsLinked to original sources

bioRxiv2026

Proton FLASH radiotherapy enhances control of triple-negative breast cancer through STING-IRF3 and CD8+ T-cell immunity

FLASH radiotherapy delivers radiation at ultra-high dose rates and has been demonstrated to spare normal tissue compared to standard radiotherapy, but it is not known if dose rate also modifies tumor response. Here we compare a single 13.5 Gy fraction of proton irradiation delivered at FLASH (F-PRT) or Standard (S-PRT) dose rate in immunocompetent C57BL/6 mice bearing EO771 or AT3 triple-negative mammary tumors. At this identical physical dose, F-PRT delays tumor growth more than S-PRT at both heterotopic and orthotopic sites. The effect is largest in EO771, where F-PRT also prolongs tumor-volume endpoint-free survival and reduces the emergence of lung metastases relative to S-PRT. F-PRT induces earlier intratumoral STING expression and IRF3 nuclear translocation, higher type I interferon levels and greater CD8+ T-cell infiltration. CD8+ T-cell depletion or systemic STING inhibition abolishes the F-PRT advantage. Combined with anti-PD-1 and agonistic anti-CD40, both modalities produce durable complete responses that reject contralateral rechallenge, but F-PRT limits tumor progression before response and accelerates regression. FLASH proton radiotherapy not only improves normal-tissue tolerance, but also antitumor immunity, suggesting that ultra-high dose rate could widen the therapeutic window from both sides.

cancer biology↗

bioRxiv2026

Serial vaccination expands and refines human CD4+ T cell memory

CD4+ T cells coordinate protective immunity against pathogens. However, a major unresolved question is how human CD4+ T cell memory is established and evolves following primary and repeated vaccination. Using COVID-19 mRNA vaccination as a model, we tracked 50 distinct antigen-specific populations directly ex vivo with peptide-MHC class II tetramers in eight SARS-CoV-2-naive individuals from pre-vaccine baseline through memory time points after three mRNA doses. Our findings identify the primary vaccine series as the main driver of memory pool size. It leverages pre-existing memory while preferentially recruiting high-avidity T cells, establishing an immunodominance hierarchy dominated by a small subset of precursors. Booster vaccination refines both the magnitude and quality of T cell memory. It increases select populations and enhances differentiation of subdominant CD4+ T cells. Populations that did not become more abundant after boosting retained their polyfunctional potential. Beyond establishing memory to the ancestral spike, vaccinations broadened responses by recruiting cross-reactive T cells recognizing viral variants. Collectively, these findings reveal how human CD4+ T cell memory evolves through sequential immunizations to generate a functionally diverse and broadly responsive memory repertoire against future viral challenges.

immunology↗

bioRxiv2019

Multimodal parameters of brain structure and function related to sex differences in cognitive performance.

The Parieto-Frontal Integration Theory (PFIT) identified a fronto-parietal network of regions where individual differences in brain parameters most strongly relate to cognitive performance. PFIT was supported and extended in adult samples, but not in youths or within single-scanner well-powered multimodal studies. We performed multimodal neuroimaging in 1601 youths age 8-22 on the same 3-Tesla scanner with contemporaneous neurocognitive assessment, measuring volume, gray matter density (GMD), mean diffusivity (MD), cerebral blood flow (CBF), resting-state functional MRI measures of amplitude of low frequency fluctuations (ALFF) and regional homogeneity (ReHo), and activation to a working memory and a social cognition task. Across age and sex groups, better performance was associated with higher volumes, greater GMD, lower MD, lower CBF, higher ALFF and ReHo and greater activation for the working memory task in PFIT regions. However, additional cortical, striatal, limbic and cerebellar regions showed comparable effects, hence PFIT needs expansion into an Extended PFIT (ExtPFIT) network incorporating nodes that support motivation and affect. Associations of brain parameters became stronger with advancing age group from childhood to adolescence to young adulthood, effects occurring earlier in females. This ExtPFIT network is developmentally fine-tuned, optimizing abundance and integrity of neural tissue while maintaining low resting energy state.

neuroscience↗