OBJECTIVE To investigate the effect and potential mechanism of toosendanin in enhancing the antileukemic activity of cytosine arabinoside against acute myeloid leukemia （AML） based on the mammalian target of rapamycin complex 1 （mTORC1） signaling pathway.METHODS Female NSG immunodeficient mice were used to establish an AML model via a single γ-ray irradiation followed by a single tail-vein injection of a U937 cell suspension. The effects of cytosine arabinoside （2.5 mg/kg）， toosendanin （1.0 mg/kg）， and cytosine arabinoside+toosendanin （2.5 mg/kg+1.0 mg/kg） on body weight， survival time， peripheral blood routine indicators， histopathological morphology， and the expressions of autophagy-related proteins were explored. Using U937 cells as the subject， the effects of cytosine arabinoside （1 μmol/L）， toosendanin （160 nmol/L）， and cytosine arabinoside+toosendanin （1 μmol/L+160 nmol/L） on the expressions of autophagy-related proteins， mTORC1 signaling pathway-related proteins and mRNAs were investigated. The targeting relationship between toosendanin and the selective autophagy ligand 1 （also known as p62） was validated， and the Gene Ontology （GO） and Kyoto Encyclopedia of Genes and Genomes （KEGG） enrichment analyses， as well as molecular docking， were performed. A p62 -knockdown U937 stable cell line was constructed， and the underlying mechanism of toosendanin-induced sensitization was verified.RESULTS Animal experiments confirmed that the combination of toosendanin and cytosine arabinoside significantly improved body weight， survival time and peripheral blood routine indicators in AML mice （ P ＜0.05）， alleviated pathological changes such as leukemic cell infiltration and focal necrosis in bone marrow， liver， and spleen tissues， and modulated the expressions of autophagy-related proteins. Cell experiments confirmed that toosendanin could reverse cytosine arabinoside-induced activation of the autophagy cascade （manifested by downregulation of the protein expressions of microtubule-associated protein 1 light chain 3B and Beclin-1， upregulation the protein expression of p62）， and might inhibit the expression of the downstream Unc-51-like autophagy activating kinase 1 （ULK1） complex （including ULK1， ULK2， autophagy-related protein 13， and FAK family interacting protein of 200 kDa） by activating the mTORC1 signaling pathway （ P ＜0.05）. The sensitizing effect of toosendanin was associated with the inhibition of autophagy and the regulation of the mTORC1 signaling pathway； it could stably bind to p62 via hydrophobic interactions. Mechanism verification experiments indicated that upon p62 knockdown， toosendanin was no longer able to activate the mTORC1 signaling pathway or inhibit autophagy.CONCLUSIONS Toosendanin may enhance chemo-sensitivity of AML cells to cytosine arabinoside by directly targeting the p62 protein， which subsequently activates the mTORC1 signaling pathway， and thereby suppresses cytosine arabinoside-induced protective autophagy.

As a relatively novel technique for drug delivery, the needle-free injection technique is characterized by transporting the drug liquid to the designated subcutaneous position through a high-speed micro-jet. Although this technique has been applied in many fields, the research on its drug dispersion mechanism and injection performance is insufficient. The presented study aims to identify critical parameters during the injection process and describe their influence on the injection effect. The injection completion rate and performance of a needle-free injector under various operating conditions were compared based on mouse experiments. The results show that the nozzle diameter imposes a more significant influence on jet characteristics than other injection parameters. Moreover, the injection completion rate increases with the nozzle diameter. The nozzle diameters of 0.14 mm and 0.25 mm correspond to injection completion rates of 89.7% and 95.8%, respectively. Furthermore, by analyzing the rate of blood glucose change in the tested mice, it is found that insulin administration through the needle-free injection can achieve a drug effect duration longer than 120 min, which is better than that obtained using conventional needle-syringe technique. In summary, the obtained conclusions can provide an important reference for the optimal design and extending application of the air-powered needle-free injector.
Animals ; Mice ; Insulin/administration & dosage* ; Needles ; Injections, Subcutaneous/methods* ; Injections, Jet/instrumentation* ; Drug Delivery Systems/instrumentation* ; Blood Glucose/analysis* ; Equipment Design

