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1.
Front Aging Neurosci ; 16: 1400447, 2024.
Article in English | MEDLINE | ID: mdl-39006222

ABSTRACT

Introduction: Dual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal VGF gene network that regulates late-onset Alzheimer's disease (AD). Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating (CDR) in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model. Methods: To investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP. Results: Barnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1-40 and Aß1-42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation, which was increased in 5xFAD mice, was significantly reduced by dHc DUSP6 overexpression in both males and females, as was the number of "microglial clusters," which correlated with reduced amyloid plaque size. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulation of inflammatory and extracellular signal-regulated kinase pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. Gene ontology analysis of DEGs (p < 0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD. Discussion: In summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.

2.
Environ Toxicol ; 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39041630

ABSTRACT

Asparagus officinalis (ASP) has antioxidation, anti-inflammatory, antiaging, and immune system-enhancing effects. We explored the preventive and therapeutic consequences of ASP on the brain damage elicited by fluorosis through network pharmacology and in vivo experimental validation. We ascertained the pharmaceutically active ingredients and drug targets of ASP from the Traditional Chinese Medicine Systems Pharmacology database, predicted the disease targets of fluorosis-induced brain injury using GeneCards and Online Mendelian Inheritance in Man databases, obtained target protein-protein interaction networks in the Search Tool for the Retrieval of Interacting Genes/Proteins database, used Cytoscape to obtain key targets and active ingredients, and conducted enrichment analyses of key targets in the Database for Annotation, Visualization and Integrated Discovery. Enrichment analyses showed that "mitogen-activated protein kinase" (MAPK), "phosphoinositide 3-kinase/protein kinase B" (PI3K-Akt), "nuclear factor-kappa B" (NF-κB), and the "neurotrophin signaling pathway" were the most enriched biological processes and signaling pathways. ASP could alleviate fluorosis-based injury, improve brain-tissue damage, increase urinary fluoride content, and improve oxidation levels and inflammatory-factor levels in the body. ASP could also reduce dental fluorosis, bone damage, fluoride concentrations in blood and bone, and accumulation of lipid peroxide. Upon ASP treatment, expression of silent information regulator (SIRT)1, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), MAPK, NF-κB, PI3K, Akt, and B-cell lymphoma-2 in rat brain tissue increased gradually, whereas that of Bax, caspase-3, and p53 decreased gradually. We demonstrated that ASP could regulate the brain damage caused by fluorosis through the SIRT1/BDNF/TrkB signaling pathway, and reported the possible part played by ASP in preventing and treating fluorosis.

3.
Ren Fail ; 46(2): 2367708, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38973391

ABSTRACT

BACKGROUND: Cellular senescence, macrophages infiltration, and vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation participate in the pathophysiology of vascular calcification in chronic kidney disease (CKD). Senescent macrophages are involved in the regulation of inflammation in pathological diseases. In addition, senescent cells spread senescence to neighboring cells via Interferon-induced transmembrane protein3 (IFITM3). However, the role of senescent macrophages and IFITM3 in VSMCs calcification remains unexplored. AIMS: To explore the hypothesis that senescent macrophages contribute to the calcification and senescence of VSMCs via IFITM3. METHODS: Here, the macrophage senescence model was established using Lipopolysaccharides (LPS). The VSMCs were subjected to supernatants from macrophages (MCFS) or LPS-induced macrophages (LPS-MCFS) in the presence or absence of calcifying media (CM). Senescence-associated ß-galactosidase (SA-ß-gal), Alizarin red (AR), immunofluorescent staining, and western blot were used to identify cell senescence and calcification. RESULTS: The expression of IFITM3 was significantly increased in LPS-induced macrophages and the supernatants. The VSMCs transdifferentiated into osteogenic phenotype, expressing higher osteogenic differentiation markers (RUNX2) and lower VSMCs constructive makers (SM22α) when cultured with senescent macrophages supernatants. Also, senescence markers (p16 and p21) in VSMCs were significantly increased by senescent macrophages supernatants treated. However, IFITM3 knockdown inhibited this process. CONCLUSIONS: Our study showed that LPS-induced senescence of macrophages accelerated the calcification of VSMCs via IFITM3. These data provide a new perspective linking VC and aging, which may provide clues for diagnosing and treating accelerated vascular aging in patients with CKD.


Subject(s)
Cellular Senescence , Lipopolysaccharides , Macrophages , Membrane Proteins , Muscle, Smooth, Vascular , RNA-Binding Proteins , Vascular Calcification , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Lipopolysaccharides/pharmacology , Vascular Calcification/pathology , Vascular Calcification/metabolism , Macrophages/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , RNA-Binding Proteins/metabolism , Humans , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/pathology , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency, Chronic/pathology , Cells, Cultured , Animals , Osteogenesis , Cell Transdifferentiation
4.
Sci Rep ; 14(1): 17055, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39048596

