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Cryptococcosis is frequently found in immunosuppressed patients. It is also a significant opportunistic infection in non-immunocompromised individuals. In this study, we present a rare case of membranous nephropathy (MN) with pulmonary cryptococcosis. A 33-year-old man with MN was referred to our hospital because of dyspnea and weakness for 1 week. Before the above symptoms occurred, the dose of Cyclosporin A was increased again for relapse of MN. Multiple massive or patchy high-density shadows were present on computed tomography of the lung. Initially the patient underwent empirical anti-bacterial therapy, which turned out to be ineffective. As the results of serum cryptococcal latex agglutination tests were positive, the administration of anti-fungal drugs was prescribed. The results of fungal culture and pathologic examination of the lung tissue revealed the findings consistent with Cryptococcus neoformans. The patient was successfully treated with voriconazole followed by fluconazole with satisfactory result. Therefore, in patients with chronic kidney disease, lung lesions with poor bactericidal effects of cephalosporins need further examination to make sure whether there is pulmonary cryptococcosis. Early diagnosis and treatment might contribute to good results. It is a problem worthy of consideration that whether immunosuppressive agents need to be discontinued or not during antifungal therapy.

During tumor expansion, breast cancer (BC) cells often experience reactive oxygen species accumulation and mitochondrial damage because of glucose shortage. However, the mechanism by which BC cells deal with the glucose-shortage-induced oxidative stress remains unclear. Here, we showed that MANF (mesencephalic astrocyte derived neurotrophic factor)-mediated mitophagy facilitates BC cell survival under glucose-starvation conditions. MANF-mediated mitophagy also promotes fatty acid oxidation in glucose-starved BC cells. Moreover, during glucose starvation, SENP1-mediated de-SUMOylation of MANF increases cytoplasmic MANF expression through the inhibition of MANF's nuclear translocation and hence renders mitochondrial distribution of MANF. MANF mediates mitophagy by binding to PRKN (parkin RBR E3 ubiquitin protein ligase), a key mitophagy regulator, in the mitochondria. Under conditions of glucose starvation, protein oxidation inhibits PRKN activity; nevertheless, the CXXC motif of MANF alleviates protein oxidation in RING II-domain of PRKN and restores its E3 ligase activity. Furthermore, MANF-PRKN interactions are essential for BC tumor growth and metastasis. High MANF expression predicts poor outcomes in patients with BC. Our results highlight the prosurvival role of MANF-mediated mitophagy in BC cells during glucose starvation, suggesting MANF as a potential therapeutic target. Abbreviation: 2DG, 2-deoxy-D-glucose; 5TG, 5-thio-D-glucose; ACSL4/FACL4, acyl-CoA synthetase long chain family member 4; Baf A1, bafilomycin A1; BRCA, breast cancer; CHX, cycloheximide; DMF, distant metastasis-free; DMFS, distant metastasis-free survival; ECM, extracellular matrix; ER, endoplasmic reticulum; ERS, endoplasmic reticulum stress; F-1,6-BP, fructose-1,6-bisphosphate; FAO, fatty acid oxidation; GSH, reduced glutathione; GSVA, gene set variation analysis; HCC, hepatocellular carcinoma; ICC, intrahepatic cholangiocarcinoma; IF, immunofluorescence; MANF, mesencephalic astrocyte derived neurotrophic factor; Mdivi-1, mitochondrial division inhibitor 1; MFI, mean fluorescence intensity; NAC, N-acetyl-L-cysteine; OCR, oxygen-consumption rate; OS, overall survival; PMI, SQSTM1/p62-mediated mitophagy inducer; PPP, pentose phosphate pathway; PRKN, parkin RBR E3 ubiquitin protein ligase; RBR, RING in between RING; RFS, relapse-free survival; ROS, reactive oxygen species; SAPLIPs, saposin-like proteins; TCGA, The Cancer Genome Atlas; TNBC, triple-negative breast cancer; WT, wild type. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is a common malignancy that affects women worldwide. Although transducing beta‐like 2 (TBL2), a member of the WD40 repeat protein family, has been implicated in various intracellular signaling pathways, its precise function in BC remains unclear. The expression of TBL2 is analyzed using real‐time PCR, western blotting, and immunohistochemistry in BC patient specimens. Kaplan–Meier survival analysis is employed to assess its prognostic significance. Proteomic analysis, immunoprecipitation tests, and protein immunoblotting are employed to examine the impact of TBL2 on AKT phosphorylation activation. The findings reveal selective overexpression of TBL2 in BC, correlating significantly with various clinicopathological characteristics and poor survival outcomes in patients with BC. Through in vivo and in vitro experiments, it is observed that TBL2 suppression inhibits BC cell proliferation, while TBL2 overexpression has the opposite effect. Mechanistically, TBL2 is identified as a scaffolding protein that promotes PRMT5 and WDR77 interaction. This interaction enhances the methyltransferase activity of PRMT5, leading to increased AKT phosphorylation activation and promotion of breast cancer cell proliferation. In conclusion, this study uncovers a novel function of TBL2 in the activation of AKT by PRMT5 and suggests TBL2 as a potential therapeutic target for BC treatment. [ABSTRACT FROM AUTHOR]