A method for determining volatile organic compounds (VOCs) emitted from medical molecular sieve oxygen concentrators was developed using thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS). The oxygen concentrator gas was sampled at a flow rate of 0.5 L/min through a branched sampling system onto Tenax GR/carbopack B adsorption tubes. The adsorbed compounds were desorbed and introduced using a programmed temperature vaporization inlet system, followed by chromatographic separation on an SH-I-624Sil MS column. Four VOCs (BHT-Q, PTBP, BHT-quinol, and EHB) were detected in the medical oxygen concentrator using this method. Calibration curves for these compounds exhibited excellent linearity ( R ²>0.99) within the range of 3~100 ng. With a sampling volume of 20 L, the detection limit of the four VOCs ranged from 0.003 9 to 0.022 2 μg/m ³. Spike recovery rates for the four VOCs were between 95% and 115%, with relative standard deviations (RSDs) below 5% ( n=6). The method is simple, rapid, highly sensitive, and accurate, making it suitable for VOCs detection in medical molecular sieve oxygen concentrators.
Volatile Organic Compounds/analysis* ; Gas Chromatography-Mass Spectrometry/methods* ; Oxygen

Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

Objective To investigate the current status of symptom burden and psychological distress among lung cancer patients in the diagnostic phase, and to explore the chain mediating role of social support and resilience between symptom burden and psychological distress. Methods The patients with lung cancer in the diagnostic phase who were treated in the Department of Thoracic Surgery of the Second Xiangya Hospital of Central South University from October 2022 to June 2023 were investigated by a general information questionnaire using the MD Anderson Symptom Inventory, the Social Support Rating Scale, the Connor-Davidson Resilience Scale, and the Distress Thermometer. The chain mediating role of social support and resilience between symptom burden and psychological distress was analyzed. Results A total of 413 lung cancer patients were enrolled, including 173 males and 240 females, aged (54.69±10.82) years. The detection rate of psychological distress among lung cancer patients in the diagnostic phase was 48.18%, and the average score was (3.84±2.50) points. Psychological distress was positively correlated with symptom burden (P<0.01), and negatively correlated with social support and resilience (P<0.01). The mediating effect of resilience between symptom burden and psychological distress was significant. The chain mediating effect of social support and resilience between symptom burden and psychological distress was also significant. Conclusion Lung cancer patients in the diagnostic phase have a high detection rate of psychological distress. Symptom burden can directly impact psychological distress, and can affect psychological distress through the indirect path of resilience as well as the chain mediating path between social support and resilience among lung cancer patients in the diagnostic phase.

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

Childhood primary renal tubular diseases are chronic kidney diseases characterized by impaired renal tubular reabsorption. Primary renal tubular disease has diverse clinical manifestations and lacks of specificity. Laboratory tests are limited，making it prone to missed diagnosis and misdiagnosis. Based on the current knowledge of renal tubular diseases，authors propose early warning signals of renal tubular diseases such as family history of primary tubular diseases，unexplained polyhydramnios during pregnancy，polydipsia，polyuria，delayed growth and development or rickets，decreased muscle strength and tone，unexplained electrolyte disturbance，hyperuricemia，acid-base disturbance，positive urine sugar test，renal tubular proteinuria，urinary imaging examination suggesting kidney stones，calcium deposition，renal cysts and early onset of eye，ear，joint and neuron injury.Meanwhile，some universal management strategies for primary renal tubular disease are proposed，emphasizing the importance of multidisciplinary collaboration，genetic testing and individualized intervention to improve the long-term prognosis of childhood primary renal tubular diseases.

INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD. METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). The study was conducted at Hainan Branch, Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patient enrollment and baseline assessments commenced in November 2023. Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging. RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs . 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs . 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs . 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline. CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies. REGISTRATION ClinicalTrials.gov , NCT07034222.
Humans ; Alzheimer Disease/drug therapy* ; Male ; Female ; Aged ; Middle Aged ; Cognitive Dysfunction/drug therapy* ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism* ; Biomarkers ; East Asian People

