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Background: Multimorbidity has become a major public health problem among Chinese middle-aged and older adults, and the most costly to the health care system. However, most previous population-based studies of multimorbidity have focused on a limited number of chronic diseases, and diagnosis was based on participants' self-report, which may oversimplify the problem. At the same time, there were few reports on the relationship between multimorbidity patterns and health care costs. This study analyzed the multimorbidity patterns and changes among middle-aged and older people in China over the past decade, and their association with medical costs, based on representative hospital electronic medical record data. Methods: Two cross-sectional surveys based on representative hospital data were used to obtain adults aged 45 years and older in Xiangyang in 2013 (n = 20,218) and 2023 (n = 63,517). Latent Class Analysis was used to analyze changes in the patterns of multimorbidity, gray correlation analysis and ordered logistics model were used to assess the association of multimorbidity patterns with medical expenses. The diagnosis and classification of chronic diseases were based on the International Classification of Diseases, Tenth Revision codes (ICD-10). Results: The detection rate of chronic disease multimorbidity has increased (70.74 vs. 76.63%, p < 0.001), and multimorbidity patterns have increased from 6 to 9 (2013: Malignant tumors pattern, non-specific multimorbidity pattern, ischemic heart disease + hypertension pattern, cerebral infarction + hypertension pattern, kidney disease + hypertension pattern, lens disease + hypertension pattern; new in 2023: Nutritional metabolism disorders + hypertension pattern, chronic lower respiratory diseases + malignant tumors pattern, and gastrointestinal diseases pattern) in China. The medical cost of all multimorbidity patients have been reduced between 2013 and 2023 (RMB: 8216.74 vs. 7247.96, IQR: 5802.28-15,737 vs. 5014.63-15434.06). The top three specific multimorbidity patterns in both surveys were malignancy tumor pattern, ischemic heart disease + hypertension pattern, and cerebral infarction + hypertension pattern. Hypertension and type 2 diabetes are important components of multimorbidity patterns. Compared with patients with a single disease, only lens disorders + hypertension pattern were at risk of higher medical costs in 2013 (aOR:1.23, 95% CI: 1.03, 1.47), whereas all multimorbidity patterns were significantly associated with increased medical costs in 2023, except for lens disorders + hypertension (aOR:0.35, 95% CI: 0.32, 0.39). Moreover, the odds of higher medical costs were not consistent across multimorbidity patterns. Among them, ischemic heart disease + hypertension pattern [adjusted odds ratio (aOR):4.66, 95%CI: 4.31, 5.05] and cerebral infarction + hypertension pattern (aOR: 3.63, 95% CI: 3.35, 3.92) were the two patterns with the highest risk. Meanwhile, men (aOR:1.12, 95CI:1.09, 1.16), no spouse (aOR:1.09, 95CI: 1.03, 1.16) had a positive effect on medical costs, while patients with total self-pay (aOR: 0.45, 95CI: 0.29, 0.70), no surgery (aOR: 0.05, 95CI: 0.05, 0.05), rural residence (aOR: 0.92, 95CI: 0.89, 0.95), hospitalization days 1-5 (aOR: 0.04, 95CI: 0.04, 0.04), and hospitalization days 6-9 (aOR: 0.15, 95CI: 0.15, 0.16) had a negative impact on medical costs. Conclusion: Multimorbidity patterns among middle-aged and older adults in China have diversified over the past decade and are associated with rising health care costs in China. Smart, decisive and comprehensive policy and care interventions are needed to effectively manage NCDS and their risk factors and to reduce the economic burden of multimorbidity on patients and the country.
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Custos de Cuidados de Saúde , Multimorbidade , Humanos , Estudos Transversais , China/epidemiologia , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Custos de Cuidados de Saúde/estatística & dados numéricos , Doença Crônica/epidemiologia , Idoso de 80 Anos ou mais , Inquéritos e Questionários , População do Leste AsiáticoRESUMO
Purpose: Approximately 50-74% of patients with metastatic HER2-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. Materials and Methods: In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cut-off date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI: 8.3-18.5). With all patients evaluated, an ORR of 38.9% (95% CI: 23.1-56.5%) and a DCR of 83.3% (95% CI: 67.2-93.6%) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Conclusion: Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.