Background: Intranasal administration is a convenient route for drug delivery that can be applied for procedural sedation. However, there is currently limited exploration into fixed dosing regimens. This study was to investigate the pharmacokinetics (PK), pharmacodynamics (PD), bioavailability (BA) and safety of dexmedetomidine after fixed doses of intranasal and intravenous administration in healthy male and female subjects. Methods: Group A subjects received intranasal or intravenous administration in two periods (12 subjects received intranasal dexmedetomidine (Dex) or the intravenous formulation, and four received the corresponding placebo). Groups B to F underwent single-period dose ascending, receiving only the intranasal Dex formulation or the corresponding placebo (the number of subjects receiving the drug/placebo in groups B to F were 12/2, 12/2, 12/2, 10/2, 10/2, respectively), with doses of 75 μg, 125 μg, 150 μg, 175 μg, and 200 μg, respectively. After administration of each group, blood samples were collected to investigate the plasma concentration of dexmedetomidine, adrenaline and noradrenaline using a HPLC-MS/MS method. Ramsay score, blood pressure and heart rate were collected for safety evaluation. Pharmacokinetic parameters (Cmax, Tmax, AUC0-24h, AUC 0 – ∞ , and t1/2) of dexmedetomidine were calculated. Results: A total of 82 subjects were randomized. One subject withdrew for personal reasons before administration and the other subjects completed the entire study process. At a dose of 25 μg, the absolute bioavailability was 59%. Across the dose range of 25 to 200 μg, the median Tmax was similar (0.5–1 h), and the mean elimination half-life was comparable (3.09–4.28 h), with exposure (Cmax and AUC0-t) increasing with dose. The pharmacokinetics after intranasal spray administration exhibited linear characteristics, although Cmax was similar in the higher dose groups (175 μg and 200 μg). PD results showed that ideal sedation effects (Ramsay score of 3 or higher in at least 90% of subjects) could be achieved within 30 min following intranasal administration of 75 μg or higher doses. All the subjects were well tolerated without any serious adverse events (SAEs). Conclusion: Dexmedetomidine nasal spray was well tolerated and achieved satisfactory sedation in the dose range of 25–200 μg in Chinese healthy male and female subjects. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, identifier CTR20201650 [ABSTRACT FROM AUTHOR]

This paper presents an event-triggered sliding mode fault-tolerant control method for networked control systems with actuator faults and external disturbance. First, an event-triggered scheme in the networked control systems is proposed to reduce the number of data transmission. In addition, considering the event-triggering, a sliding mode surface based on the system structure is constructed. Besides, to obtain the controller parameters that meet the H ∞ performance, the bounded real lemma in the form of linear matrix inequality is obtained using the Lyapunov functional. In addition, a sliding mode fault-tolerant control is designed to guarantee that the system can still run stably under the condition of faults and disturbances. Finally, the simulation results of gas turbine system are given to verify the feasibility of the theoretical method. [ABSTRACT FROM AUTHOR]

We developed and validated a sensitive, heart-cutting, two-dimensional liquid chromatography–tandem mass spectrometry (2D-LC‒MS/MS) method to determine the concentration of mometasone furoate in human plasma after nasal spray administration. Isotopically labeled mometasone furoate-13C,d6 was used as an internal standard (IS). Plasma samples were prepared using a solid-phase extraction (SPE) method. With this 2D-LC strategy, the analytes were trapped in the first dimension (1D) column, and only judiciously selected portions of the 1D effluent were transferred to the second dimension (2D) column for further separation to obtain high-resolution information. MS/MS quantification was performed in positive ionization mode via multiple-reaction monitoring (MRM). This analytical method was fully validated according to related regulatory guidance, and the results showed that the method is robust and sensitive enough for pharmacokinetic investigation of mometasone furoate with satisfactory linearity from 0.25 to 30 pg mL−1. This method was successfully applied to a bioequivalence (BE) study of mometasone furoate aqueous nasal sprays in healthy volunteers. [ABSTRACT FROM AUTHOR]