岐阜药科大学

Spontaneous reporting databases play a central role in pharmacovigilance for monitoring the safety of drugs and vaccines. Conventional statistical signal detection has relied primarily on disproportionality analyses based on reporting frequencies, whereas information on the timing of adverse event onset has not been fully exploited. Time to onset (TTO), defined as the interval between the initiation of drug administration and the occurrence of an adverse event, provides complementary information that captures temporal patterns of event manifestation beyond simple occurrence counts. This review summarizes the definition, calculation, characteristics, and limitations of TTO analyses in spontaneous reporting databases and provides an overview of statistical signal detection methods incorporating TTO information. In particular, nonparametric distribution-comparison approaches, such as the Kolmogorov–Smirnov and Anderson–Darling tests, are well suited to spontaneous reporting data, in which the underlying population and exposure size are unknown. These methods enable the detection of abnormalities in the temporal structure of adverse event onset that may not be identifiable through frequency-based analyses alone. Furthermore, disproportionality analysis and TTO-based approaches are not competing methods but complementary strategies that capture different dimensions of safety signals—reporting frequency and temporal patterns—and their combined use may improve both sensitivity and interpretability of signal detection. The review also discusses survival analysis-based methods and Weibull modeling for TTO data, outlining their theoretical background and applications while emphasizing their inherent limitations when applied to spontaneous reporting systems. Because of reporting bias, incomplete time information, and the absence of non-event cases, such methods should not be used to estimate population-level risks or to infer causality. In conclusion, TTO analyses using spontaneous reporting databases should be positioned as exploratory tools for characterizing onset patterns, generating hypotheses, and informing the design of subsequent epidemiological and safety studies, rather than as a direct basis for clinical or regulatory decision making.

Osteosarcomas are high-grade primary bone malignancies that primarily affect children and young adults. Osteosarcoma stem cells (OSCs) play pivotal roles in the progression of malignancy and therapeutic resistance. In this study, we re-analyzed our previous RNA sequencing data from an OSC model and identified Matrix metalloproteinase 10 (MMP10) as among the most highly upregulated genes in OSC. We assessed the clinical relevance of MMP10 expression in patients with an osteosarcoma prognosis and elucidated its functional role in OSCs using knockdown approaches, both in vitro and in vivo. Among the MMP family members, MMP10 showed one of the highest expressions in OSCs, which was significantly associated with a poor prognosis in patients with high cancer stemness cell signatures. Knockdown of MMP10 caused a significant impairment of the tumor sphere formation and self-renewal capacities of OSCs in vitro, and suppressed tumor growth in a xenograft model. Bioinformatic analysis, based on gene set enrichment analysis, further revealed that a high expression of MMP10 was significantly associated with activation of the NF-κB signaling pathway in this high-stemness population. Collectively, these findings provided evidence that MMP-10 contributes to maintenance of the stem-like properties of osteosarcomas and could serve as a potential therapeutic target and candidate biomarker for osteosarcomas characterized by high stemness.