ABSTRACT

It has been believed that immunosenescence plays a crucial role in tumorigenesis and cancer therapy. Nevertheless, there is still a lack of understanding regarding its role in determining clinical outcomes and therapy selection for gastric cancer patients, due to the lack of a feasible immunosenescence signature. Therefore, this research aims to develop a gene signature based on immunosenescence, which is used for stratification of gastric cancer. By integrative analysis of bulk transcriptome and single-cell data, we uncovered immunosenescence features in gastric cancer. Random forest algorithm was used to select hub genes and multivariate Cox algorithm was applied to construct a scoring system to evaluate the prognosis and the response to immunotherapy and chemotherapy. The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) cohort was implemented as the training cohort and two independent cohorts from the Gene Expression Omnibus (GEO) database were used for validation. The model was further tested by our Fudan cohort. In this study, immunosenescence was identified as a hallmark of gastric cancer that is linked with transcriptomic features, genomic variations, and distinctive tumor microenvironment (TME). Four immunosenescence genes, including APOD, ADIPOR2, BRAF, and C3, were screened out to construct a gene signature for risk stratification. Higher risk scores indicated strong predictive power for poorer overall survival. Notably, the risk score signature could reliably predict response to chemotherapy and immunotherapy, with patients with high scores benefiting from immunotherapy and patients with low scores responding to chemotherapy. We report immunosenescence as a hitherto unheralded hallmark of gastric cancer that affects prognosis and treatment efficiency.


Subject(s)
Immunosenescence , Single-Cell Analysis , Stomach Neoplasms , Transcriptome , Tumor Microenvironment , Stomach Neoplasms/genetics , Stomach Neoplasms/immunology , Humans , Single-Cell Analysis/methods , Tumor Microenvironment/immunology , Tumor Microenvironment/genetics , Prognosis , Immunosenescence/genetics , Gene Expression Regulation, Neoplastic , Gene Expression Profiling , Female , Male , Biomarkers, Tumor/genetics , Middle Aged
5.
J Inflamm Res ; 17: 4297-4308, 2024.
Article in English | MEDLINE | ID: mdl-38973997

ABSTRACT

Purpose: To evaluate the prognostic significance of platelet distribution width-to-lymphocyte ratio (PDWLR) in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Moreover, a nomogram based on PDWLR was built and validated to predict the overall survival (OS) of this population. Patients and Methods: All LA-NPC patients who were diagnosed and treated between January 2015 and December 2017 at Guangxi Medical University Cancer Hospital were included. Cox regression analyses were performed to assess PDWLR and clinical features that might affect OS to screen for independent predictors. The independent predictors and important clinical variables were used to build and validate a nomogram for predicting OS. Then, the capability of the model was estimated by discrimination, calibration and clinical usefulness. Risk stratification was conducted using the nomogram-calculated risk score, and the comparison of survival in the high-risk group and the low-risk group was through Kaplan-Meier method. Results: This study included 746 LA-NPC patients. Multivariate Cox analysis suggested that age (hazard ratio [HR]: 1.81, 95% confidence interval [CI]: 1.18-2.78, P = 0.007), gender (HR: 2.03, 95% CI: 1.12-3.68, P = 0.019), pre-treatment plasma Epstein-Barr virus (EBV) DNA (HR: 1.55, 95% CI: 1.01-2.39, P = 0.047), PDWLR (HR: 2.61, 95% CI: 1.67-4.09, P < 0.001) were independent predictors of OS. Compared to the 8th edition TNM staging system, the nomogram based on the above four factors and important clinical variables (T stage and N stage) demonstrated better predictive performance. Moreover, the model had the ability to identify individuals at high risk. Conclusion: PDWLR was a promising negative predictor for patients with LA-NPC. The nomogram based on PDWLR demonstrated better predictive performance than the current staging system.

6.
Small ; : e2401655, 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38966887

ABSTRACT

Despite the advantages of high tissue penetration depth, selectivity, and non-invasiveness of photothermal therapy for cancer treatment, developing NIR-II photothermal agents with desirable photothermal performance and advanced theranostics ability remains a key challenge. Herein, a universal surface modification strategy is proposed to effectively improve the photothermal performance of vanadium carbide MXene nanosheets (L-V2C) with the removal of surface impurity ions and generation of mesopores. Subsequently, MnOx coating capable of T1-weighted magnetic resonance imaging can be in situ formed through surface redox reaction on L-V2C, and then, stable nanoplatforms (LVM-PEG) under physiological conditions can be obtained after further PEGylation. In the tumor microenvironment irradiated by NIR-II laser, multivalent Mn ions released from LVM-PEG, as a reversible electronic station, can consume the overexpression of glutathione and catalyze a Fenton-like reaction to produce ·OH, resulting in synchronous cellular oxidative damage. Efficient synergistic therapy promotes immunogenic cell death, improving tumor-related immune microenvironment and immunomodulation, and thus, LVM-PEG can demonstrate high accuracy and excellent anticancer efficiency guided by multimodal imaging. As a result, this study provides a new approach for the customization of 2D surface strategies and the study of synergistic therapy mechanisms, highlighting the application of MXene-based materials in the biomedical field.

