Pemetrexed, a multi-target antifolate chemotherapeutic widely used in non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM), is associated with various adverse drug events (ADEs), some of which may be underrecognized in clinical trials. This study conducted a comprehensive pharmacovigilance analysis using two major spontaneous reporting systems—FAERS (2004Q1–2024Q3) and JADER (2007Q1–2024Q3)—to evaluate pemetrexed-related ADEs. Disproportionality analysis was performed using four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Time-to-onset (TTO) patterns were assessed using Weibull distribution modeling. A total of 12,026 and 4,522 pemetrexed-related ADE reports were retrieved from FAERS and JADER, respectively. The most frequently reported ADEs included hematologic toxicities (anemia, neutropenia, thrombocytopenia), gastrointestinal disorders (nausea, vomiting, diarrhea), and renal impairment. Strong safety signals were consistently identified for these events. Notably, novel ADE signals such as hepatobiliary injury, endocrine dysfunction, and thromboembolic events were observed in both databases. Subgroup analyses revealed sex- and age-specific ADE patterns, with younger patients and males showing distinct toxicity profiles. Sensitivity analysis excluding combination therapies confirmed the robustness of primary signals. TTO analysis revealed that most ADEs occurred within the first two months after pemetrexed initiation, with a median TTO of 27 days and a predominance of early failure patterns (Weibull β < 1), highlighting the importance of close monitoring during early treatment. Rare but severe ADEs, including myocarditis, sepsis, cholestasis, and pseudocellulitis, were identified, several of which are not currently listed in official drug labeling. This study provides a comprehensive safety assessment of pemetrexed, confirming known toxicities and identifying new safety signals. Continuous pharmacovigilance is essential to optimize its clinical use and improve patient safety.

Pericardiocentesis is usually completed under fluoroscopy. The electroanatomic mapping (EAM) system allows visualizing puncture needle tip (NT) while displaying the electrogram recorded from NT, making it possible to obtain epicardial access (EA) independent of fluoroscopy. This study was designed to establish and validate a technique by which EA is obtained under guidance of three-dimensional (3D) EAM combined with NT electrogram. 3D shell of the heart was generated, and the NT was made trackable in the EAM system. Unipolar NT electrogram was continuously monitored. Penetration into pericardial sac was determined by an increase in NT potential amplitude and an injury current. A long guidewire of which the tip was also visible in the EAM system was advanced to confirm EA. Epicardial access was successfully obtained without complication in 13 pigs and 22 patients. In the animals, NT potential amplitude was 3.2 ± 1.0 mV when it was located in mediastinum, 5.2 ± 1.6 mV when in contact with fibrous pericardium, and 9.8 ± 2.8 mV after penetrating into pericardial sac (all P ≤ 0.001). In human subjects, it measured 1.54 ± 0.40 mV, 3.61 ± 1.08 mV, and 7.15 ± 2.88 mV, respectively (all P < 0.001). Fluoroscopy time decreased in every 4–5 cases (64 ± 15, 23 ± 17, and 0 s for animals 1–4, 5–8, 9–13, respectively, P = 0.01; 44 ± 23, 31 ± 18, 4±7 s for patients 1–7, 8–14, 15–22, respectively, P < 0.001). In five pigs and seven patients, EA was obtained without X-ray exposure. By tracking NT in the 3D EAM system and continuously monitoring the NT electrogram, it is feasible and safe to obtain EA with minimum or no fluoroscopic guidance. Demonstration of connection of pericardiocentesis needle to the EAM system and recording of needle tip electrogram. (A–C) The proximal end of a modified Tuohy needle was connected to the EAM system via a jumper wire (J), the body of needle was covered by outer sheath (N + S) except for the tip that remained electrically conductive. The needle was inserted underneath the subxiphoid at an angle of 45–60° to the body surface and was kept at a direction towards to the front one-half of the inferior wall of the right ventricle. (D) A closer view at LAO 45° of the needle tip (NT) and its relative location to the heart. The red circles represented the needle tip location when it was in the mediastinum over the diaphragm (MD), in contact with fibrotic epicardium (FP), and penetrated into pericardial sac (PS). The typical needle tip unipolar electrogram (N1) at these three locations were shown in panel F. (E) In the EAM system, the needle was detected as a bipolar catheter (yellow arrow). It was real-timely tracked and displayed with pre-acquired 3D shells of LV and RV in different projections (left: AP view; right: LAO 45° view). (F) The dominant component of the needle electrogram was the electrical activity from ventricles, namely Ned potential, corresponding to the QRS complex on surface ECG. Lower row—small Ned potential when NT in the mediastinal; middle row—larger Ned potential with small injury current (white arrow) when NT in contact with fibrotic pericardium. A PVC (blue arrow) indicated that the needle tip has been in contact with the heart; upper row—giant Ned potential with significant injury current (red arrow) when NT penetrated into pericardial sac. FP, fibrous pericardium; MD, mediastinum; PS, pericardial space; Myo, myocardium; Ned, the dominant potential on needle electrogram; J, jumper wire; N + S, needle with outer sheath; other abbreviations as Figures 1–6.