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Rationale: Mesenchymal stromal cells (MSCs) are considered a promising resource for cell therapy, exhibiting efficacy in ameliorating diverse bone diseases. However, most MSCs undergo apoptosis shortly after transplantation and produce apoptotic extracellular vesicles (ApoEVs). This study aims to clarify the potential role of ApoEVs from apoptotic MSCs in ameliorating osteoporosis and molecular mechanism. Methods: In this study, Dio-labeled bone marrow mesenchymal stem cells (BMSCs) were injected into mice to track BMSCs apoptosis and ApoEVs production. ApoEVs were isolated from BMSCs after inducing apoptosis, the morphology, size distribution, marker proteins expression of ApoEVs were characterized. Protein mass spectrometry analysis revealed functional differences in proteins between ApoEVs and BMSCs. BMSCs were adopted to test the cellular response to ApoEVs. Ovariectomy mice were used to further compare the ability of ApoEVs in promoting bone formation. SiRNA and lentivirus were used for gain and loss-of-function assay. Results: The results showed that BMSCs underwent apoptosis within 2 days after being injected into mice and produce a substantial quantity of ApoEVs. Proteomic analysis revealed that ApoEVs carried a diverse functional array of proteins, and easily traversed the circulation to reach the bone. After being phagocytized by endogenous BMSCs, ApoEVs efficiently promoted the proliferation, migration, and osteogenic differentiation of BMSCs. In an osteoporosis mouse model, treatment of ApoEVs alleviated bone loss and promoted bone formation. Mechanistically, ApoEVs carried Ras protein and activated the Ras/Raf1/Mek/Erk pathway to promote osteogenesis and bone formation in vitro and in vivo. Conclusion: Given that BMSC-derived ApoEVs are high-yield and easily obtained, our data underscore the substantive role of ApoEVs from dying BMSCs to treat bone loss, presenting broad implications for cell-free therapeutic modalities.
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Apoptose , Vesículas Extracelulares , Células-Tronco Mesenquimais , Osteogênese , Osteoporose , Animais , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/transplante , Células-Tronco Mesenquimais/metabolismo , Osteoporose/terapia , Osteoporose/metabolismo , Camundongos , Feminino , Osteogênese/fisiologia , Diferenciação Celular , Transplante de Células-Tronco Mesenquimais/métodos , Proliferação de Células , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças , Ovariectomia , Proteômica , Transdução de SinaisRESUMO
OBJECTIVE: Most cases of hepatocellular carcinoma (HCC) arise as a consequence of cirrhosis. In this study, our objective is to construct a comprehensive diagnostic model that investigates the diagnostic markers distinguishing between cirrhosis and HCC. METHODS: Based on multiple GEO datasets containing cirrhosis and HCC samples, we used lasso regression, random forest (RF)-recursive feature elimination (RFE) and receiver operator characteristic analysis to screen for characteristic genes. Subsequently, we integrated these genes into a multivariable logistic regression model and validated the linear prediction scores in both training and validation cohorts. The ssGSEA algorithm was used to estimate the fraction of infiltrating immune cells in the samples. Finally, molecular typing for patients with cirrhosis was performed using the CCP algorithm. RESULTS: The study identified 137 differentially expressed genes (DEGs) and selected five significant genes (CXCL14, CAP2, FCN2, CCBE1 and UBE2C) to construct a diagnostic model. In both the training and validation cohorts, the model exhibited an area under the curve (AUC) greater than 0.9 and a kappa value of approximately 0.9. Additionally, the calibration curve demonstrated excellent concordance between observed and predicted incidence rates. Comparatively, HCC displayed overall downregulation of infiltrating immune cells compared to cirrhosis. Notably, CCBE1 showed strong correlations with the tumour immune microenvironment as well as genes associated with cell death and cellular ageing processes. Furthermore, cirrhosis subtypes with high linear predictive scores were enriched in multiple cancer-related pathways. CONCLUSION: In conclusion, we successfully identified diagnostic markers distinguishing between cirrhosis and hepatocellular carcinoma and developed a novel diagnostic model for discriminating the two conditions. CCBE1 might exert a pivotal role in regulating the tumour microenvironment, cell death and senescence.