7.
J Biol Chem ; : 107516, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38960036

ABSTRACT

Focal segmental glomerulosclerosis (FSGS), a common cause of primary glomerulonephritis, has a poor prognosis and is pathologically featured by tubulointerstitial injury. Thrombospondin-1 (TSP-1) is an extracellular matrix protein that acts in combination with different receptors in the kidney. Here, we analyzed the tubular expression of TSP-1 and its receptor integrin ß3 (ITGB3) in FSGS. Previously the renal interstitial chip analysis of FSGS patients with tubular interstitial injury showed that the expressions of TSP-1 and ITGB3 were up-regulated. We found that the level of TSP-1 and ITGB3 increased in the tubular cells of FSGS patients. The serum level of TSP-1 increased and was correlated to the degree of tubulointerstitial lesions in FSGS patients. THBS1/ITGB3 signaling induced renal tubular injury in HK-2 cells exposure to BSA and the ADR-induced nephropathy model. THBS1 knockout ameliorated tubular injury and renal fibrosis in ADR-treated mice. THBS1 knockdown decreased the expression of KIM-1 and caspase 3 in the HK-2 cells treated with BSA, while THBS1 overexpression could induce tubular injury. In vivo, we identified cyclo-RGDfK as an agent to block the binding of TSP-1 to ITGB3. Cyclo-RGDfK treatment could alleviate ADR-induced renal tubular injury and interstitial fibrosis in mice. Moreover, TSP-1 and ITGB3 were colocalized in tubular cells of FSGS patients and ADR-treated mice. Taken together, our data showed that TSP-1/ITGB3 signaling contributed to the development of renal tubulointerstitial injury in FSGS, potentially identifying a new therapeutic target for FSGS.

8.
Cancer Biol Ther ; 25(1): 2371632, 2024 Dec 31.
Article in English | MEDLINE | ID: mdl-38946404

ABSTRACT

To investigate the impact of the effective radiation dose to immune cells (EDIC) and gross tumor volume (GTV) on lymphopenia and survival in patients with locally advanced esophageal squamous cell carcinoma (LAESCC). Between January 2013 and December 2020, 272 LAESCC patients were treated with definitive radiotherapy in two institutions. Based on radiation doses to the lungs, heart, and body region scanned, EDIC was calculated as an equal uniform dose to the total blood considering blood flow and fraction effect. The radiotherapy plan was used to calculate the GTVs. Lymphopenia was graded based on the lowest lymphocyte count during RT. The overall survival (OS), progress-free survival (PFS), and local recurrence-free survival (LRFS) were analyzed statistically. The lowest lymphocyte count was significantly correlated with EDIC (r= -0.389, p < .001) and GTV (r= -0.211, p < .001). Lymphopenia, EDIC, and GTV are risk factors for patients with ESCC. In a Kaplan-Meier analysis with EDIC and GTV as stratification factors, lymphopenia was not associated with OS in the EDIC>12.9 Gy group (p = .294)and EDIC ≤ 12.9 Gy group, and it was also not associated with OS in GTV>68.8 cm3 group (p = .242) and GTV ≤ 68.8 cm3 group(p = .165). GTV and EDIC had an impact on the relationship between lymphopenia and OS in patients with LAESCC undergoing definitive RT. Poorer OS, PFS, and LRFS are correlated with lymphopenia, higher EDIC, and larger GTV.


Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Lymphopenia , Humans , Lymphopenia/etiology , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/mortality , Esophageal Squamous Cell Carcinoma/radiotherapy , Male , Female , Middle Aged , Esophageal Neoplasms/mortality , Esophageal Neoplasms/pathology , Esophageal Neoplasms/radiotherapy , Aged , Adult , Retrospective Studies , Prognosis , Aged, 80 and over , Tumor Burden , Lymphocyte Count , Radiotherapy Dosage
9.
Sci Rep ; 14(1): 13042, 2024 06 06.
Article in English | MEDLINE | ID: mdl-38844625

ABSTRACT

Colon cancer (CC) is a highly malignant tumor with a high incidence and poor prognosis. This study aimed to explore the function and molecular mechanisms of activating transcription factor 4 (ATF4) in CC. The expression levels of ATF4, GCN2, and ASNS in CC tissues were measured using immunohistochemistry (IHC) and reverse transcription quantitative PCR (RT-qPCR). Cell counting kit-8 (CCK-8), clone formation, transwell, and flow cytometry assays were conducted to assess cell viability, clonogenicity, migration, invasion, cell cycle, and apoptosis, respectively, in the ATF4 knockdown and overexpression SW480 cell lines. The effect of ATF4 on the expression of GCN2 and ASNS was detected using RT-qPCR, Chip-qPCR, and western blotting. ATF4, GCN2, and ASNS were expressed at low levels in CC tissues, and all had a significant negative correlation with tumor diameter. ATF4 knockdown promoted cell proliferation, invasion, and S-phase cell cycle and inhibited apoptosis in SW480 cells. In contrast, ATF4 overexpression had the opposite effect. Furthermore, ATF4 overexpression enhanced ATF4 binding to the ASNS promoter region. ATF4 knockdown significantly inhibited the expression of p-GCN2 and ASNS, whereas ATF4 overexpression significantly upregulated their expression. ATF4 inhibited CC cell viability, clone formation ability, migration, and invasion and promoted apoptosis, possibly by regulating the expression of p-GCN2 and ASNS. Our study provides a novel potential therapeutic target for the treatment of CC.


