Supramolecular coordination platinum metallacycle-based multilevel wound dressing for bacteria sensing and wound healing.

The exploitation of novel wound healing methods with real-time infection sensing and high spatiotemporal precision is highly important for human health. Pt-based metal-organic cycles/cages (MOCs) have been employed as multifunctional antibacterial agents due to their superior Pt-related therapeutic efficiency, various functional subunits and specific geometries. However, how to rationally apply these nanoscale MOCs on the macroscale with controllable therapeutic output is still challenging. Here, a centimeter-scale Pt MOC film was constructed via multistage assembly and subsequently coated on a N,N'-dimethylated dipyridinium thiazolo[5,4-d]thiazole (MPT)-stained silk fabric to form a smart wound dressing for bacterial sensing and wound healing. The MPT on silk fabric could be used to monitor wound infection in real-time through the bacteria-mediated reduction of MPT to its radical form via a color change. The MPT radical also exhibited an excellent photothermal effect under 660 nm light irradiation, which could not only be applied for photothermal therapy but also induce the disassembly of the Pt MOC film suprastructure. The highly ordered Pt MOC film suprastructure exhibited high biosafety, while it also showed improved antibacterial efficiency after thermally induced disassembly. In vitro and in vivo studies revealed that the combination of the Pt MOC film and MPT-stained silk can provide real-time information on wound infection for timely treatment through noninvasive techniques. This study paves the way for bacterial sensing and wound healing with centimeter-scale metal-organic materials.

Chaotropic Effect-Induced Sol-Gel Transition and Radical Stabilization for Bacterially Sensitive Near-Infrared Photothermal Therapy.

Deep-seated bacterial infections (DBIs) are stubborn and deeply penetrate tissues. Eliminating deep-seated bacteria and promoting tissue regeneration remain great challenges. Here, a novel radical-containing hydrogel (SFT-B Gel) cross-linked by a chaotropic effect was designed for the sensing of DBIs and near-infrared photothermal therapy (NIR-II PTT). A silk fibroin solution stained with 4,4',4″-(1,3,5-triazine-2,4,6-triyl)tris(1-methylpyridin-1-ium) (TPT3+) was employed as the backbone, which could be cross-linked by a closo-dodecaborate cluster (B12H122-) through a chaotropic effect to form the SFT-B Gel. More interestingly, the SFT-B Gel exhibited the ability to sense DBIs, which could generate a TPT2+• radical with obvious color changes in the presence of bacteria. The radical-containing SFT-B Gel (SFT-B★ Gel) possessed strong NIR-II absorption and a remarkable photothermal effect, thus demonstrating excellent NIR-II PTT antibacterial activity for the treatment of DBIs. This work provides a new approach for the construction of intelligent hydrogels with unique properties using a chaotropic effect.

miR-34a/TAN1/CREB Axis Engages in Alleviating Oligodendrocyte Trophic Factor-Induced Myelin Repair Function and Astrocyte-Dependent Neuroinflammation in the Early Stages of Alzheimer's Disease: The Anti-Neurodegenerative Effect of Treadmill Exercise.

Reduced myelin stability observed in the early stages of Alzheimer's disease leads to spatial learning and memory impairment. Exercise has been shown to protect nerves, reduce the risk of Alzheimer's disease, and strengthen synaptic connectivity. However, the underlying mechanisms of how exercise can promote myelin repair and coordinate inflammation and proliferation are still uncertain. In this study, we conducted histological and biochemical assays of cortical lysates after behavioral testing to detect pathological changes, myelin sheath thickness, and mRNA and protein levels. It is notable that D-galactose model mice exhibited elevated miRNA-34a levels, overactive astrocytes, decreased myelin staining scores, increased apoptosis, and decreased synaptic plasticity in the brain. Significantly, after eight weeks of exercise, we observed improvements in LFB scores, NeuN( +) neuron counts, and myelin basic protein (MBP) expression. Additionally, exercise promoted the expression of oligodendrocyte markers Olig2 and PDFGR-α associated with brain proliferation, and improved spatial cognitive function. Furthermore, it decreased the inflammation caused by astrocyte secretions (TNF-α, Cox-2, CXCL2). Interestingly, we also observed downregulation of miR-34a and activation of the TAN1/PI3K/CREB signaling pathway. Our data shed light on a previously unsuspected mechanism by which exercise reduces miR-34a levels and protects neuronal function and survival by preventing excessive demyelination and inflammatory infiltration in the CNS.