Abstract:Carex kobomugi is a dioecious perennial sedge native to coastal sand dunes in temperate northeastern Asia. While previous phytochemical investigations of this species have focused exclusively on its roots and rhizomes, this study represents the first report on the chemical constituents of its flowers. From the methanolic extract of the staminate flowers, two new styrylchromones, kobochromones B (1: ) and C (2: ), and a new suberin derivative, kobosuberin (5: ), were isolated. Their structures were elucidated by spectroscopic analysis (1D/2D NMR and HRESIMS). Their cytotoxic activity was assessed against four human cancer cell lines (HCT15, MCF7, 22Rv1, and PANC1), and the normal human hepatic stellate cell line LX-2 was used as a reference normal cell line. The study revealed a unique chemical profile of the staminate flowers, contributing to the understanding of the specialized metabolites in this dioecious species.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer lacking estrogen receptor (ER), progesterone receptor (PR), and HER2 expression. Among its heterogeneous subtypes, luminal androgen receptor-positive (LAR) TNBC is driven by androgen signaling and presents limited treatment options. We previously identified dehydrogenase/reductase SDR family member 11 (DHRS11) as a novel enzyme involved in androgen biosynthesis, and demonstrated that Kobochromone A (KC-A), a polyphenol isolated from Carex kobomugi, inhibited androgen-driven proliferation in LAR TNBC cells via DHRS11 inhibition and AR downregulation. In this study, we synthesized 23 structural derivatives of KC-A and identified WH23 as the most potent DHRS11 inhibitor (IC50 = 37 nM). Molecular docking and MM-PBSA analysis revealed that the 2'-hydroxy group of WH23 forms a hydrogen bond with His210 of DHRS11, which was validated by site-directed mutagenesis. WH23 suppressed AR mRNA and protein expression, reduced 11-ketodihydrotestosterone (11KDHT)-induced c-Myc expression, and inhibited proliferation of MDA-MB-453 cells. Additionally, WH23 inhibited PI3K/AKT signaling, reducing phosphorylation of PDK1, AKT, mTOR, and ERK. Capivasertib (Cap), a clinically approved pan-AKT inhibitor, induced DHRS11 expression in MDA-MB-453 cells. Although Cap and WH23 did not show synergistic cytotoxicity in parental cells, Cap-resistant (Cap-R) cells, which exhibited elevated DHRS11 and c-Myc expression, showed significant sensitivity to the combination. In Cap-R cells, the combination of Cap and WH23 significantly induced apoptosis, demonstrating a synergistic anticancer effect. These findings establish WH23 as a dual-acting compound targeting both androgen biosynthesis and AR signaling, with potential to overcome AKT inhibitor resistance in LAR TNBC.

As the survival rate of extremely preterm infants has increased, postnatal CMV infection (pCMV) has been considered a potential contributor to morbidities in this population. This study aimed to clarify the risk, symptoms, and complications of pCMV. This is a multicenter prospective cohort study of infants born < 29 weeks of postmenstrual age (PMA) with CMV-PCR negative results in urine tests within 2 weeks of birth. Serial viral loads in breast milk and infant blood and urine were monitored every 2 weeks until 36 weeks of PMA. Binding, neutralizing and non-neutralizing functions of maternal serum CMV-specific antibodies, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), were assessed for the infection risk. During the study period from Dec 2021 to Sep 2024, 139 infants were enrolled. Eighty-three (59%) of these infants were born to CMV-seropositive mothers. The infants' gestational age and birth body weight were 26 weeks (IQR 24-27), and 763 g (515-1011), respectively. The prevalence of pCMV by 36 weeks of PMA was 14/139 (10%) overall and 13/83 (16%) in infants born to seropositive mothers. Symptoms associated with pCMV were transient neutropenia (< 1000/µL) (pCMV+ 42% vs. pCMV- 11%, p< 0.01) and acute respiratory exacerbation after 3 weeks of age (31 vs. 11%, p=0.08). Infants with pCMV were born at a lower gestational age (24 vs 25 weeks, p=0.06) and experienced premature rupture of membranes more than 24 hours before birth (58% vs 17%, p=0.01). pCMV was associated with a higher CMV load in maternal milk at 2 weeks (141820 vs 7815 copies/µL, p< 0.01) and 4 weeks (40296 vs 8415 copies/µL, p< 0.04) after birth. In maternal serum, CMV-specific antibody levels were not different, but ADCP activity was lower (85% vs 78%, p=0.01) in the pCMV group. In addition, total serum IgG levels tended to be lower in the pCMV group (245 vs. 340 mg/dL, p=0.07). Approximately 16% of extremely preterm infants born to CMV-seropositive mothers develop pCMV by term equivalent age. Risk factors for infection include low maternal ADCP activity, lower gestational age, and premature rupture of membranes more than 24 hours prior to birth. Neutropenia and chronic lung disease may be symptoms of pCMV. All Authors: No reported disclosures