Subject(s)
Activating Transcription Factor 4 , Apoptosis , Cell Movement , Cell Proliferation , Colonic Neoplasms , Gene Expression Regulation, Neoplastic , Protein Serine-Threonine Kinases , Up-Regulation , Humans , Activating Transcription Factor 4/metabolism , Activating Transcription Factor 4/genetics , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Colonic Neoplasms/metabolism , Cell Line, Tumor , Cell Proliferation/genetics , Apoptosis/genetics , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Cell Movement/genetics , Male , Female , Middle Aged
10.
Signal Transduct Target Ther ; 9(1): 148, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38890298

ABSTRACT

Penpulimab is an anti-programmed cell death-1 (PD-1) IgG1 antibody with no Fc gamma receptor (FcγR) binding activity, and thus theoretically reduced immune-related adverse events (irAEs) while maintaining efficacy. This single-arm, phase II trial conducted across 20 tertiary care centers in China enrolled adult patients with metastatic nasopharyngeal carcinoma (NPC) who had failed two or more lines of previous systemic chemotherapy. Patients received 200-mg penpulimab intravenously every 2 weeks (4 weeks per cycle) until disease progression or intolerable toxicities. The primary endpoint was objective response rate (ORR) per RECIST (version 1.1), as assessed by an independent radiological review committee. The secondary endpoints included progression-free survival (PFS) and overall survival (OS). One hundred thirty patients were enrolled and 125 were efficacy evaluable. At the data cutoff date (September 28, 2022), 1 patient achieved complete response and 34 patients attained partial response. The ORR was 28.0% (95% CI 20.3-36.7%). The response was durable, with 66.8% still in response at 9 months. Thirty-three patients (26.4%) were still on treatment. The median PFS and OS were 3.6 months (95% CI = 1.9-7.3 months) and 22.8 months (95% CI = 17.1 months to not reached), respectively. Ten (7.6%) patients experienced grade 3 or higher irAEs. Penpulimab has promising anti-tumor activities and acceptable toxicities in heavily pretreated metastatic NPC patients, supporting further clinical development as third-line treatment of metastatic NPC.


Subject(s)
Nasopharyngeal Carcinoma , Neoplasm Metastasis , Programmed Cell Death 1 Receptor , Humans , Male , Middle Aged , Female , Nasopharyngeal Carcinoma/drug therapy , Nasopharyngeal Carcinoma/pathology , Adult , Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/pathology , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/adverse effects
11.
Cancer Manag Res ; 16: 603-616, 2024.
Article in English | MEDLINE | ID: mdl-38855327

ABSTRACT

Purpose: The aims of the study were to monitor circulating lymphocyte subset counts before and after therapy for nasopharyngeal carcinoma (NPC), and investigate their relationships with patient outcomes. Patients and Methods: Subjects comprised patients with TNM stage I-IVA NPC who underwent radiotherapy. Peripheral venous blood samples were collected before and after treatment. Lymphocyte subset counts were analyzed by flow cytometry. Differences between post-treatment and baseline counts were calculated to determine Δ values. Patients were divided into high and low groups, based on median lymphocyte subset counts; propensity score matching was applied to balance groups. Progression-free survival (PFS) and overall survival (OS) were plotted using Kaplan-Meier curves and compared using a Log rank test. Relationships between lymphocyte subset counts and patient survival were subjected to Cox regression analysis. Results: Patients with NPC (n=746) were enrolled from 2012-2022. Higher CD8+ and total T cell baseline counts were associated with better 5-year PFS (73.7% vs 63.1%, P=0.002 and 73.8% vs 64.1%, P=0.005, respectively). Similarly, higher Δ values of CD4+ and total T cells were associated with higher 5-year PFS (76.2% vs 63.5%, P=0.001; 74.3% vs 65.4%, P=0.010) and OS (89.8% vs 81.6%, P=0.005; 88.6% vs 82.5%, P=0.009). Multivariate Cox regression revealed that CD8+ (hazard ratio (HR) 0.651, P=0.002) and total T (HR 0.600, P<0.001) cells were significantly associated with PFS. CD4+ (HR 0.708, P=0.038) and total T (HR 0.639, P=0.031) cells were independent prognostic factors for OS. Conclusion: NPC patients with low total or CD8+ T cell counts before treatment had worse prognosis; however, those with more significant decreases in total or CD4+ T cells possibly had better outcomes. T cell counts can be reliable indicators to predict prognosis.