Desulfurative Functionalization of ß-Acyl Allylic Sulfides with N-H Free Indoles Highly Regioselective at C3 and N1 Positions: Rapid Access to α-Branched Enones.

A regiodivergent allylation of 1H-indoles highly selectively at the C3 and N1 positions with ß-acyl allylic sulfides through desulfurative C-C/C-N bond-forming reactions has been developed under mild conditions. Notably, the remarkable site-selective switch can be achieved by a delicate choice of solvents and bases. This cost-efficient method displays a broad substrate scope, good functional compatibility, and excellent site-selectivity, thus offering a divergent synthesis of indole substituted α-branched enones, which possess diverse potential opportunities for further applications and derivatization.

Prevalence and unfavorable outcome of frailty in older adults with gastric cancer: a systematic review and meta-analysis.

BACKGROUND AND AIM: Previous studies reported inconsistent results on the prevalence and prognostic implications of frailty among older adults with gastric cancer. This systematic review synthesized available literature pertaining on this topic to establish the prevalence and unfavorable outcomes of frailty in older adults with gastric cancer. METHODS: A comprehensive search was conducted across multiple English databases including PubMed, Cochrane Library, CINAHL, Embase, and Web of Science as well as Chinese databases, namely, CNKI, Wan Fang, and CBM, from inception to July 4, 2023, to identify potential studies. Data related to the incidence of frailty and its unfavorable outcomes in older adults with gastric cancer were extracted. RevMan5.3 and R 4.2.2 were used to evaluate pooled prevalence, hazard ratios (HR), and 95% confidence interval (CI). RESULTS: This review comprehensively selected 13 studies, comprising 9 cohort studies and 4 cross-sectional studies, on 44,117 older adults diagnosed with gastric cancer. The incidence of frailty among older adults with gastric cancer ranged from 10 to 71%. The pooled prevalence of frailty was 29% (95% CI 0.21-0.39). Frailty was found to be associated with an elevated risk of postoperative complications (HR = 1.99, 95% CI 1.45-2.73), prolonged postoperative hospital stay (HR = 2.68, 95% CI 2.38-3.02), likelihood of readmission (HR = 3.28, 95% CI 1.77-6.08), and an increased mortality risk (HR = 1.60, 95% CI 1.36-1.90). CONCLUSIONS: Frailty was associated with a poor prognosis in older adults with gastric cancer. Clinical medical staff should focus on the frailty of older adults with gastric cancer, conduct large-scale, multicenter, and prospective studies and early screening of patients, and provide guidance for the implementation of prevention and treatment strategies.

Pharmacokinetic/pharmacodynamic evaluation of gamithromycin against rabbit pasteurellosis.