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Biomarcadores Tumorais , Carcinoma Hepatocelular , Cirrose Hepática , Neoplasias Hepáticas , Aprendizado de Máquina , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica , Análise de Sequência com Séries de OligonucleotídeosAssuntos
Hidroxiureia , Esplenectomia , Trombocitose , Talassemia beta , Humanos , Hidroxiureia/uso terapêutico , Trombocitose/etiologia , Trombocitose/tratamento farmacológico , Talassemia beta/tratamento farmacológico , Talassemia beta/complicações , Talassemia beta/cirurgia , Masculino , Feminino , Antidrepanocíticos/uso terapêutico , CriançaRESUMO
BACKGROUD: Li-Fraumeni syndrome is a hereditary tumor syndrome characterized by an elevated risk of malignancy, particularly acute lymphoblastic leukemia (ALL), which can be caused by the heterozygous germline mutation. TP53 gene germline mutation is considered a potential risk factor and crucial prognostic parameter for acute leukemia development and diagnosis, but rarely occurs in adults, and its specific pathogenic significance in acute leukemia is unclear. CASE PRESENTATION: We describes a case of a 45-year-old woman diagnosed with ALL. Whole-exome sequencing approach identified one of the TP53 germline mutations from her bone marrow sample with possible pathogenic significance, c.848G>A (p.Arg283His) heterozygous missense mutation located on exon 8, which was further verified in her hair, oral mucous and nail samples. Family pedigree screening revealed that the same TP53 genetic variant was present in the patient's father and non-donor son, whereas not in the donor. Digital PCR observed that this point mutation frequency dropped post-transplantation but remained low during maintenance therapy when the patient was leukemia-free. CONCLUSION: This suspected Li-Fraumeni syndrome case report with a likely pathogenic heterozygous TP53 variant expands the cancer genetic spectrum. Screening her family members for mutations facilitates identifying the optimal relative donor and avoids unnecessary treatment by monitoring TP53 germline mutations for minimal residual disease following hematopoietic stem cell transplantation. Its potential roles in hematological malignant tumor development and clinical pathogenic implications necessitate further probing.
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Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni , Leucemia-Linfoma Linfoblástico de Células Precursoras , Proteína Supressora de Tumor p53 , Humanos , Feminino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/diagnóstico , LinhagemRESUMO
Oral lichen planus (OLP) is a carcinogenic chronic inflammatory oral disease, which lacks effective treatments. Fraxin is an active ingredient of the traditional Chinese medicine Qin Pi, which has an anti-inflammatory effect, but its effect on OLP is unclear. The aim of this study was to investigate the therapeutic effect of fraxin on OLP and the underlying mechanism. Human immortalized keratinocytes (HaCat) were incubated with fraxin (10, 20, or 40 µM) for 48 h and then treated with 10 µg/mL LPS for 24 h. Cell viability and apoptosis were detected. Next, the interaction between OCT3 and FGF2 was predicted by online database and verified by Co-IP analysis. Fraxin, Ad-OCT3, sh-OCT3, and sh-FGF2 were, respectively, applied to treat LPS-incubated HaCat cells, and cell viability, apoptosis, and secretion of inflammatory factors were detected with MTT, flow cytometry, and ELISA assays. Then, the involvement of OCT3 and FGF2 in the prevention of fraxin on HaCat cells from LPS-induced cell apoptosis and inflammation was investigated through multiple rescue experiments. In addition, OLP models were constructed in VDR-/- mice and NOD/SCID mice by injecting with human OLP pathological tissue homogenates to verify the therapeutic effect of fraxin on OLP. Fraxin treatment increased cell viability and reduced cell apoptosis and the secretion of IL-6 and TNF-α in a dose-dependent manner. OCT3 was significantly upregulated in oral mucosa tissues of OLP mice. OCT3 silencing inhibited LPS-induced cell apoptosis and secretion of inflammatory factors. Fraxin incubation reduced the expression of OCT3, and OCT3 interacted with FGF2 to upregulate FGF2 protein. FGF2 silencing reduced the expression of p-p65/NF-κB protein and improved LPS-induced cell apoptosis and secretion of inflammatory factors. OCT3 overexpression increased the expression of FGF2 and p-p65/NF-κB proteins, rh-FGF2 aggravated this effect, while FGF2-Neu-Ab reversed this effect. The results of in vivo experiments showed that fraxin alleviated cell apoptosis and inflammation in oral buccal mucosa tissues of OLP mice. Fraxin inhibited cell apoptosis and inflammation by suppressing OCT3-mediated activation of the FGF2/NF-κB pathway, alleviating the progression of OLP.