12.
Drug Des Devel Ther ; 18: 2435-2447, 2024.
Article in English | MEDLINE | ID: mdl-38915864

ABSTRACT

Purpose: SN-38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan, has been extensively studied in drug delivery systems. However, its impact on neural metabolism remains unclear. This study aims to investigate the toxic effects of SN-38 on mouse brain metabolism. Methods: Male mice were divided into an SN-38 group and a control group. The SN-38 group received SN-38 (20 mg/kg/day) via intraperitoneal injection, while the control group was given an equal volume of a blank solvent mixture (DMSO and saline, ratio 1:9). Gas chromatography-mass spectrometry (GC-MS) was employed to analyze differential metabolites in the cortical and hippocampal regions of the SN-38-treated mice. Results: SN-38 induced metabolic disturbances in the central nervous system. Eighteen differential metabolites were identified in the hippocampus and twenty-four in the cortex, with six common to both regions. KEGG pathway enrichment analysis revealed statistically significant alterations in six metabolic pathways in the hippocampus and ten in the cortex (P<0.05). Conclusion: This study is the first to demonstrate the neurotoxicity of SN-38 in male mice through metabolomics. Differential metabolites in the hippocampal and cortical regions were closely linked to purine metabolism, pyrimidine metabolism, amino acid metabolism, and glyceride metabolism, indicating disruptions in the blood-brain barrier, energy metabolism, and central signaling pathways.


Subject(s)
Brain , Irinotecan , Metabolomics , Animals , Male , Irinotecan/pharmacology , Mice , Brain/metabolism , Brain/drug effects , Gas Chromatography-Mass Spectrometry , Injections, Intraperitoneal
13.
Lancet ; 403(10445): 2720-2731, 2024 Jun 22.
Article in English | MEDLINE | ID: mdl-38824941

ABSTRACT

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.


Subject(s)
Antibodies, Monoclonal, Humanized , Chemoradiotherapy , Induction Chemotherapy , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms , Humans , Middle Aged , Male , Female , Nasopharyngeal Carcinoma/therapy , Nasopharyngeal Carcinoma/drug therapy , Adult , China/epidemiology , Nasopharyngeal Neoplasms/drug therapy , Nasopharyngeal Neoplasms/therapy , Chemoradiotherapy/methods , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Aged , Cisplatin/therapeutic use , Cisplatin/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gemcitabine , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Deoxycytidine/administration & dosage , Young Adult , Adolescent , Progression-Free Survival
14.
Front Cell Infect Microbiol ; 14: 1375874, 2024.
Article in English | MEDLINE | ID: mdl-38887493

ABSTRACT

Background: The interplay between gut microbiota and metabolites in the early stages of sepsis-induced acute kidney injury (SA-AKI) is not yet clearly understood. This study explores the characteristics and interactions of gut microbiota, and blood and urinary metabolites in patients with SA-AKI. Methods: Utilizing a prospective observational approach, we conducted comparative analyses of gut microbiota and metabolites via metabolomics and metagenomics in individuals diagnosed with SA-AKI compared to those without AKI (NCT06197828). Pearson correlations were used to identify associations between microbiota, metabolites, and clinical indicators. The Comprehensive Antibiotic Resistance Database was employed to detect antibiotic resistance genes (ARGs), while Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways informed on metabolic processes and microbial resistance patterns. Results: Our study included analysis of four patients with SA-AKI and five without AKI. Significant disparities in bacterial composition were observed, illustrated by diversity indices (Shannon index: 2.0 ± 0.4 vs. 1.4 ± 0.6, P = 0.230; Simpson index: 0.8 ± 0.1 vs. 0.6 ± 0.2, P = 0.494) between the SA-AKI group and the non-AKI group. N6, N6, N6-Trimethyl-L-lysine was detected in both blood and urine metabolites, and also showed significant correlations with specific gut microbiota (Campylobacter hominis and Bacteroides caccae, R > 0, P < 0.05). Both blood and urine metabolites were enriched in the lysine degradation pathway. We also identified the citrate cycle (TCA cycle) as a KEGG pathway enriched in sets of differentially expressed ARGs in the gut microbiota, which exhibits an association with lysine degradation. Conclusions: Significant differences in gut microbiota and metabolites were observed between the SA-AKI and non-AKI groups, uncovering potential biomarkers and metabolic changes linked to SA-AKI. The lysine degradation pathway may serve as a crucial link connecting gut microbiota and metabolites.


Subject(s)
Acute Kidney Injury , Gastrointestinal Microbiome , Metabolomics , Metagenomics , Sepsis , Humans , Acute Kidney Injury/metabolism , Sepsis/microbiology , Sepsis/urine , Male , Prospective Studies , Metabolomics/methods , Female , Middle Aged , Metagenomics/methods , Aged , Bacteria/classification , Bacteria/genetics , Bacteria/isolation & purification , Bacteria/metabolism , Metabolome , Urine/microbiology , Urine/chemistry
15.
Arch Argent Pediatr ; : e202310236, 2024 Jun 06.
Article in English, Spanish | MEDLINE | ID: mdl-38820115