BACKGROUND: Gamithromycin is an effective therapy for bovine and swine respiratory diseases but not utilized for rabbits. Given its potent activity against respiratory pathogens, we sought to determine the pharmacokinetic profiles, antimicrobial activity and target pharmacokinetic/pharmacodynamic (PK/PD) exposures associated with therapeutic effect of gamithromycin against Pasteurella multocida in rabbits. RESULTS: Gamithromycin showed favorable PK properties in rabbits, including high subcutaneous bioavailability (86.7 ± 10.7%) and low plasma protein binding (18.5-31.9%). PK analysis identified a mean plasma peak concentration (Cmax) of 1.64 ± 0.86 mg/L and terminal half-life (T1/2) of 31.5 ± 5.74 h after subcutaneous injection. For P. multocida, short post-antibiotic effects (PAE) (1.1-5.3 h) and post-antibiotic sub-inhibitory concentration effects (PA-SME) (6.6-9.1 h) were observed after exposure to gamithromycin at 1 to 4× minimal inhibitory concentration (MIC). Gamithromycin demonstrated concentration-dependent bactericidal activity and the PK/PD index area under the concentration-time curve over 24 h (AUC24h)/MIC correlated well with efficacy (R2 > 0.99). The plasma AUC24h/MIC ratios of gamithromycin associated with the bacteriostatic, bactericidal and bacterial eradication against P. multocida were 15.4, 24.9 and 27.8 h in rabbits, respectively. CONCLUSIONS: Subcutaneous administration of 6 mg/kg gamithromycin reached therapeutic concentrations in rabbit plasma against P. multocida. The PK/PD ratios determined herein in combination with ex vivo activity and favorable rabbit PK indicate that gamithromycin may be used for the treatment of rabbit pasteurellosis.

[Research progress of non-coding RNA involved in glycolysis regulation of hepatocellular carcinoma].

Liver cancer is a common tumor of digestive system. Hepatocellular carcinoma (HCC) is a common type of liver cancer, which has a high degree of malignancy and ranks among the top causes of cancer-related death in the world. Metabolic reprogramming is considered to be an important marker of carcinogenesis. Glucose metabolism is one of the main ways for cells to produce energy. Glycolysis, as the basic reaction of glucose metabolism, plays an important role in cell metabolism. Therefore, the regulation of glycolysis is of great significance to the proliferation and evolution of tumors. More and more non-coding RNAs (ncRNA) have been proved to play an important role in the regulation of tumor glycolysis. This article reviews the role of ncRNA in the regulation of HCC glycolysis and its related mechanisms. At the same time, the prospect of targeted therapy for HCC based on the related mechanisms of glycolysis regulation is put forward.

Correlation between PRDX2 and spermatogenesis under oxidative stress.

BACKGROUND: Obesity is one of the world's diseases that endanger human health, causing systemic inflammation caused by excessive reactive oxygen damage. An increase in the proportion of obese people with reduced sperm motility has been reported. But the mechanism behind it remains unclear. Peroxiredoxin 2 (PRDX2) is a member of the peroxidase family that effectively removes hydrogen peroxide. This study is to clarify the expression of PRDX2 in the testes of obese mice and lay a foundation for further exploration of the regulatory and protective effects of PRDX2 on spermatogenesis. METHOD: A model of high-fat-induced obesity in animals was constructed, and the expression of PRDX2 in the testes of the two groups was detected by immunohistochemistry, western blotting, immunofluorescence and other techniques. Hydrogen peroxide (H2O2) and cholesterol were co-cultured in testicular support cells for 48 h to observe the expression of PRDX2. RESULT: PRDX2 expression was reduced in the testes of the obese group, and immunohistochemistry showed that it was mainly localized to supporting cells. H2O2 inhibits the expression of PRDX2 in Sertoli cells, and high cholesterol upregulates the expression of PRDX2 in Sertoli cells. CONCLUSION: PRDX2 has some antioxidant properties against changes in the testicular environment caused by HFD. And under short-term oxidative stress to enhance its antioxidant capacity. PRDX2 may be involved in maintaining the oxidative balance of the spermatogenesis environment.

Eletrocarboxylation Reactions Using CO2 Both as Promoter and Carboxylative Reagent.

Electrocarboxylation reaction, which employs organic electrosynthesis to achieve the utilization of CO2 as a carboxylative reagent, provides a powerful and efficient tool for the preparation of organic carboxylic acid. In some electrocarboxylation reactions, CO2 also acts as a promoter to facilitate the desired reaction. This concept mainly highlights recent CO2 -promoted electrocarboxylation reactions via CO2 ⋅- intermediate or transiently protective carboxylation of active intermediate with CO2 .