Sestrin2 (Sesn2) is involved in the progression of cardiovascular diseases, such as hypertension and myocardial infarction. This study aimed to examine Sesn2 expression in human calcific aortic valve disease (CAVD) and explore its possible mechanisms by which Sesn2 participates in this process. CAVD and normal aortic valves were collected. Sesn2 expression and sources were examined, and the results showed that Sesn2 expression was increased in aortic valves from patients with CAVD and was mainly secreted by macrophages. Additionally, U937 macrophages were pretreated with si-Sesn2 or cDNA-Sesn2 and further treated with oxidized low-density lipoprotein (ox-LDL); M1 macrophages and their markers were measured, and we found that pretreatment with si-Sesn2 increased ox-LDL–induced M1 macrophage polarization and marker mRNA levels, whereas pretreatment with cDNA-Sesn2 had the opposite effects. In ox-LDL–treated U937 macrophages, oxidative stress levels were increased in the si-Sesn2 pretreatment group and further increased by si-Nrf2 treatment, whereas oxidative stress levels were decreased in the cDNA-Sesn2 pretreatment group and significantly reversed by ML385, a specific Nrf2 inhibitor. The effects of Sesn2 on ox-LDL-induced oxidative stress and the osteogenic differentiation of ox-LDL-induced valvular interstitial cells (VICs) was examined by down-regulating Nrf2 pathway. When U937 macrophages were co-cultured with VICs, downregulation of Sesn2 increased ox-LDL-induced osteogenic differentiation in VICs, whereas overexpression of Sesn2 exerted the opposite effects. Our study suggests that Sesn2 is increased in CAVD aortic valves and may participate in the development of CAVD by regulating oxidative stress via the Nrf2 pathway.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease and currently there is no pharmacological therapy. Sympathetic nerve overactivity plays an important role in the development of TAAD. Sympathetic innervation is mainly controlled by nerve growth factor (NGF, a key neural chemoattractant) and semaphoring 3A (Sema3A, a key neural chemorepellent), while the roles of these two factors in aortic sympathetic innervation and especially TAAD are unknown. We hypothesized that genetically manipulating the NGF/Sema3A ratio by the Ngf-driven Sema3a expression approach may reduce aortic sympathetic nerve innervation and mitigate TAAD progression. A mouse strain of Ngf gene-driven Sema3a expression (namely Ngf ^{Sema3a/Sema3a} mouse) was established by inserting the 2A-Sema3A expression frame to the Ngf terminating codon using CRISPR/Cas9 technology. TAAD was induced by β-aminopropionitrile monofumarate (BAPN) both in Ngf ^{Sema3a/Sema3a} mice and wild type (WT) littermates. Contrary to our expectation, the BAPN-induced TAAD was severer in Ngf ^{Sema3a/Sema3a} mice than in wild-type (WT) mice. In addition, Ngf ^{Sema3a/Sema3a} mice showed higher aortic sympathetic innervation, inflammation and extracellular matrix degradation than the WT mice after BAPN treatment. The aortic vascular smooth muscle cells isolated from Ngf ^{Sema3a/Sema3a} mice and pretreated with BAPN in vivo for two weeks showed stronger capabilities of proliferation and migration than that from the WT mice. We conclude that the strategy of Ngf-driven Sema3a expression cannot suppress but worsens the BAPN-induced TAAD. By investigating the aortic phenotype of Ngf ^{Sema3a/Sema3a} mouse strain, we unexpectedly find a path to exacerbate BAPN-induced TAAD which might be useful in future TAAD studies.

Objective: Immune checkpoint inhibitors (ICIs) are pivotal in oncology but carry risks of immune-related adverse events (irAEs). Aseptic meningitis (AM) represents a serious neurological irAE, yet real-world evidence on regimen-specific risk variations remains limited. This study aimed to characterize AM reporting patterns and safety signals across ICI regimens using FDA Adverse Event Reporting System (FAERS) data.Methods: We analyzed FAERS reports (January 2011–December 2024) for ICIs-associated AM. Descriptive statistics summarized demographics, clinical profiles, and temporal trends. Disproportionality analyses employed four algorithms: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS).Results: Among 498 ICIs-associated AM reports, monotherapy predominated (78.7%) with pembrolizumab (34.9%), ipilimumab/nivolumab (21.3%), nivolumab (17.1%), and atezolizumab (15.9%) as leading agents. Patients had a median age of 64 years; 98% met serious adverse event criteria. Hospitalization (45.8%) was the most common outcome. Symptom onset was rapid (median: 34 days). Disproportionality analysis revealed pronounced signals for ipilimumab/nivolumab (ROR 5.71, 95% CI 4.71–6.91) and ipilimumab monotherapy (ROR 4.21, 95% CI 3.05–5.82). Anti-PD-1 agents collectively showed moderate association (ROR 2.55, 95% CI 2.25–2.88).Conclusions: ICIs-associated AM presents a clinically significant safety concern, particularly with ipilimumab-containing regimens. Rapid symptom onset underscores the need for vigilant neurological monitoring during early treatment phases. These findings warrant integration into clinical risk-assessment protocols and warrant further mechanistic investigation.