ABSTRACT

Introduction: This study investigated the serum concentration of vancomycin during prolonged infusion in children. Population and methods: This retrospective cohort study included pediatric patients who received vancomycin from June 2017 to June 2020 at a tertiary referral hospital. The patients were divided into two groups according to infusion strategy, the SII (standard intermittent infusion) group and the PI (prolonged infusion) group. Demographic details, infusion period, serum creatinine, duration of vancomycin therapy, trough concentration of vancomycin, and pediatric intensive care unit stay were reviewed. Differences of the concentrations were measured. Results: Sixty-eight patients were included: 31 in the SII group and 37 in the PI group. The trough concentration of vancomycin was significantly higher in the PI group than in SII group (11.2 mg/L [5.9-13.7] vs. 7 mg/L [3.5- 9.3]; p = 0.02). The target attainment rate was higher in the PI group than in the SII group (59.4% and 19.3%, respectively; p = 0.001). There were no significant differences between the SII and PI groups regarding the peak concentrations of vancomycin, final creatinine and peak creatinine. There were no differences between the SII and PI groups regarding the failure events, PICU stay and duration of vancomycin therapy. The multivariable analysis showed that PI was significantly associated with higher trough serum concentrations of vancomycin (OR = 2.27; p = 0.005). Conclusion: Compared to the SII strategy, the PI strategy may be an optimized option to children with severe infection, as it can achieve higher trough concentrations and target concentration attainment.


Introducción: Este estudio investigó la concentración plasmática de vancomicina en los niños, durante la infusión prolongada. Población y métodos: Estudio retrospectivo de una cohorte que incluyó pacientes pediátricos tratados con vancomicina desde junio de 2017 hasta junio de 2020, en un hospital de referencia de nivel III. Los pacientes se dividieron en dos grupos sogún el tipo de infusión: el grupo de infusión intermitente estándar (IIE) y el grupo de infusión prolongada (IP). Se registraron detalles demográficos, periodo de infusión, creatinina plasmática, duranción del tratamiento con vancomicina, concentración valle de vancomicina y permanencia en la unidad de cuidados intensivos pediátricos (UCIP). Se midieron las diferencias entre concentraciones. Resultados: Se incluyeron 68 pacientes, 31 en el gruop IIE y 37 en el grupo IP. La concentración valle de vancomicina fue significativamente más alta en el grupo IP en comparación con el grupo IIE (11,2mg/L [5,9-13,7] vs. 7 mg/L [3,5-9,3]; p = 0,02). La tasa de logro del objetivo fue más alta en el grupo IP que en el grupo IIE (59,4 % y 19,3 % repectivamente; p = 0,001). No hubo diferencias significativas entre ambos grupos en las concentraciones pico de vancomicina, valor de creatinina final, pico de creatinina, fracaso terapéutico, duración de la estadía en la UCIP y duración del tratamiento con vancomicina. El análisis multivariado mostró que la IP se asoció en forma significativa con concentraciones valle más altas de vancomicina (OR: 2,27, p = 0,005). Conclusión: En comparación con la estrategia de IIE, la infusión prolongada puede ser una opción optimizada para los niños con infección grave, porque puede alcanzar concentraciones valle más altas y mejorar la obtención de la concentración objetivo.

16.
Front Immunol ; 15: 1310239, 2024.
Article in English | MEDLINE | ID: mdl-38711515

ABSTRACT

Background: For decades, stratification criteria for first-line clinical studies have been highly uniform. However, there is no principle or consensus for restratification after systemic treatment progression based on immune checkpoint inhibitors (ICIs). The aim of this study was to assess the patterns of disease progression in patients with advanced hepatocellular carcinoma (HCC) who are not eligible for surgical intervention, following the use of immune checkpoint inhibitors. Methods: This is a retrospective study that involved patients with inoperable China liver stage (CNLC) IIIa and/or IIIb. The patients were treated at eight centers across China between January 2017 and October 2022. All patients received at least two cycles of first-line treatment containing immune checkpoint inhibitors. The patterns of disease progression were assessed using RECIST criteria 1.1. Different progression modes have been identified based on the characteristics of imaging progress. The study's main outcome measures were post-progression survival (PPS) and overall survival (OS). Survival curves were plotted using the Kaplan-Meier method to compare the difference among the four groups. Subgroup analysis was conducted to compare the efficacy of different immunotherapy combinations. Variations in the efficacy of immunotherapy have also been noted across patient groups exhibiting alpha-fetoprotein (AFP) levels equal to or exceeding 400ng/mL, in contrast to those with AFP levels below 400ng/mL. Results: The study has identified four distinct patterns of progress, namely p-IIb, p-IIIa, p-IIIb, and p-IIIc. Diverse patterns of progress demonstrate notable variations in both PPS and OS. The group p-IIb had the longest PPS of 12.7m (95% 9.3-16.1) and OS 19.6m (95% 15.6-23.5), the remaining groups exhibited p-IIIb at PPS 10.5 months (95%CI: 7.9-13.1) and OS 19.2 months (95%CI 15.1-23.3). Similarly, p-IIIc at PPS 5.7 months (95%CI: 4.2-7.2) and OS 11.0 months (95%CI 9.0-12.9), while p-IIIa at PPS 3.4 months (95%CI: 2.7-4.1) and OS 8.2 months (95%CI 6.8-9.5) were also seen. Additional stratified analysis was conducted and showed there were no differences of immunotherapy alone or in combination in OS (HR= 0.92, 95%CI: 0.59-1.43, P=0.68) and PPS (HR= 0.88, 95%CI: 0.57-1.36, P=0.54); there was no significant difference in PPS (HR=0.79, 95% CI: 0.55-1.12, P=0.15) and OS (HR=0.86, 95% CI: 0.61-1.24, P=0.39) for patients with AFP levels at or over 400ng/mL. However, it was observed that patients with AFP levels above 400ng/mL experienced a shorter median progression of PPS (8.0 months vs. 5.0 months) after undergoing immunotherapy. Conclusion: In this investigation of advanced hepatocellular carcinoma among Chinese patients treated with immune checkpoint inhibitors, we identified four distinct progression patterns (p-IIb, p-IIIa, p-IIIb and p-IIIc) that showed significant differences in PPS and OS. These findings demonstrate the heterogeneity of disease progression and prognosis after immunotherapy failure. Further validation in large cohorts is necessary to develop prognostic models that integrate distinct progression patterns to guide subsequent treatment decisions. Additionally, post-immunotherapy progression in patients with AFP levels ≥400ng/mL indicates a shortened median PPS. These findings provide valuable insights for future personalized treatment decisions.