Halomonas dongshanensis sp. nov., isolated from the seawater of Dongshan Island.

A taxonomic study was carried out on strain yzlin-01T, isolated from Dongshan Island seawater. The bacterium was Gram-stain-negative, catalase-positive, oxidase-negative, rod-shaped, and motile by polar flagella. Growth was observed at temperatures of 10-40 °C, at salinities of 0.5-18 %, and at pH of 6-10. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain yzlin-01T belonged to the genus Halomonas, with the highest sequence similarity to Halomonas malpeensis YU-PRIM-29T (96.7 %), followed by Halomonas johnsoniae T68687T (96.4 %) and Halomonas gomseomensis M12T (96.4 %), and other species of the genus Halomonas (93.4-96.3 %). The ANI and digital DNA-DNA hybridization estimate values between strain yzlin-01T and the closest type strain Halomonas malpeensis YU-PRIM-29T were 77.44 and 21.6 %, respectively. The principal fatty acids were summed feature 8 (consisting of C18 : 1 ω7c and/or C18 : 1 ω6c; 55.7 %), C16 : 0 (20.6 %), C12 : 0 3-OH (6.8 %), summed feature 3 (consisting of C16 : 1 ω7c and/or C16 : 1 ω6c; 5.1 %). The G+C content of the chromosomal DNA was 60.0 mol %. The respiratory quinone was identified as Q-9 (100 %). Phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, aminophospholipid, and three unidentified phospholipids were present. Combined genotypic and phenotypic data suggest that strain yzlin-01T represents a novel species within the genus Halomonas, for which the name Halomonas dongshanensis sp. nov. is proposed, with the type strain yzlin-01T (=GDMCC 1.3202T=KCTC 92467T).

Electroreductive Ring-Opening Carboxylation of Cycloketone Oxime Esters with Carbon Dioxide.

Electroreductive ring-opening carboxylation of cycloketone oxime esters with atmospheric carbon dioxide is reported. This reaction proceeded under simple constant current conditions in an undivided cell using glassy carbon as the cathode and magnesium as the sacrificial anode, providing substituted γ- and δ-cyanocarboxylic acids in moderate to good yields. Electrochemically generated cyanoalkyl radicals and cyanoalkyl anion are proposed as the key intermediates.

Epidemiological characteristics and spatiotemporal analysis of mumps at township level in Wuhan, China, 2005-2019.

The resurgence and outbreaks of mumps occur frequently in many countries worldwide in recent years, even in countries with high vaccination coverage. In this study, a descriptive and spatiotemporal clustering analysis at the township level was conducted to explore the dynamic spatiotemporal aggregation and epidemiological characteristics of mumps in Wuhan. During 2005 and 2019, there were 40 685 cases reported in Wuhan, with an average annual morbidity of 28.11 per 100 000 populations. The morbidity showed a fluctuating tendency, and peaked in 2010 and 2018. Bimodal seasonality was found, with a large peak between May and July, and a mild peak from November to January in the following year. Male students aged 5-9-year-old were the main risk group of mumps infection. Significant global spatial auto-correlation was detected except in 2007, 2009 and 2015. The spatial and temporal scan statistics indicated that the hot-spots mainly located at the western and southern areas of Wuhan with variations almost every year. Our findings could assist the public health authorities to develop and improve targeted health strategies, and allocate health resources rationally.

A cross-sectional study reveals a chronic low-grade inflammation in achalasia.