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OBJECTIVE: The cardiovascular system effects of environmental low-dose radiation exposure on radiation practitioners remain uncertain and require further investigation. The aim of this study was to initially investigate and explore the mechanisms by which low-dose radiation may contribute to atherosclerosis through a multi-omics joint comprehensive basic experiment. METHODS: We used WGCNA and differential analyses to identify shared genes and potential pathways between radiation injury and atherosclerosis sequencing datasets, as well as tissue transcriptome immune infiltration level extrapolation and single-cell transcriptome data correction using the CIBERSORT deconvolution algorithm. Animal models were constructed by combining a high-fat diet with 5 Gy γ-ray whole-body low-dose ionizing radiation. The detection of NETs release was validated by enzyme-linked immunosorbent assay. RESULTS: Analysis reveals shared genes in both datasets of post-irradiation and atherosclerosis, suggesting that immune system neutrophils may be a key node connecting radiation to atherosclerosis. NETs released by neutrophil death can influence the development of atherosclerosis. Animal experiments showed that the number of neutrophils decreased (P < 0.05) and the concentration of NETs reduced after low-dose radiation compared with the control group, and the concentration of NETs significantly increased (P < 0.05) in the HF group. Endothelial plaques were significantly increased in the high-fat feed group and significantly decreased in the low-dose radiation group compared with the control group. CONCLUSIONS: Long-term low-dose ionizing radiation exposure stimulates neutrophils and inhibits their production of NETs, resulting in inhibition of atherosclerosis.
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Aterosclerose , Aterosclerose/prevenção & controle , Animais , Camundongos , Armadilhas Extracelulares , Exposição à Radiação , NeutrófilosRESUMO
INTRODUCTION: The underlying mechanisms of gastric cancer (GC) remain unknown. Therefore, in this study, we employed a comprehensive approach, combining computational and experimental methods, to identify potential key genes and unveil the underlying pathogenesis and prognosis of GC. METHODS: Gene expression profiles from GEO databases (GSE118916, GSE79973, and GSE29272) were analyzed to identify DEGs between GC and normal tissues. A PPI network was constructed using STRING and Cytoscape, followed by hub gene identification with CytoHubba. Investigations included expression and promoter methylation analysis, survival modeling, mutational and miRNA analysis, gene enrichment, drug prediction, and in vitro assays for cellular behaviors. RESULTS: A total of 83 DEGs were identified in the three datasets, comprising 41 up-regulated genes and 42 down-regulated genes. Utilizing the degree and MCC methods, we identified four hub genes that were hypomethylated and up-regulated: COL1A1, COL1A2, COL3A1, and FN1. Subsequent validation of their expression and promoter methylation on clinical GC samples through targeted bisulfite sequencing and RT-qPCR analysis further confirmed the hypomethylation and overexpression of these genes in local GC patients. Furthermore, it was observed that these hub genes regulate tumor proliferation and metastasis in in vivo and exhibited mutations in GC patients. CONCLUSION: We found four potential diagnostic and prognostic biomarkers, including COL1A1, COL1A2, COL3A1, and FN1 that may be involved in the occurrence and progression of GC.