Objective To specifically extract and analyze nascent proteins synthesized by bone marrow mesenchymal stem cells(BMSCs)after transplantation into ischemic hearts using a technique employing mutant methionyl-tRNA synthetase(MetRSL247G)for nascent protein labeling,in order to explore the potential mechanisms of action in BMSCs post-transplantation.Methods Point mutation at position 274 of the MetRS gene in BMSCs was induced via lentiviral infection to enable azidonorleucine(ANL)-mediated labeling of nascent proteins in BMSCs.The labeling efficiency was verified by means of fluorescent non-canonical amino-acid tagging(FUNCAT).Thirty healthy female C57BL/6J mice(8-10 weeks old)were divided into control and experimental groups,with 15 mice in each group.The acute myocardial infarction model was constructed by ligating the left anterior descending coronary artery in experimental group,while control mice underwent only thoracotomy without coronary ligation.After modeling,both groups received intramyocardial injections of MetRSL247G-modified BMSCs(MetRSL247G-BMSCs)at 3 different sites in the peri-infarct ischemic region.Mice were intraperitoneally injected with ANL every 6 hours for 4 times on postoperative days 0,2,and 6(n=5 for each time point)respectively,euthanized 24 h after the last injection,and cardiac tissues were isolated.The newly synthesized and labeled proteins produced by BMSCs after transplantation into the myocardium of experimental and control groups were collected,using an enrichment technique for ANL-tagged proteins and liquid chromatography-tandem mass spectrometry(LC-MS)analysis.Gene ontology(GO)analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis,protein-protein interaction(PPI)analysis,and heatmap visualization analysis were performed to identify differentially expressed proteins at the 3 time points and screen key pathways and genes.Results Under fluorescence microscopy,the MetRSL247G lentivirus-infected BMSCs were observed to be labelled with mCherry signals,confirming the successful construction of the MetRSL247G-BMSCs cell line.Green fluorescent signals were detected only in nascent proteins in culture medium containing both MetRSL247G-BMSCs and ANL,validating the sensitivity and specificity of the labeling method.GO analysis revealed that differentially expressed proteins were primarily involved in basic cellular biological processes such as extracellular exosome formation,extracellular matrix organization,and focal adhesion.KEGG and PPI analyses indicated that the differential proteins were mainly involved in complement and coagulation cascade pathway,actin cytoskeleton regulation pathway,and apoptosis pathway.Heatmap analysis showed significantly upregulated expression of anti-apoptosis and cell adhesion-related factors in experimental group on day 1(P＜0.05),upregulated anti-apoptotic factors,pro-apoptotic factors,and cell adhesion-related factors on day 3(P＜0.05),and upregulated anti-apoptotic factors,cell differentiation-related factors,and cell adhesion-related factors on day 7(P＜0.05)compared with control group.Expression of apoptosis-inducing factor 1 was significantly downregulated on days 1 and 7(P＜0.05).On day 3,most differentially expressed proteins,including anti-apoptosis factors(Protein S100-A11,Clusterin,Gelsolin),pro-apoptosis factor(Cathepsin B),cell differentiation-related factor(Transgelin-2),and cell adhesion-related factors(Cofilin-1,Periostin,Fibronectin)were significantly upregulated(P＜0.05).Conclusions The MetRSL247G mutation enables BMSCs to incorporate ANL and synthesize labeled proteins,confirming the feasibility of this nascent protein labeling technique.Nascent proteins of BMSCs in ischemic myocardium primarily contribute to extracellular exosome secretion and extracellular matrix organization.BMSCs may adapt to and respond to ischemic and hypoxic environments by influencing complement and coagulation cascades,activating inflammatory factors,regulating actin cytoskeleton structure,and modulating apoptosis,thereby maintaining the survival of BMSCs.

To formulate an expert consensus on the principles of preoperative hair removal and provide scientific guidance for standardized removal of hair before surgical procedures so as to reduce the incidence of surgical site infections.METHODS Led by the Hospital Management Institute of National Health Commission of the People's Republic of China,this consensus was reached with the joint efforts from the expects of relevant fields such as surgeries,interventional therapies,nursing,and infection prevention and control.The consensus facilitates the classification and evaluation of literatures by following the evidence grade formulated by Oxford Evidence-based Medicine Center and focuses on the association of preoperative hair removal with surgical site infection,it reaches the evidence grade of expert consensus and recommendation intensity by integrating with discussions on meetings and clinical experience of the expects from relevant fields.RESULTS A total of 6 items of consensus were reached by summarizing the latest evidence on the aspects including the indications for preoperative hair removal,tools,range,timing and places.CONCLUSION The consensus,to some extent,make supplements to and complete the exiting regulations and standards.It provides guidance for the medical institutions to carry out the preoperative hair removal.