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.

P3, N=1889, Active, not recruiting, AstraZeneca | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2028 --> Sep 2027

This study provides a first-in-class characterization of saruparib resistance and maps a clear therapeutic path forward. By identifying these specific PARP1 mutations and their collateral DDR vulnerabilities, we provide the molecular framework necessary to monitor and treat patients who progress on next-generation PARP1-selective inhibitors.

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.

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.

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.

P1/2, N=152, Not yet recruiting, AstraZeneca

P1, N=180, Recruiting, Duke Street Bio Ltd | N=90 --> 180 | Trial completion date: Aug 2028 --> Dec 2028 | Trial primary completion date: Aug 2027 --> Aug 2028

P1, N=78, Recruiting, Duke Street Bio Limited

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

This study integrated established diagnostic standards, laryngostroboscopy for clinical assessment, and histopathology as the gold standard for grading, while the analysis of SOX2 gene expression showed a promising predictive molecular marker for tumorigenesis.