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Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Humanos , Metilação de DNA/genética , Regiões Promotoras Genéticas/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Simulação por Computador , Prognóstico , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Mapas de Interação de Proteínas/genética , Redes Reguladoras de Genes , Bases de Dados Genéticas , Biologia Computacional , Proliferação de Células/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Fibronectinas , Colágeno Tipo IRESUMO
BACKGROUND: Permanent hypoparathyroidism is a significant complication after total thyroidectomy. This study aimed to evaluate the long-term impact of postoperative permanent hypoparathyroidism on kidney outcomes. METHODS: Data of patients undergoing total thyroidectomy from 1999 to 2014 were retrieved. The estimated glomerular filtration rate was determined from serum creatinine results. Permanent hypoparathyroidism was defined as requiring oral calcium and vitamin D supplements postoperatively for at least 6 months. The primary outcome was a sustained decline in the estimated glomerular filtration rate from baseline by ≥50%. Secondary outcomes were end-stage kidney disease (a composite of sustained estimated glomerular filtration rate <15 mL/min/1.73 m2, need for dialysis, and kidney transplantation) and rate of estimated glomerular filtration rate decline. Patients with and without permanent hypoparathyroidism were compared. Multivariable Cox regression analysis was performed to identify independent risk factors for sustained estimated glomerular filtration rate decline by ≥50%. RESULTS: In total, 3,245 patients were eligible for analysis; 418 patients (12.9%) had permanent hypoparathyroidism. Upon median follow-up of 11.6 years, more patients with permanent hypoparathyroidism had a sustained decline in estimated glomerular filtration rate from baseline by ≥50% compared to those without (15.6% vs 6.9%, P < .001). Similar findings were obtained on Kaplan-Meier analysis (P < .001). Permanent hypoparathyroidism was an independent risk factor for sustained estimated glomerular filtration rate decline by ≥50% (adjusted hazard ratio 2.77, P < .001). Other risk factors included age, preoperative estimated glomerular filtration rate <60 mL/min/1.73m2, and diabetes mellitus. Patients with permanent hypoparathyroidism had a more rapid estimated glomerular filtration rate decline (-1.60 vs -0.70 mL/min/1.73 m2/year, difference -0.91 mL/min/1.73m2/year, P < .001). CONCLUSION: Patients with postsurgical permanent hypoparathyroidism were at greater risk of renal impairment. Further research is warranted to improve the identification and preservation of parathyroid glands during thyroidectomy to minimize patient morbidity.
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Taxa de Filtração Glomerular , Hipoparatireoidismo , Complicações Pós-Operatórias , Tireoidectomia , Humanos , Hipoparatireoidismo/etiologia , Hipoparatireoidismo/epidemiologia , Tireoidectomia/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/diagnóstico , Estudos Retrospectivos , Falência Renal Crônica/cirurgia , Fatores de Risco , Idoso , SeguimentosRESUMO
To study the pharmacokinetics of deoxypodophyllotoxin and its metabolites in non-small cell lung cancer (NSCLC) bearing mice.Using the established LC-MS/MS method for simultaneous determination of deoxypodophyllotoxin and its three main metabolites (M1, M2 and M7) in biological samples, the concentrations of deoxypodophyllotoxin and its metabolites in plasma, tumour and major tissues of tumour-bearing mice were investigated after 6.25 and 25 mg/kg intravenous administration of deoxypodophyllotoxin.The exposure results of drug concentration showed that after intravenous injection of 6.25 and 25 mg/kg of DPT into tumour-bearing mice, the AUC ratio of DPT in tumour tissue to DPT in plasma was 4.23 and 3.80, respectively. While, the AUC ratio of metabolite M2 in tumour tissue to M2 in plasma was 0.82 and 0.76, respectively.Deoxypodophyllotoxin had higher affinity with tumour tissues than plasma, while its metabolite M2 had less affinity with tumour tissues than deoxypodophyllotoxin, but the exposure level of M2 in plasma was higher than that of deoxypodophyllotoxin. Deoxypodophyllotoxin was widely distributed in tumour-bearing mice. After intravenous injection of 25 mg/kg deoxypodophyllotoxin, the concentration of deoxypodophyllotoxin in other tissues except liver and muscle was relatively high, especially in lung, fat and reproductive organs.