BACKGROUND AND AIM: Immune-mediated neuroinflammation has been proposed to underlie the loss of lower esophageal sphincter (LES) myenteric neurons in achalasia. However, the immune status and key pathogenic immune subpopulations remain unclear. This study aims to evaluate the inflammatory status of patients with achalasia and their correlation with clinical characteristics, and further explore the key pathogenic subpopulations. METHODS: We investigated the complete blood cell count and inflammatory markers in a large population of patients with achalasia (n = 341) and healthy controls (n = 80). The subpopulations of lymphocytes were analyzed by flow cytometry. Immunofluorescence was used to determine immune cell infiltration in the LES. Transcriptome changes of the key subpopulation were determined by RNA sequencing analysis. RESULTS: NLR, MLR, CRP, globulin, IL-6 and IL-10 were significantly elevated in patients with achalasia. MLR and globulin were positively correlated with disease duration. The absolute count and percentage of CD8+ T cells in peripheral blood and its infiltration around ganglion in the LES were significantly increased in achalasia. Transcriptome analysis indicated that CD8+ T cells were activated and proliferative. In addition to multiple inflammatory pathways, regulation of neuroinflammatory response pathway was also significantly up-regulated in achalasia. GSEA analysis revealed a close association with autoimmune diseases. CONCLUSIONS: Patients with achalasia suffered from chronic low-grade inflammation with dysregulated immune cells and mediators associated with disease duration. CD8+ T cells might be the key pathogenic subpopulation of achalasia. Our results provide an important immune cell signature of the pathogenesis of achalasia.

Liver cirrhosis and tumor location can affect the range of intrahepatic microwave ablation zone.

BACKGROUND: The range of an ablation zone (AZ) plays a crucial role in the treatment effect of microwave ablation (MWA). The aim of this study was to analyze the factors influencing the AZ range. METHODS: Fourteen factors in four areas were included: patient-related factors (sex, age), disease-related factors (tumor location, liver cirrhosis), serological factors (ALT, AST, total protein, albumin, total bilirubin, direct bilirubin, and platelets), and MWA parameters (ablation time, power, and needle type). Multiple sequence MRI was used to delineate AZ by three radiologists using 3D Slicer. MATLAB was used to calculate the AZ length, width, and area of the largest section. Linear regression analysis was used to analyze influencing factors. Moreover, a subgroup analysis was conducted for patients with viral hepatitis. RESULT: 220 patients with 290 tumors were included between 2010-2021. In addition to MWA parameters, cirrhosis and tumor location were significant factors that influenced AZ (p < 0.001). The standardized coefficient (beta) of cirrhosis (cirrhosis vs. non-cirrhosis) was positive, which meant cirrhosis would lead to a decrease in AZ range. The beta of tumor location (near the hepatic hilar zone, intermediate zone, and periphery zone) was negative, indicating that AZ range decreased as the tumor location approached the hepatic hilum. For viral hepatitis patients, Fibrosis 4 (FIB4) score was a significant factor influencing AZ (p < 0.001), and the beta was negative, indicating that AZ range decreased as FIB4 increased. CONCLUSION: Liver cirrhosis, tumor location, and FIB4 affect the AZ range and should be considered when planning MWA parameters.

Identification and functional study of AA11 family polysaccharide monooxygenase genes in filamentous fungus Podospora anserina.

The lytic polysaccharide monooxygenase (LPMO) in the auxiliary active protein family (AA family) catalyzes the oxidative depolymerization of various refractory carbohydrates including cellulose, chitin and starch. While accumulating studies investigate the enzymology of LPMO, the research on the inactivation of LPMO genes has been rarely explored. In this study, five LPMO genes PaLPMO11A (Pa_4_4790), PaLPMO11B (Pa_1_5310), PaLPMO11C (Pa_2_7840), PaLPMO11D (Pa_2_8610) and PaLPMO11E (Pa_3_9420) of the AA11 family in the filamentous fungus Podospora anserina were knocked out by homologous recombination. Single mutants ΔPaLPMO11A (ΔA), ΔPaLPMO11B (ΔB), ΔPaLPMO11C (ΔC), ΔPaLPMO11D (ΔD) and ΔPaLPMO11E (ΔE) were constructed, and then all polygenic mutants were constructed via genetic crosses. The differences in the growth rate and sexual reproduction between wild type and mutant strains were observed on different carbon source media. The alteration of oxidative stress and cellulose degradation ability were found on DAB and NBT staining and cellulase activity determination. These results implicated that LPMO11 genes play a key role in the growth, development, and lignocellulose degradation of P. anserina. The results showed that the spore germination efficiency, growth rate and reproductive capacity of mutant strains including ΔBΔCΔE, ΔAΔBΔCΔE, ΔAΔCΔDΔE and ΔAΔBΔCΔDΔE was significantly decreased on different cellulose carbon sources and the remaining strains have no difference. The reduced utilization of various carbon sources, the growth rate, the spore germination rate, the number of fruiting bodies, the normal fruiting bodies, the shortened life span and the ability to degrade cellulose were found in strains which all five genes in the PaLPMO11 family were deleted. However, the strain still had 45% cellulase activity compared to wild type. These results suggest that LPMO11 genes may be involved in the growth and development, sexual reproduction, senescence and cellulose degradation of P. anserina. This study provides information for systematically elucidating the regulatory mechanism of lignocellulose degradation in filamentous fungus P. anserina.

