Developing biomimetic nanoparticles without loss of the integrity of proteins remains a major challenge in cancer chemotherapy. Here, we develop a biocompatible tumor-cell-exocytosed ...exosome-biomimetic porous silicon nanoparticles (PSiNPs) as drug carrier for targeted cancer chemotherapy. Exosome-sheathed doxorubicin-loaded PSiNPs (DOX@E-PSiNPs), generated by exocytosis of the endocytosed DOX-loaded PSiNPs from tumor cells, exhibit enhanced tumor accumulation, extravasation from blood vessels and penetration into deep tumor parenchyma following intravenous administration. In addition, DOX@E-PSiNPs, regardless of their origin, possess significant cellular uptake and cytotoxicity in both bulk cancer cells and cancer stem cells (CSCs). These properties endow DOX@E-PSiNPs with great in vivo enrichment in total tumor cells and side population cells with features of CSCs, resulting in anticancer activity and CSCs reduction in subcutaneous, orthotopic and metastatic tumor models. These results provide a proof-of-concept for the use of exosome-biomimetic nanoparticles exocytosed from tumor cells as a promising drug carrier for efficient cancer chemotherapy.
•Non-invasive mALPS-index was closely related to the classical detected glymphatic clearance function, providing an alternative method in researches on glymphatic system.•WMHs, lacunas, microbleeds ...and EPVS in basal ganglia were related to glymphatic clearance function.•Glymphatic clearance function was related to cognitive function in CSVD patients.
Few studies have focused on the connection between glymphatic dysfunction and cerebral small vessel disease (CSVD), partially due to the lack of non-invasive methods to measure glymphatic function. We established modified index for diffusion tensor image analysis along the perivascular space (mALPS-index), which was calculated on diffusion tensor image (DTI), compared it with the classical detection of glymphatic clearance function calculated on Glymphatic MRI after intrathecal administration of gadolinium (study 1), and analyzed the relationship between CSVD imaging markers and mALPS-index in CSVD patients from the CIRCLE study (ClinicalTrials.gov ID: NCT03542734) (study 2). Among 39 patients included in study 1, mALPS-index were significantly related to glymphatic clearance function calculated on Glymphatic MRI ( r = -0.772~-0.844, p < 0.001). A total of 330 CSVD patients were included in study 2. Severer periventricular and deep white matter hyperintensities (β = -0.332, p < 0.001; β = -0.293, p < 0.001), number of lacunas (β = -0.215, p < 0.001), number of microbleeds (β = -0.152, p = 0.005), and severer enlarged perivascular spaces in basal ganglia (β = -0.223, p < 0.001) were related to mALPS-index. Our results indicated that non-invasive mALPS-index might represent glymphatic clearance function, which could be applied in clinic in future. Glymphatic clearance function might play a role in the development of CSVD.
Leaf senescence is essential for the growth and development of deciduous trees in the next season. Larix gmelinii, a deciduous coniferous tree, exhibits its most distinctive feature by turning yellow ...in the autumn and eventually shedding its leaves, resulting in significant changes in its appearance during the fall. Lysine acetylation plays an important role in diverse cellular processes; however, limited knowledge is available regarding acetylations in the needle senescence of L. gmelinii. In this study, the proteomics and acetylated modification omics of two phenotypic leaves, yellow and green (senescent and non-senescent) needles, were analyzed before autumn defoliation. In total, 5022 proteins and 4469 unique acetylation sites in 2414 lysine acylated proteins were identified, and this resulted in the discovery of 1335 differentially expressed proteins (DEPs) and 605 differentially expressed acetylated proteins (DAPs) in yellow versus green needles. There are significant differences between the proteome and acetylome; only 269 proteins were found to be DEP and DAP, of which 136 proteins were consistently expressed in both the DEP and DAP, 91 proteins were upregulated, and 45 proteins were down-regulated. The DEPs participate in the metabolism of starch and sucrose, while the DAPs are involved in glycolysis and the tricarboxylic acid cycle. Among them, DEPs underwent significant changes in glycolysis and citric acid cycling. Most of the enzymes involved in glycolysis and the citrate cycle were acetylated. DAPs were down-regulated in glycolysis and up-regulated in the citrate cycle. In all, the results of this study reveal the important role of lysine acetylation in the senescence of L. gmelinii needles and provide a new perspective for understanding the molecular mechanism of leaf senescence and tree seasonal growth.