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Carcinoma Pulmonar de Células não Pequenas , Podofilotoxina , Animais , Podofilotoxina/farmacocinética , Podofilotoxina/metabolismo , Podofilotoxina/análogos & derivados , Camundongos , Distribuição Tecidual , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Espectrometria de Massas em Tandem , Medicamentos de Ervas ChinesasRESUMO
With advances in next-generation sequencing technology, there is growing evidence that the gut microbiome plays a key role in the host's innate and adaptive immune system. Gut microbes and their metabolites directly or indirectly regulate host immune cells. Crucially, dysregulation of the gut microbiota is often associated with many immune system diseases. In turn, microbes modulate disease immunotherapy. Data from preclinical to clinical studies suggest that the gut microbiota may influence the effectiveness of tumor immunotherapy, particularly immune checkpoint inhibitors (ICIs). In addition, the most critical issue now is a COVID-19 vaccine that generates strong and durable immunity. A growing number of clinical studies confirm the potential of gut microbes to enhance the efficacy of COVID-19 vaccines. However, it is still unclear how gut bacteria interact with immune cells and what treatments are based on gut microbes. Here, we outline recent advances in the effects and mechanisms of the gut microbiota and its metabolites (tryptophan metabolites, bile acids, short-chain fatty acids, and inosine) on different immune cells (dendritic cells, CD4+T cells, and macrophages). It also highlights innovative intervention strategies and clinical trials of microbiota-based checkpoint blocking therapies for tumor immunity, and ongoing efforts to maintain the long-term immunogenicity of COVID-19 vaccines. Finally, the challenges to be overcome in this area are discussed. These provide an important basis for further research and clinical translation of gut microbiota.
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COVID-19 , Microbioma Gastrointestinal , Imunoterapia , Humanos , Microbioma Gastrointestinal/imunologia , Imunoterapia/métodos , COVID-19/imunologia , COVID-19/prevenção & controle , COVID-19/terapia , Vacinas contra COVID-19/imunologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Animais , SARS-CoV-2/imunologia , Neoplasias/imunologia , Neoplasias/terapiaRESUMO
Beryllium sulfate (BeSO4) can cause inflammation through the mechanism, which has not been elucidated. Mitochondrial DNA (mtDNA) is a key contributor of inflammation. With mitochondrial damage, released mtDNA can bind to specific receptors (e.g., cGAS) and then activate related pathway to promote inflammatory responses. To investigate the mechanism of mtDNA in BeSO4-induced inflammatory response in 16HBE cells, we established the BeSO4-induced 16HBE cell inflammation model and the ethidium bromide (EB)-induced ρ016HBE cell model to detect the mtDNA content, oxidative stress-related markers, mitochondrial membrane potential, the expression of the cGAS-STING pathway, and inflammation-related factors. Our results showed that BeSO4 caused oxidative stress, decline of mitochondrial membrane potential, and the release of mtDNA into the cytoplasm of 16HBE cells. In addition, BeSO4 induced inflammation in 16HBE cells by activating the cGAS-STING pathway. Furthermore, mtDNA deletion inhibited the expression of cGAS-STING pathway, IL-10, TNF-α, and IFN-ß. This study revealed a novel mechanism of BeSO4-induced inflammation in 16HBE cells, which contributes to the understanding of the molecular mechanism of beryllium and its compounds-induced toxicity.