Subject(s)
Carcinoma, Hepatocellular , Disease Progression , Immune Checkpoint Inhibitors , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/therapy , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/immunology , Liver Neoplasms/therapy , Liver Neoplasms/mortality , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Immune Checkpoint Inhibitors/therapeutic use , Male , Middle Aged , Female , Retrospective Studies , China , Aged , Adult , Neoplasm Staging , alpha-Fetoproteins/metabolism , alpha-Fetoproteins/analysis , Treatment Outcome , East Asian People
17.
Am J Kidney Dis ; 2024 May 14.
Article in English | MEDLINE | ID: mdl-38750878

ABSTRACT

RATIONALE & OBJECTIVE: Light and heavy chain deposition disease (LHCDD) is a rare form of monoclonal immunoglobulin (Ig) deposition disease, and limited clinical data are available characterizing this condition. Here we describe the clinicopathological characteristics and outcomes of LHCDD. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 13 patients with biopsy-proven LHCDD diagnosed between January 2008 and December 2022 at one of 2 Chinese medical centers. FINDINGS: Among the 13 patients described, 6 were men and 7 were women, with a mean age of 52.6±8.0 years. Patients presented with hypertension (76.9%), anemia (84.6%), increased serum creatinine concentrations (84.6%; median, 1.7mg/dL), proteinuria (100%; average urine protein, 3.0g/24h), nephrotic syndrome (30.8%), and microscopic hematuria (76.9%). Serum immunofixation electrophoresis showed monoclonal Ig for 11 patients (84.6%). Serum free light chain ratios were abnormal in 11 patients (84.6%), and heavy/light chain ratios were abnormal in 9 of 10 patients (90%) with available data. Five patients were diagnosed with multiple myeloma. A histological diagnosis of nodular mesangial sclerosis was made in 10 patients (76.9%). Immunofluorescence demonstrated deposits of IgG subclass in 7 patients (γ-κ, n=4; γ-λ, n=3) and IgA in 5 patients (α-κ, n=2; α-λ, n=3). Six patients underwent IgG subclass staining (γ1, n=3; γ2, n=2; γ3, n=1). The deposits of IgD-κ were confirmed by mass spectrometry in 1 patient. Among 12 patients for whom data were available during a median of 26.5 months, 11 received chemotherapy and 1 received conservative treatment. One patient died, and disease progressed to kidney failure in 3 (25%). Among the 9 patients evaluable for hematological and kidney disease progression, 5 (56%) had a hematologic response and 1 (11%) exhibited improvement in kidney disease. LIMITATIONS: Retrospective descriptive study, limited number of patients, urine protein electrophoresis or immunofixation electrophoresis test results missing for most patients. CONCLUSIONS: In this case series of LHCDD, light and heavy chain deposition in kidney tissues were most frequent with monoclonal IgG1-κ. Among patients with evaluable data, more than half had a hematologic response, but a kidney response was uncommon.

18.
Oral Oncol ; 153: 106834, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38718458

ABSTRACT

OBJECTIVES: To meet the demand for personalized treatment, effective stratification of patients with metastatic nasopharyngeal carcinoma (mNPC) is essential. Hence, our study aimed to establish an M1 subdivision for prognostic prediction and treatment planning in patients with mNPC. MATERIALS AND METHODS: This study included 1239 patients with mNPC from three medical centers divided into the synchronous mNPC cohort (smNPC, n = 556) to establish an M1 stage subdivision and the metachronous mNPC cohort (mmNPC, n = 683) to validate this subdivision. The primary endpoint was overall survival. Univariate and multivariate Cox analyses identified covariates for the decision-tree model, proposing an M1 subdivision. Model performance was evaluated using time-dependent receiver operating characteristic curves, Harrell's concordance index, calibration plots, and decision curve analyses. RESULTS: The proposed M1 subdivisions were M1a (≤5 metastatic lesions), M1b (>5 metastatic lesions + absent liver metastases), and M1c (>5 metastatic lesions + existing liver metastases) with median OS of 34, 22, and 13 months, respectively (p < 0.001). This M1 subdivision demonstrated superior discrimination (C-index = 0.698; 3-year AUC = 0.707) and clinical utility over those of existing staging systems. Calibration curves exhibited satisfactory agreement between predictions and actual observations. Internal and mmNPC cohort validation confirmed the robustness. Survival benefits from local metastatic treatment were observed in M1a, while immunotherapy improved survival in patients with M1b and M1c disease. CONCLUSION: This novel M1 staging strategy provides a refined approach for prognostic prediction and treatment planning in patients with mNPC, emphasizing the potential benefits of local and immunotherapeutic interventions based on individualized risk stratification.


