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Background: Despite advances in treatments for gastric cancer (GC), new targets are needed to enhance treatment, especially when mesenchymal‐epithelial transition (MET) amplification is involved. Therefore, we investigated the genomic features of MET‐amplified GC and efficacy of anti‐MET therapy. Methods: Genomic features were investigated in 2284 patients (cohort 1) and 438 patients in the Cancer Genome Atlas (TCGA cohort). RNA data were obtained from TCGA for expression analysis. Clinical responses of 71 patients (cohort 2) were investigated. Survival rates were compared by Kaplan–Meier and log‐rank tests. Results: In cohort 1, 95 (4.2%) exhibited MET amplifications. In TCGA cohort, 15 (3.4%) exhibited MET amplifications. The five top mutated genes were TP53, CDH1, ARID1A, KMT2D and PIK3CA in cohort 1 and TTN, TP53, MUC16, LRP1B and SYNE1 in TCGA cohort. TP53, PIK3CA, KRAS and GNAS showed significant single nucleotide variants (SNVs) in cohort 1, and TP53 SNVs were significant in TCGA cohort. Fifteen and 18 genes showed significant copy number variations (CNVs) between the MET‐ and non‐MET‐amplified groups in cohort 1 and TCGA cohort, respectively. The PI3K pathway was significantly activated in Chinese patients with MET‐amplified GC (p = 0.002). TP53 expression is negatively associated with MET amplification. Real‐world data obtained with cohort 2 revealed that anti‐MET treatment significantly affected overall survival (OS) (p = 0.002), whereas CNVs did not affect progression‐free or OS even when treatment lines were considered. Conclusions: MET‐amplified GC has a distinctive mutation landscape. Our findings provide valuable information for clinicians who treat patients with MET‐amplified GC. [ABSTRACT FROM AUTHOR]

Background: The clinicopathological features of MET‐amplified gastric cancer (GC) and real‐world data on the efficacy of MET‐targeted therapies remain unknown. Pulmonary lymphangitis carcinomatosis (PLC) is a peculiar manifestation of GC, whose management has not been thoroughly described. Methods: This study analyzed patients diagnosed with MET‐amplified GC or GC with PLC at any time point of the disease course from 2011 to 2021 in two centers. Clinicopathological features and survival outcomes of MET‐amplified GC were analyzed. The clinical and molecular implications of GC with PLC were discussed. Results: Fifty‐eight patients with MET‐amplified GC and 20 patients with GC accompanied by PLC were finally enrolled for analysis (including 13 overlapped patients). GC with PLC was more common in female patients (p = 0.010), diagnosed at a younger age (p = 0.002), presented with a higher baseline ECOG PS (p = 0.016), and was more likely to develop lung metastasis (p < 0.001), and serous effusion (p = 0.026) than GC without PLC. Patients with primary MET‐amplified GC had a worse prognosis than those with secondary MET‐amplified GC (p = 0.005). The application of anti‐MET therapy was associated with numerically prolonged survival, but the association was not statistically significant (p = 0.07). MET amplification was concentrated in patients with PLC, in which anti‐MET therapies elicited a high response rate. Conclusions: MET‐targeted therapies are efficacious in real‐world populations with MET‐amplified GC. Patients with PLC have distinct clinical and molecular features and might benefit from MET‐targeted therapies. [ABSTRACT FROM AUTHOR]

More immune-related adverse events (irAEs) have emerged along with increased immune checkpoint inhibitor (ICI) treatment. ICI-induced myocarditis is a rare type of irAE with early onset, rapid progression, and high mortality. Its specific pathophysiological mechanism is not fully understood. In total, 46 patients with tumors and 16 patients with ICI-induced myocarditis were included. We performed single-cell RNA sequencing on CD3 + T cells, flow cytometry, proteomics, and lipidomics to improve our understanding of the disease. First, we demonstrate the clinical features of patients with PD-1 inhibitor–induced myocarditis. We then identified 18 subsets of T cells using single-cell RNA sequencing and performed comparative analysis and further verification. The composition of T cells in the peripheral blood of patients has changed remarkably. Compared with non-irAE patients, effector T cells were increased in irAE patients, while naive T cells, γδ T cells, and mucosal-associated invariant T cell cluster cells were decreased. Besides, reduced γδ T cells characterized with effector functions, increased natural killer T cells with high levels of FCER1G in patients may suggest an association with disease development. Meanwhile, the peripheral inflammatory response was exacerbated in patients, accompanied by upregulation of exocytosis as well as increased levels of multiple lipids. We provide a comprehensive overview of the composition, gene profiles, and pathway signatures of CD3+ T cells driven by PD-1 inhibitor–induced myocarditis, as well as illustrate clinical features and multi-omic characteristics, providing a unique perspective on disease progression and therapy in clinical practice. We describe the peripheral immune mapping and multi-omics characteristics providing a unique perspective on disease progression and therapy in clinical practice. [ABSTRACT FROM AUTHOR]