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Berílio , DNA Mitocondrial , Inflamação , Proteínas de Membrana , Nucleotidiltransferases , Transdução de Sinais , Humanos , DNA Mitocondrial/efeitos dos fármacos , DNA Mitocondrial/metabolismo , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Inflamação/induzido quimicamente , Inflamação/metabolismo , Berílio/toxicidade , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Estresse Oxidativo/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Solid tumors are complex ecosystems with heterogeneous 3D structures, but the spatial intra-tumor heterogeneity (sITH) at the macroscopic (i.e., whole tumor) level is under-explored. Using a phylogeographic approach, we sequence genomes and transcriptomes from 235 spatially informed sectors across 13 hepatocellular carcinomas (HCC), generating one of the largest datasets for studying sITH. We find that tumor heterogeneity in HCC segregates into spatially variegated blocks with large genotypic and phenotypic differences. By dissecting the transcriptomic heterogeneity, we discover that 30% of patients had a "spatially competing distribution" (SCD), where different spatial blocks have distinct transcriptomic subtypes co-existing within a tumor, capturing the critical transition period in disease progression. Interestingly, the tumor regions with more advanced transcriptomic subtypes (e.g., higher cell cycle) often take clonal dominance with a wider geographic range, rejecting neutral evolution for SCD patients. Extending the statistical tests for detecting natural selection to many non-SCD patients reveal varying levels of selective signal across different tumors, implying that many evolutionary forces including natural selection and geographic isolation can influence the overall pattern of sITH. Taken together, tumor phylogeography unravels a dynamic landscape of sITH, pinpointing important evolutionary and clinical consequences of spatial heterogeneity in cancer.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Ecossistema , Filogeografia , Neoplasias Hepáticas/genética , Perfilação da Expressão GênicaRESUMO
Acute kidney injury (AKI) is often accompanied by uremic encephalopathy resulting from accumulation of uremic toxins in brain possibly due to impaired blood-brain barrier (BBB) function. Anionic uremic toxins are substrates or inhibitors of organic anionic transporters (OATs). In this study we investigated the CNS behaviors and expression/function of BBB OAT3 in AKI rats and mice, which received intraperitoneal injection of cisplatin 8 and 20 mg/kg, respectively. We showed that cisplatin treatment significantly inhibited the expressions of OAT3, synaptophysin and microtubule-associated protein 2 (MAP2), impaired locomotor and exploration activities, and increased accumulation of uremic toxins in the brain of AKI rats and mice. In vitro studies showed that uremic toxins neither alter OAT3 expression in human cerebral microvascular endothelial cells, nor synaptophysin and MAP2 expressions in human neuroblastoma (SH-SY5Y) cells. In contrast, tumour necrosis factor alpha (TNFα) and the conditioned medium (CM) from RAW264.7 cells treated with indoxyl sulfate (IS) significantly impaired OAT3 expression. TNFα and CM from IS-treated BV-2 cells also inhibited synaptophysin and MAP2 expressions in SH-SY5Y cells. The alterations caused by TNFα and CMs in vitro, and by AKI and TNFα in vivo were abolished by infliximab, a monoclonal antibody designed to intercept and neutralize TNFα, suggesting that AKI impaired the expressions of OAT3, synaptophysin and MAP2 in the brain via IS-induced TNFα release from macrophages or microglia (termed as IS-TNFα axis). Treatment of mice with TNFα (0.5 mg·kg-1·d-1, i.p. for 3 days) significantly increased p-p65 expression and reduced the expressions of Nrf2 and HO-1. Inhibiting NF-κB pathway, silencing p65, or activating Nrf2 and HO-1 obviously attenuated TNFα-induced downregulation of OAT3, synaptophysin and MAP2 expressions. Significantly increased p-p65 and decreased Nrf2 and HO-1 protein levels were also detected in brain of AKI mice and rats. We conclude that AKI inhibits the expressions of OAT3, synaptophysin and MAP2 due to IS-induced TNFα release from macrophages or microglia. TNFα impairs the expressions of OAT3, synaptophysin and MAP2 partly via activating NF-κB pathway and inhibiting Nrf2-HO-1 pathway.
