Cholinergic dysfunction is a key feature of cognitive impairment, and currently available acetylcholinesterase (AChE) inhibitors provide limited symptomatic benefit and are often associated with adverse effects. This study evaluated the cognitive-protective effects of bavachin (BVC), a prenylated flavonoid from Psoralea corylifolia, and its interaction with Donepezil (DNP) in a scopolamine (SCP)-induced amnesia model. Male Swiss albino mice were pretreated with BVC (10-40 mg/kg), DNP (2.5 mg/kg), or their combination for 7 days prior to SCP challenge, followed by assessment using multiple behavioral paradigms, including novel object recognition, elevated plus maze, passive avoidance, Y-maze, and Morris water maze. BVC attenuated SCP-induced memory deficits in a dose-dependent manner, with the 40 mg/kg dose producing performance statistically comparable to, though not formally demonstrated to be equivalent to, the normal control across tests. Bliss independence analysis of behavioral endpoints indicated predominantly additive interactions, with occasional greater-than-additive trends. Biochemical evaluation demonstrated that BVC inhibits AChE in vitro (IC50 = 27.7 µM) and attenuates SCP-induced elevations of AChE activity ex vivo in the frontal cortex and hippocampus. Combination treatment showed a greater-than-additive interaction in the frontal cortex (ΔBliss = 0.054) and an approximately additive effect in the hippocampus (ΔBliss = 0.013). Molecular docking and molecular dynamics simulations further suggested stable binding of BVC within the active sites of AChE and butyrylcholinesterase (BChE). Collectively, these findings indicate that BVC attenuates cognitive deficits, at least in part, through cholinesterase inhibition, and exhibits additive effects with DNP, supporting its potential as an adjunctive candidate for cognitive disorders.

Autosomal dominant STAT1 gain-of-function (GOF) is an inborn error of immunity characterized by chronic mucocutaneous candidiasis and variable immune dysregulation. JAK inhibitors are a promising therapy, but their efficacy in STAT1 GOF remains variable. We longitudinally evaluated the clinical and molecular impact of JAK inhibitors in two STAT1 GOF patients, harboring p.R321S and p.T385M mutations, using Cellular Indexing of Transcriptomes and Epitopes by sequencing, flow cytometry, cytokine measurement, and allele-specific expression analysis in peripheral blood mononuclear cells and serum. Rapid yet incomplete immune reconstitution was observed as early as 1 week after treatment initiation. T cells rebalanced to a more homeostatic status and TCR repertoire diversity increased rapidly. However, some immune defects remained, including natural killer deficiency in one patient. The pronounced transcriptional dysregulation in monocytes was not explained by an unbalanced mutant STAT1 expression but improved with JAK-inhibitor treatment. JAK inhibitors provided significant clinical and immunological benefits to STAT1 GOF patients but did not fully restore immune homeostasis. These findings highlight the therapeutic potential and limitations of JAK inhibitors in STAT1 GOF.

Antibody-drug conjugate (ADC) development in solid tumors faces efficacy and safety challenges from heterogeneous target expression, limited tumor penetration, and off-target payload exposure. We developed a spatial quantitative systems pharmacology (QSP) framework integrating ADC-analyte physiologically based pharmacokinetics (PBPK), a Krogh-cylinder tumor model, and a non-small cell lung cancer (NSCLC) tumor size-overall survival (TS-OS) relationship developed without ADC-treated populations. Applied to trastuzumab deruxtecan (T-DXd) in HER2-mutant NSCLC and datopotamab deruxtecan (Dato-DXd), a TROP2-directed ADC, in EGFR-mutated NSCLC, all parameters came from literature or independent assays; only nonspecific antibody uptake and unconjugated-payload hepatic clearances were estimated from population-level T-DXd serum PK. Using a common structure and virtual-patient framework with independently informed ADC-specific inputs, simulations generated PK, objective response rate (ORR), disease control rate (DCR), and exploratory OS trends consistent with clinical data. Heterogeneous tumor trajectories emerged without fitting individual trajectories, adding ad hoc response compartments, or retuning tumor growth solely to reproduce ORR/DCR. Tumor growth kinetics and target-expression characteristics, represented by histological score and antigen-positive cell fraction, were associated with response, but responder/non-responder distributions overlapped, indicating limited discrimination and need for predictive biomarkers. The TS-OS sub-model reproduced median OS and survival trends, supporting transportability despite absent individual-level tumor and survival data. Tumor growth rate was the strongest survival-associated input, consistent with TS-OS covariate structure. Across doses, 5.4 mg/kg Q3W T-DXd and 6 mg/kg Q3W Dato-DXd were preferred based on predicted efficacy and off-tumor tissue payload exposure, consistent with approved doses. The framework supports ADC design and dose evaluation despite limited individual-level data.

Aging is associated with cognitive deterioration accompanied by a reduction in hippocampal neurogenesis. Murine models have been widely used to study aging and age-related cognitive decline, as they recapitulate many of the key features of the degenerative process. Among these, the SAMP8 strain represents a well-established model of accelerated aging, characterized by early-onset and progressive cognitive impairment, Alzheimer's disease-like neuropathology, and an initial increase in hippocampal neurogenesis that ultimately depletes the neural stem cell pool. Notably, most studies using murine models of aging or neurodegeneration have focused on males or mixed-sex cohorts, leaving sex-specific differences in neurogenesis and cognitive decline largely unexplored. Recent evidence indicates that diterpenoid treatment is associated with improved cognitive performance and enhanced neurogenesis in 6-month-old male SAMP8 mice. However, whether females exhibit similar responses remains unknown. In this study, we characterized sex differences in hippocampal neurogenesis in 6-month-old SAMP8 mice and examined potential sex-dependent effects of diterpenoid therapy. Our findings reveal sex-specific differences in physiological and pathological hippocampal neurogenesis and in responsiveness to ER272 treatment. Male SAMR1 mice displayed higher baseline neurogenesis than females, while male and female SAMP8 mice followed distinct neurogenic aging trajectories. ER272 was associated with improved cognitive performance and preservation of multiple neurogenic parameters in males but showed limited effects in females. These results suggest sex-specific mechanisms of brain aging and indicate that mixed-sex analyses may mask biologically relevant differences, highlighting the importance of considering sex in aging studies and therapeutic development.