Subject(s)
Decision Trees , Nasopharyngeal Carcinoma , Humans , Male , Female , Middle Aged , Nasopharyngeal Carcinoma/pathology , Nasopharyngeal Carcinoma/mortality , Nasopharyngeal Carcinoma/therapy , Retrospective Studies , Adult , Neoplasm Staging , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/mortality , Prognosis , Aged
19.
Molecules ; 29(7)2024 Apr 05.
Article in English | MEDLINE | ID: mdl-38611908

ABSTRACT

As reversible fluorescent probes, HTP-1 and HTP-2 have favourable applications for the detection of Zn2+ and H2S. Herein, the impact of solvent on the excited-state intramolecular proton transfer (ESIPT) of HTP-1 and HTP-2 was comprehensively investigated. The obtained geometric parameters and infrared (IR) vibrational analysis associated with the intramolecular hydrogen bond (IHB) indicated that the strength of IHB for HTP-1 was weakened in the excited state. Moreover, structural torsion and almost no ICT behaviour indicated that the ESIPT process did not occur in HTP-1. Nevertheless, when the 7-nitro-1,2,3-benzoxadiazole (NBD) group replaced the H atom, the IHB strength of HTP-2 was enhanced after photoexcitation, which inhibited the twisting of tetraphenylethylene, thereby opening the ESIPT channel. Notably, hole-electron analysis and frontier molecular orbitals revealed that the charge decoupling effect was the reason for the fluorescence quenching of HTP-2. Furthermore, the potential energy curves (PECs) revealed that HTP-2 was more inclined to the ESIPT process in polar solvents than in nonpolar solvents. With a decrease in solvent polarity, it was more conducive to the ESIPT process. Our study systematically presents the ESIPT process and different detection mechanisms of the two reversible probe molecules regulated by solvent polarity, providing new insights into the design and development of novel fluorescent probes.

20.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 38(4): 438-443, 2024 Apr 15.
Article in Chinese | MEDLINE | ID: mdl-38632063

ABSTRACT

Objective: To investigate the effectiveness of a new hook-shaped anatomical locking plate in the treatment of Danis-Weber type A lateral malleolus fractures. Methods: A retrospective analysis was performed on the clinical data of 45 patients with Danis-Weber type A lateral malleolus fractures who met the selection criteria between November 2020 and November 2022. According to the surgical methods, they were divided into the observation group (treated with the new hook-shaped anatomical locking plate, 23 cases) and the control group (treated with the conventional lateral malleolus anatomical locking plate, 22 cases). There was no significant difference in baseline data such as gender, age, cause of injury, Danis-Weber type of fracture, time from injury to operation, and combined ligament injury between the two groups ( P>0.05). The operation time, partial weight-bearing time, return to work time, and postoperative complications were recorded and compared between the two groups. The function and pain of ankle joint were evaluated by the range of motion of ankle dorsiflexion, plantarflexion, varus, valgus, and visual analogue scale (VAS) score at 1 and 3 months after operation, and at last follow-up, and the American Orthopaedic Foot and Ankle Society (AOFAS) score at 3 months after operation and at last follow-up. Results: All patients were followed up 10-18 months (mean, 15.1 months). There was no significant difference in operation time between the two groups ( P>0.05); the postoperative partial weight-bearing time and return to work time of the observation group were significantly earlier than those of the control group ( P<0.05). During the follow-up, there was 1 case of joint stiffness in the observation group, and 1 case of joint surface displacement, 1 case of joint stiffness, and 1 case of traumatic arthritis in the control group. There was no significant difference in the incidences of complications between the two groups ( P>0.05). With the extension of time after operation, the range of motion of ankle dorsiflexion, plantarflexion, varus, valgus, and VAS score of the two groups gradually improved, and there were significant differences between different time points ( P<0.05); At 1 and 3 months after operation, the above indexes in the observation group were significantly better than those in the control group ( P<0.05), and there was no significant difference between the two groups at last follow-up ( P>0.05). The difference of AOFAS score between the last follow-up and 3 months after operation in the observation group was significantly better than that in the control group ( P<0.05). Conclusion: Compared with the conventional lateral malleolus anatomical locking plate, the new hook-shaped anatomical locking plate has a more reliable fixation effect in the treatment of Danis-Weber type A lateral malleolus fracture, which is conducive to early functional exercise of the ankle joint, so that patients can bear weight earlier and return to work earlier, and the operation time is not significantly prolonged, and the effectiveness is satisfactory.


Subject(s)
Ankle Fractures , Humans , Ankle Fractures/surgery , Ankle Joint/surgery , Fracture Fixation, Internal/methods , Retrospective Studies , Treatment Outcome
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