Chronic kidney disease (CKD) affects 15% of the US adult population. However, most clinically available drugs for CKD show low bioavailability to the kidneys and non‐specific uptake by other organs ...which results in adverse side effects. Hence, a targeted, drug delivery strategy to enhance kidney drug delivery is highly desired. Recently, our group developed small, organic nanoparticles called peptide amphiphile micelles (PAM) functionalized with the zwitterionic peptide ligand, (KKEEE)3K, that passage through the glomerular filtration barrier for kidney accumulation. Despite high bioavailability to the kidneys, these micelles also accumulated in the liver to a similar extent. To further optimize the physicochemical properties and develop design rules for kidney‐targeting micelles, we synthesized a library of PAMs of varying size, charge, and peptide repeats. Specifically, variations of the original (KKEEE)3K peptide including (KKEEE)2K, (KKEEE)K, (EEKKK)3E, (EEKKK)2E, (EEKKK)E, KKKKK, and EEEEE were functionalized onto nanoparticles, and peptide surface density and PEG linker molecular weight were altered. After characterization with transmission electron microscopy (TEM) and dynamic light scattering (DLS), nanoparticles were intravenously administered into wildtype mice, and biodistribution was assessed through ex vivo imaging. All micelles localized to the kidneys, but nanoparticles that are positively‐charged, close to the renal filtration size cut‐off, and consisted of additional zwitterionic peptide sequences generally showed higher renal accumulation. Upon immunohistochemistry, micelles were confirmed to bind to the multiligand receptor, megalin, and histological analyses showed no tissue damage. Our study provides insight into the design of micelle carriers for kidney targeting and their potential for future therapeutic application.
Wall-associated kinases comprise a sub-family of receptor-like kinases that function in plant growth and stress responses. Previous studies have shown that the rice wall-associated kinase, OsWAK25, ...interacts with a diverse set of proteins associated with both biotic and abiotic stress responses. Here, we show that wounding and BTH treatments induce OsWAK25 transcript expression in rice. We generated OsWAK25 overexpression lines and show that these lines exhibit a lesion mimic phenotype and enhanced expression of rice NH1 (NPR1 homolog 1), OsPAL2, PBZ1 and PR10. Furthermore, these lines show resistance to the hemibiotrophic pathogens, Xanthomonas oryzae pv. oryzae (Xoo) and Magnaporthe oryzae, yet display increased susceptibility to necrotrophic fungal pathogens, Rhizoctonia solani and Cochliobolus miyabeanus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal tumors arising from perivascular epithelial cells. There was no standard treatment for unresectable PEComa before 2021. For a low ...incidence and a rarely curable disease, development of new therapy is essential. A 45-year-old female was diagnosed with malignant renal PEComa (likely with
TFE3
rearrangement) that underwent rapid progression after 10 months of surgery. The patient then received the tyrosine kinase inhibitor (TKI) Apatinib, and the tumor remained stable for 15 months before another progression. The patient then received the MTOR inhibitor everolimus that alleviated her symptoms but the tumor went into remission again after another 15 months. This result suggests that antagonizing the vascular endothelial growth factor receptor (VEGFR) pathway be a useful strategy for malignant PEComas, along with the MTOR pathway inhibition that had recently been approved for the rare tumor.
Background
Non‐small‐cell lung cancer (NSCLC) is the primary cause of brain metastases (BM). This study aimed to investigate differences in clinical and magnetic resonance imaging (MRI) features of ...BM between anaplastic lymphoma kinase (ALK) gene fusion (ALK+) and ALK wild‐type (ALK‐) NSCLC, and to preliminarily assess the efficacy of radiotherapy for treating BM.
Methods
A retrospective analysis included 101 epidermal growth factor receptor (EGFR)‐ NSCLC patients with BM: 41 with ALK gene fusion and 60 being ALK‐. The brain MRI and clinical features were compared between different ALK status using the multivariate analysis, and a nomogram was constructed to predict ALK gene fusion. Fifty‐six patients who did not undergo cerebral surgery and had complete pre‐ and post‐ treatment data were further divided based on whether they received radiotherapy. Log‐rank test was used to compare the short‐term effect of treatment between the two groups under different genotypes.
Results
ALK+ BM exhibited decreased peritumoral brain edema size, lower peritumoral brain edema index (PBEI), and a more homogeneous contrast enhancement pattern compared to ALK‐ BM. Age (OR = 1.04; 95%CI: 1.02–1.06), time to BM (OR = 1.50; 95% CI: 1.04–2.14), PBEI (OR = 1.26; 95% CI: 0.97–1.62), smoking status (smoking index >400 vs. non‐smoking status: OR = 1.42; 95% CI: 0.99–2.04) and contrast enhancement pattern (OR = 1.89; 95% CI: 1.28–2.78) were associated with ALK gene fusion. A nomogram based on these variables demonstrated acceptable predictive efficiency (AUC = 0.844). In the ALK+ group, patients who received radiotherapy did not show increased disease control rate (DCR) or progression‐free survival (PFS). In contrast, in the ALK‐ group, those who received radiotherapy had improved objective response rate (ORR), DCR, and PFS compared to those who were only treated with systemic therapy.
