Abiraterone acetate was initiated immediately...Autopsy revealed widespread metastases, all histologically confirmed as neuroendocrine prostate cancer. Strong androgen receptor suppression in metastatic castration-sensitive prostate cancer can lead to aggressive radiographic progression without prostate-specific antigen elevation, underscoring the limitations of antigen-based monitoring.

BMAL1 functional downregulation, REV-ERBα oscillatory output attenuation, NAD+ oscillatory amplitude reduction, and gut-liver axis circadian desynchronization together constitute an inferential framework for hepatic circadian failure...This evidence gap limits the clinical actionability of current mechanistic findings across all disease categories. Circadian phase inference algorithms and prospective temporally designed cohort studies offer a methodologically grounded path toward clinically actionable circadian hepatology.

P2, N=61, Completed, Masonic Cancer Center, University of Minnesota | Active, not recruiting --> Completed | N=22 --> 61

To delineate underlying mechanisms, we employed Network Perturbation Amplitude (NPA) analysis, which uncovered qualitatively distinct toxicity architectures: HTP-1 exhibited higher overall toxicity and elicited broad-spectrum network perturbations involving cell stress, proliferation, and immune regulation, correlating with greater apoptotic induction; HTP-2 triggered focused activation of damage-sensing pathways, consistent with its earlier membrane disruption and more pronounced genotoxicity. Multi-omics analysis further linked these mechanistic perturbations to human disease-relevant pathways, with HTP-1 showing stronger enrichment for COPD-associated expression patterns and HTP-2 for lung cancer-related signatures, suggesting the acute molecular response to each product exhibits similarity to specific pulmonary disease-associated molecular signatures. These findings establish human-derived airway organoids as a sensitive, human-relevant platform within the New Approach Methodologies‌ (NAMs) framework for qualitative comparison and mechanistic interrogation of product-specific toxicity.

P2, N=12, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Aug 2028 --> May 2026

E. fischeriana disrupts intestinal metabolic and circadian coordination, leading to epithelial barrier dysfunction. Milk processing partially mitigates intestinal metabolic disturbance and structural injury, but fails to fully restore circadian regulation. These findings provide mechanistic insight into the intestinal toxicity of E. fischeriana and the detoxification mechanism of traditional milk processing.

Tildrakizumab and abiraterone acetate combination therapy is well tolerated but did not show clinical efficacy in this small, unselected, cohort of ARPI-resistant mCRPC patients. Further study into the causes of primary resistance to IL23 targeting in mCRPC, and development of biomarkers of downstream IL23-IL23R activity, are now needed to translate IL23 blockade into the clinic.

Pyramidal neurons in the auditory cortex of TNF-α KO mice had larger miniature excitatory postsynaptic current (mEPSC) amplitude and lower miniature inhibitory postsynaptic current (mIPSC) frequency, suggesting a shift in synaptic E/I balance...Here, we show that TNF-α-deficient mice have reduced parvalbumin-positive (PV) inhibitory interneuron density, an increased E/I ratio, impaired sensory restriction-induced homeostatic plasticity, and persistent critical period-like plasticity in adulthood. Together, these findings suggest a nonlinear, bell-shaped relationship between TNF-α signaling and cortical circuit function, in which both excessive and deficient TNF-α levels are associated with impaired PV interneuron function and increased E/I ratio.

This concept may be particularly relevant to in vivo CAR T platforms, which could extend temporal control beyond infusion timing through repeatable induction, tunable amplitude, and reversible shutdown...We further examine how viral vectors, lipid nanoparticles, and programmable control circuits might enable circadian-aware CAR installation and duty-cycling. Together, these observations support chrono-synthetic CAR T as a testable translational framework for precision immuno-oncology.

Combination therapy with the PARP inhibitor niraparib and the androgen-receptor inhibitor abiraterone acetate plus prednisone (AAP) has recently shown improvement in radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, particularly BRCA1/2, in the phase III MAGNITUDE trial. However, the very small sample size, retrospective design, and absence of standardized rPFS assessment limit generalizability. These findings are primarily hypothesis-generating but align with prospective trial results and underscore the heterogeneity of HRR-mutated mCRPC, highlighting the need for individualized therapeutic strategies.

P2, N=8, Active, not recruiting, Mayo Clinic | Trial completion date: Mar 2026 --> Jul 2026 | Trial primary completion date: Mar 2026 --> Jul 2026

In this phase II single-arm study, olaparib plus abiraterone and ADT showed preliminary activity and a manageable safety profile in patients with HRR-mutated mHSPC, but these findings need to be confirmed in larger phase III studies.