Osteoblast MR deficiency protects against adverse ventricular remodeling after myocardial infarction.

RATIONALE: Mineralocorticoid receptor (MR) antagonists have been clinically used to treat heart failure. However, the underlying cellular and molecular mechanisms remain incompletely understood. METHODS AND RESULTS: Using osteoblast MR knockout (MRobko) mouse in combination with myocardial infarction (MI) model, we demonstrated that MR deficiency in osteoblasts significantly improved cardiac function, promoted myocardial healing, as well as attenuated cardiac hypertrophy, fibrosis and inflammatory response after MI. Gene expression profiling using RNA sequencing revealed suppressed expression of osteocalcin (OCN) in calvaria from MRobko mice compared to littermate control (MRfl/fl) mice with or without MI. Plasma levels of undercarboxylated OCN (ucOCN) were also markedly decreased in MRobko mice compared to MRfl/fl mice. Administration of ucOCN abolished the protective effects of osteoblast MR deficiency on infarcted hearts. Mechanistically, ucOCN treatment promoted proliferation and inflammatory cytokine secretion in macrophages. Spironolactone, an MR antagonist, significantly inhibited the expression and secretion of OCN in post-MI mice. More importantly, spironolactone decreased plasma levels of ucOCN and inflammatory cytokines in heart failure patients. CONCLUSIONS: MR deficiency in osteoblasts alleviates pathological ventricular remodeling after MI, likely through its regulation on OCN. Spironolactone may work through osteoblast MR/OCN axis to exert its therapeutic effects on pathological ventricular remodeling and heart failure in mice and human patients.

Bone Repairment via Mechanosensation of Piezo1 Using Wearable Pulsed Triboelectric Nanogenerator.

Bone repair in real time is a challenging medical issue for elderly patients; this is mainly because aged bone marrow mesenchymal stem cells (BMSCs) possess limited osteogenesis potential and repair capacity. In this study, triboelectric stimulation technology is used to achieve bone repair via mechanosensation of Piezo1 by fabricating a wearable pulsed triboelectric nanogenerator (WP-TENG) driven by human body movement. A peak value of 30 µA has the optimal effects to rejuvenate aged BMSCs, enhance their osteogenic differentiation, and promote human umbilical vein endothelial cell tube formation. Further, previous studies demonstrate that triboelectric stimulation of a WP-TENG can reinforce osteogenesis of BMSCs and promote the angiogenesis of human umbilical vein endothelial cells (HUVECs). Mechanistically, aged BMSCs are rejuvenated by triboelectric stimulation via the mechanosensitive ion channel Piezo1. Thus, the osteogenesis potential of BMSCs is enhanced and the tube formation capacity of HUVECs is improved, which is further confirmed by augmented bone repair and regeneration in in vivo investigations. This study provides a potential signal transduction mechanism for rejuvenating aged BMSCs and a theoretical basis for bone regeneration using triboelectric stimulation generated by a WP-TENG.