Background: The pyrethroid deltamethrin (DM) is broadly used for insect control. Although DM hyperexcites neuronal networks by delaying inactivation of axonal voltage-dependent [Na.sup.+] channels, this mechanism is unlikely to mediate neurotoxicity at lower exposure levels during critical perinatal periods in mammals. OBJECTIVES: We aimed to identify mechanisms by which acute and subchronic DM altered axonal and dendritic growth, patterns of synchronous [Ca.sup.2+] oscillations (SCOs), and electrical spike activity (ESA) functions critical to neuronal network formation. METHODS: Measurements of SCOs using [Ca.sup.2+] imaging, ESA using microelectrode array (MEA) technology, and dendritic complexity using Sholl analysis were performed in primary murine cortical neurons from wild-type (WT) and/or ryanodine receptor 1 ([RyR1.sup.T4826I/T48261]) mice between 5 and 14 d in vitro (DIV). [[sup.3]H]ryanodine binding analysis and a single-channel voltage clamp were utilized to measure engagement of RyRs as a direct target of DM. Results: Neuronal networks responded to DM (30-70 nM) as early as 5 DIV, reducing SCO amplitude and depressing ESA and burst frequencies by 60-70%. DM (10-300 nM) enhanced axonal growth in a nonmonotonic manner. DM [greater than or equal to]100nM enhanced dendritic complexity. DM stabilized channel open states of RyR1, RyR2, and cortical preparations expressing all three isoforms. DM (30 nM) altered gating kinetics of RyR1 channels, increasing mean open time, decreasing mean closed time, and thereby enhancing overall open probability. SCO patterns from cortical networks expressing [RyR1.sup.T4826I/T48261] were more responsive to DM than WT. [RyR1.sup.T4826I/T48261] neurons showed inherently longer axonal lengths than WT neurons and maintained less length-promoting responses to nanomolar DM. Conclusions: Our findings suggested that RyRs were sensitive molecular targets of DM with functional consequences likely relevant for mediating abnormal neuronal network connectivity in vitro. https://doi.org/10.1289/EHP4583, Introduction Pyrethroids are synthetic insecticides that structurally mimic pyrethrins derived from the flower of Chrysanthemum sp. (Casida and Quistad 1998). Pyrethroids account for approximately 25% of the insecticidal market worldwide [...]

Purpose: The prognosis of diffuse‐type gastric cancer (DGC) is poorer than that of intestinal type, but S‐1 is a potential treatment option in DGC. This study explored the maximal tolerated dose (MTD) and the recommended dose for phase II study (RP2D) of nab‐paclitaxel combined with S‐1 (AS regimen) as adjuvant chemotherapy in stage III DGC. Methods: Patients with stage III DGC were recruited into this phase I dose‐escalation study between July 2019 and June 2020 in Zhongshan Hospital. Nab‐paclitaxel and S‐1 (80–120 mg/day, d1‐14, q3w) were administrated for 6 cycles, and then 8 cycles of S‐1 monotherapy were applied. The patients received nab‐paclitaxel at 180, 220, or 260 mg/m2 according to the 3 + 3 design based on dose‐limiting toxicity (DLT). The primary endpoint was RP2D. Secondary endpoints were the 1‐year disease‐free survival (DFS) rate and adverse events (AEs). Results: One case experienced DLT in 180‐mg/m2 dose group, subsequently three additional subjects were enrolled. DLT was not observed in the 220‐ and 260‐mg/m2 dose groups (both n = 3). Therefore, the MTD has not reached, and the RP2D of nab‐paclitaxel would be 260 mg/m2. Five participants showed progressive disease, with three and two participants in the 180‐ and 220‐mg/m2 dose groups, respectively. The 6‐, 12‐, and 18‐month DFS rates were 100%, 63.6%, and 50.9%, respectively. The most frequently observed AEs were neutropenia (83.3%) and leukopenia (66.7%). Conclusion: The RP2D of nab‐paclitaxel as adjuvant chemotherapy in DGC was 260 mg/m2. The AS regimen had a tolerable AE profile in stage III DGC. [ABSTRACT FROM AUTHOR]

Overuse of antibiotics has led to an increased threat of drug-resistant pathogens and sustained chronic infections, suggesting an urgent need for effective strategies against drug-resistant bacterial infections. Herein, we developed au gold nanorods coated with pH-responsive polymers (GNR-DPArPEGMA) for photothermal therapy against multidrug-resistant bacteria. The size and zeta potential of GNR-DPArPEGMA was 78 nm and −37.96 mV, respectively. In subacidic conditions, the nanocomposite surface was positively (14.18 mV) charged, leading to better bacterial adhesion and antibacterial efficiency. The nanocomposites showed augmented in vitro photothermal efficiency up to 70 °C under 808 nm irradiation for 3 min, which further demonstrated an enhanced photothermal bacteria-killing efficiency. The in vivo assays showed that GNR-DPArPEGMA irradiated with near-infrared radiation could treat a drug-resistant Staphylococcus aureus-caused subcutaneous abscess and drug-resistant Pseudomonas aeruginosa-caused pneumonia while reducing the number of bacteria and attenuating inflammation in the infected sites. These results indicate that the nanocomposites could be used as a potential photothermal agent to combat drug-resistant bacterial infections in the future. [ABSTRACT FROM AUTHOR]