Conclusions
The clinical and MRI features of BM can indicate the status of ALK in NSCLC. In the ALK‐ group, patients who received radiotherapy showed higher ORR, DCR, and PFS compared to those who did not.
Acquired immune deficiency syndrome (AIDS), hepatitis B virus (HBV), hepatitis C virus (HCV), gonorrhea and syphilis are the major sexually transmitted diseases (STDs) in the world, which are the ...focus of epidemic prevention and control in China. The epidemiological trend analysis of STDs in Shanghai could reflect the epidemic situation of these diseases in high-income areas of China, providing a reference for how to control their epidemic. Although the overall incidence rate of infectious diseases levelled off after 2009, Shanghai still faces many new obstacles in the fight against STDs. Without effective prevention and control strategies for high-risk behaviors, such as active sexual activity without protection, for key susceptible populations, there may be a more serious epidemic of STDs in the future. Given these situations, strategies for controlling STDs in Shanghai should be more targeted with the development of epidemics, focusing on the following key areas for future work: i) attaching importance to health education; ii) strengthening epidemic surveillance; and iii) developing Community Health Service Centers (CHSC) as intervention subjects.
High-temperature and drought events significantly impact crop growth and development. In the soybean-producing region of the Guanzhong Plain in China, understanding the dynamics of these climatic ...phenomena is vital for soybean yield preservation. Through a fixed-position observation experiment that analyzed four growth stages, nine agronomic traits, and soybean yield per unit area from 1998 to 2023, this research evaluated the characteristics of high-temperature and drought processes in various growth stages. It also examined the influence of high-temperature processes, drought processes, and their combined effects on agronomic traits and yield. The results indicate the following: (1) High temperature was a constant factor during the soybean growth period, with temperature-related indices markedly surpassing those related to drought. Notably, the occurrence of high-temperature and drought events was more prevalent during the flowering–podding stage than at the podding or grain-filling stages. (2) High temperature profoundly affected soybean yield components, primarily through a decrease in the number of grains per plant during the flowering–podding stage, subsequently impacting the grain weight per plant and yield. In years with extremely high temperatures, the soybean plant height was reduced by 6.1 to 15 cm, the main stem node number decreased by 0.1 to 2.9, the branch number decreased by 0.2 to 0.6, the number of pods per plant decreased by 4.8 to 13.7, the number of grains per pod decreased by 0.1 to 0.3, the number of grains per plant decreased by 13.5 to 32.6, the grain weight per plant decreased by 3.8 to 6.9 g, and the 100-grain weight decreased by 0.1 to 4.5 g. The common impact of high temperature combined with drought processes in different growth stages was reflected in the reduction in the number of branches by 0.1 to 1.4 and the reduction in the number of grains per pod by 0.02 to 13.7. This study underscores the importance of addressing the quantitative effects of climate change and extreme weather on soybean yield, which could help to develop effective adaptation and mitigation strategies.
Introduction: Trimethylamine N-oxide (TMAO) is a metabolite produced by gut bacteria. Although increased TMAO levels have been linked to hypertension (HTN) and chronic kidney disease (CKD) with poor ...prognosis, no clinical studies have directly addressed the relationship between them. In this study, we investigated the relationship between TMAO and renal dysfunction in hypertensive patients. Methods: We included healthy controls (n = 50), hypertensive patients (n = 46), and hypertensive patients with renal dysfunction (n = 143). Their blood pressure values were taken as the highest measured blood pressure. Renal function was evaluated using the estimated glomerular filtration rate. Plasma TMAO levels were measured using high-performance liquid chromatography tandem mass spectrometry. Results: We found significant differences in plasma TMAO levels among the 3 groups (p < 0.01). The plasma TMAO of patients with HTN was significantly higher than that of healthy people, and the plasma TMAO of patients with HTN complicated by renal dysfunction was significantly higher than either of the other groups. Patients in the highest TMAO quartile were at a higher risk of developing CKD stage 5 than those in the lowest quartile. In the receiver operating characteristic curve, the area under the curve of TMAO combined with β 2-macroglobulin for predicting renal dysfunction in patients with HTN was 0.85 (95% confidence interval 0.80–0.90). Conclusion: An elevated TMAO level reflects higher levels of HTN and more severe renal dysfunction. TMAO, combined with β 2-macroglobulin levels, may assist in diagnosing CKD in hypertensive patients. Plasma TMAO has predictive value for early kidney disease in hypertensive patients.
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