Chaotropic Effect Stabilized Radical-Containing Supramolecular Organic Frameworks for Photothermal Therapy.

Radical-containing frameworks (RCFs) have emerged as promising functional materials in various fields due to the combination of the highly ordered frame structure and the fascinating property of organic radicals. Here, the first example of radical-containing supramolecular organic frameworks (SOFs) fabricated by the chaotropic effect between closo-dodecaborate cluster (B12 H122- ) and 2,4,6-tri(4-pyridyl)-1,3,5-triazine (TPT3+ ) is presented. The SOFs can be easily synthesized by stirring the B12 H122- and the TPT3+ in aqueous solution through self-assembly. Upon 435 nm light irradiation, the SOFs exhibits photochromic behavior from slight yellow (SOF-1) to dark purple (SOF-2). Electron paramagnetic resonance spectroscopy also reveals that stable radicals are generated in situ after light irradiation. Powder X-ray diffraction demonstrates the SOFs maintain their structural stabilities upon light irradiation. More interestingly, the radical-containing SOFs exhibit efficient photothermal effect under 660 nm light irradiation, which can be applied as photothermal agent for antibacterial application both in vitro and in vivo. This work highlights the construction of RCFs through supramolecular self-assembly, which may arouse applications in energy, catalysis, photoluminescence, and biomedical fields.

Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway.

RATIONALE: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. OBJECTIVE: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. METHODS AND RESULTS: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE-/- (apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE-/- mice. Myeloid cell-specific SNX10 deficiency (Δ knockout [KO]) attenuated atherosclerosis progression in APOE-/- mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. CONCLUSIONS: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.

Are all local tumour progressions of HCC related to thermal ablation? A study of the causes and classification of local tumour progression.

OBJECTIVES: Local tumour progression (LTP) is believed to be a negative consequence of imperfect thermal ablation, but we wondered if all LTP is truly due to imperfect ablation. METHODS: This study included 185 LTPs occurring within 1 cm of the ablation zone (AZ) after clinical curative thermal ablation for ≤ 5 cm hepatocellular carcinoma between 2010 and 2019. The AZ was divided into 8 quadrants by coronal, sagittal, and horizontal planes. Two methods, visual assessment through pre- and post-MRI (VA) and tumour mapping for 3D visualisation pre- and post-MRI fusion (MF), were used to assess which AZ quadrant included the shortest ablation margin (AM) by three doctors. LTP subclassification was based on whether LTP contacted the AZ margin (contacted LTP and dissociated-type LTP) and occurrence at different time points (12, 18, and 24 months). RESULTS: Fleiss's Kappa of VA and MF was 0.769 and 0.886, respectively. Cohen's Kappa coefficient between VA and MF was 0.830. For all LTPs, 98/185 (53.0%) occurred in the shortest AM quadrant, which showed a significant central tendency (p < 0.001). However, only 8/51 (15.7%) dissociated - type LTPs and 6/39 (15.4%) LTPs after 24 months occurred in the shortest AM quadrant, which showed no evenly distributed difference (p = 0.360 and 0.303). CONCLUSIONS: MF is an accurate and convenient method to assess the shortest AM quadrant. LTP is a central tendency in the shortest AM quadrant, but dissociated-type and LTPs after 24 months are not, and these LTP types could be considered nonablation-related LTPs. KEY POINTS: • LTPs are not evenly distributed around the AZ. More than half of LTPs occur in the shortest AM quadrant. • Subgroup analysis showed that the occurrence of contacted-type LTPs (tumour margin has direct contact with the AZ) within 24 months after ablation indeed had a high proportion in the shortest AM quadrant, and they could be called ablation-related LTPs. • However, the dissociated-type LTPs (tumour margin adjacent to but not in contact with the AZ) or LTPs occurring beyond 24 months after ablation were evenly distributed around the AZ, and they could be called nonablation-related LTPs.