Periprosthetic joint infection (PJI) remains one of the most serious complications of arthroplasty. Since the publication of major guidelines, several aspects of the prevention of PJI have been refined, although high-quality evidence remains limited in many areas. The aim of this annotation was to provide an updated overview of current preventive strategies, and to summarize the latest recommendations in perioperative practice.

Antibody-guided therapeutics, including antibody-drug conjugates and radiopharmaceuticals, efficiently deliver payloads to tumor lesions, but the weeks-long half-life of antibodies promotes accumulation in normal tissues, increasing the risk of off-target toxicity. Although conventional linkers generally provide systemic stability, recent studies indicate that retention of intact antibody-guided conjugates in normal tissues can cause chronic toxicity. Here, we report an antibody-guided delivery platform leveraging the pH-responsive properties of i-motif functional nucleic acids (iM) for targeted chemo- and radiotherapy. Using trastuzumab as the targeting moiety, the platform (Tra-iM) achieves selective payload delivery. Within the acidic tumor microenvironment, the i-motif forms a stable quadruplex, promoting effective payload accumulation in tumor lesions. Under physiological conditions, nuclease-sensitive linear i-motif structures trigger rapid disassembly of Tra-iM, generating hydrophilic nucleic acid fragments that minimize off-target penetration and facilitate clearance of hydrophobic payloads. Fluorescence and PET imaging showed reduced normal-organ retention and faster clearance of the labeled payload-bearing components. Therapeutic evaluations demonstrate that Tra-iM preserves targeted delivery and efficacy while markedly reducing hematologic and hepatic toxicity after high-dose administration. This strategy significantly enhances the biosafety of antibody-guided therapeutics and highlights the potential of metabolite-regulated delivery platforms to advance targeted nanomedicine.

IntroductionEnvironmental monitoring of antineoplastic drug contamination has primarily focused on medication preparation areas and frequently touched surfaces. Consequently, contamination in nonpreparation areas and on infrequently touched surfaces, such as ceilings, remains poorly characterized. This study evaluated fluorouracil contamination on floors and ceilings in preparation and nonpreparation areas.MethodsThis study was conducted at Aichi Cancer Center, Japan. Samples were collected from floor and ceiling surfaces in the hospital pharmacy, outpatient chemotherapy center, and inpatient ward. Cleaning practices at the sampling sites were also assessed. Fluorouracil concentrations were measured using liquid chromatography-tandem mass spectrometry. At the time of sampling, closed-system drug-transfer devices (CSTDs) were not used for fluorouracil preparation or administration.ResultsFluorouracil was detected on all sampled floor and ceiling surfaces, including those in nonpreparation areas where antineoplastic drugs were not handled. The highest contamination levels were detected on the preparation room floor (3.104 ng/cm2) and the pharmacy break room ceiling (2.440 ng/cm2). In the outpatient chemotherapy center, relatively high contamination levels were detected on the nursing station floor (0.622 ng/cm2) and nursing break room ceiling (0.419 ng/cm2).ConclusionsFluorouracil contamination was detected in nonpreparation areas and on ceiling surfaces near air-conditioning units that were not routinely touched or cleaned. These findings suggest that contamination may spread through the movement of healthcare workers and materials and may accumulate on infrequently cleaned surfaces. As part of contamination control, the use of CSTDs may need to be implemented and environmental monitoring may need to be extended beyond medication preparation areas.

BackgroundExtranodal extension, defined as tumor invasion beyond the lymph node capsule into perinodal adipose tissue, has been associated with adverse outcomes in several malignancies but is not included in the AJCC-TNM staging system for colorectal cancer. This study evaluated the clinicopathological and prognostic significance of extranodal extension and its extent in lymph node-positive colorectal carcinoma.MethodsSixty-nine patients who underwent curative-intent resection for lymph node-positive colorectal carcinoma were retrospectively analyzed. Patients were classified according to the presence of extranodal extension, and extranodal extension-positive tumors were further categorized as limited (<1 mm) or extensive (≥1 mm). Associations with clinicopathological variables and survival outcomes were analyzed using Cox proportional hazards regression models.ResultsExtranodal extension was identified in 29 patients (42%) and was associated with a higher metastatic lymph node count, higher N stage, and an increased incidence of distant metastasis (all P < .05). In multivariate analysis adjusted for T stage, N stage, and postoperative adjuvant chemotherapy, extranodal extension remained independently associated with shorter disease-free survival (hazard ratio 2.65; 95% confidence interval 1.10-6.38; P = .031). Extranodal extension was not independently associated with overall survival. Although the extent of extranodal extension correlated with nodal burden, it was not independently associated with survival outcomes.ConclusionExtranodal extension is associated with increased nodal tumor burden and independently predicts shorter disease-free survival in colorectal carcinoma. Routine assessment and reporting of extranodal extension may improve pathological risk stratification.