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Injúria Renal Aguda , Cisplatino , Indicã , Fator de Necrose Tumoral alfa , Animais , Injúria Renal Aguda/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Camundongos , Masculino , Células RAW 264.7 , Ratos , Camundongos Endogâmicos C57BL , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ratos Sprague-Dawley , Sinaptofisina/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Uremia/metabolismo , Uremia/complicações , Linhagem Celular TumoralRESUMO
BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMN) are very rare, accounting for approximately 0.2%-0.5% of gastrointestinal tumors. We conducted a multicenter retrospective study to explore the impact of different surgical procedures combined with HIPEC on the short-term outcomes and long-term survival of patients. METHODS: We retrospectively analyzed the clinicopathological data of 91 LAMN perforation patients from 9 teaching hospitals over a 10-year period, and divided them into HIPEC group and non-HIPEC group based on whether or not underwent HIPEC. RESULTS: Of the 91 patients with LAMN, 52 were in the HIPEC group and 39 in the non-HIPEC group. The Kaplan-Meier method predicted that 52 patients in the HIPEC group had 5- and 10-year overall survival rates of 82.7% and 76.9%, respectively, compared with predicted survival rates of 51.3% and 46.2% for the 39 patients in the non-HIPEC group, with a statistically significant difference between the two groups (χ2 = 10.622, p = 0.001; χ2 = 10.995, p = 0.001). Compared to the 5-year and 10-year relapse-free survival rates of 75.0% and 65.4% in the HIPEC group, respectively, the 5-year and 10-year relapse-free survival rates of 48.7% and 46.2% in the non-HIPEC group were significant different between the two outcomes (χ2 = 8.063, p = 0.005; χ2 = 6.775, p = 0.009). The incidence of postoperative electrolyte disturbances and hypoalbuminemia was significantly higher in the HIPEC group than in the non-HIPEC group (p = 0.023; p = 0.044). CONCLUSIONS: This study shows that surgery combined with HIPEC can significantly improve 5-year and 10-year overall survival rates and relapse-free survival rates of LAMN perforation patients, without affecting their short-term clinical outcomes.
Assuntos
Adenocarcinoma Mucinoso , Neoplasias do Apêndice , Quimioterapia Intraperitoneal Hipertérmica , Humanos , Estudos Retrospectivos , Masculino , Feminino , Neoplasias do Apêndice/terapia , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/patologia , Pessoa de Meia-Idade , Adulto , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/patologia , Idoso , Terapia Combinada , Resultado do Tratamento , Taxa de Sobrevida , Gradação de Tumores , Perfuração Intestinal/etiologia , Neoplasias Peritoneais/terapia , Neoplasias Peritoneais/mortalidadeRESUMO
OBJECTIVES: This network meta-analysis aimed to evaluate the association of anti-thyroid drugs (ATD), radioactive iodine (RAI), and thyroidectomy with subsequent outcomes in patients with newly-diagnosed hyperthyroidism. METHODS: The Ovid Medline, Ovid Embase, and Cochrane Library databases were searched for observational studies and randomized controlled trials. Included studies were published on or before 1st May 2022 involving at least two of the treatments among ATD, RAI, and thyroidectomy for hyperthyroidism. Pairwise comparisons and Bayesian network meta-analysis were used to estimate hazard ratios (HRs) and their credible interval (CrI) of outcomes, including cardiovascular disease (CVD), cancer, overall mortality, and Graves' ophthalmopathy (GO). RESULTS: A total of 22 cohort studies with 131,297 hyperthyroidism patients were included. Thyroidectomy was associated with lower risks of mortality and GO than ATD (HR = 0.54, 95% CrI: 0.31, 0.96; HR = 0.31, 95% CrI: 0.12, 0.64) and RAI (HR = 0.62, 95% CrI: 0.41, 0.95; HR = 0.18, 95% CrI: 0.07, 0.35). RAI had a higher risk of GO (HR = 1.70, 95% CrI: 1.02, 2.99) than ATD treatment. CONCLUSIONS: This Bayesian network meta-analysis indicated that thyroidectomy was associated with lower risks of mortality and GO in newly-diagnosed hyperthyroid patients compared to ATD and RAI. Relative to ATD, RAI therapy increased the risk of GO.
Assuntos
Teorema de Bayes , Oftalmopatia de Graves , Metanálise em Rede , Humanos , Antitireóideos/uso terapêutico , Doenças Cardiovasculares/mortalidade , Oftalmopatia de Graves/mortalidade , Oftalmopatia de Graves/terapia , Hipertireoidismo/mortalidade , Hipertireoidismo/terapia , Radioisótopos do Iodo/uso terapêutico , Neoplasias/mortalidade , Neoplasias/terapia , TireoidectomiaRESUMO
Indeed, tumors are a significant health concern worldwide, and understanding the underlying mechanisms of tumor development is crucial for effective prevention and treatment. Epigenetics, which refers to changes in gene expression that are not caused by alterations in the DNA sequence itself, plays a critical role in the entire process of tumor development. It goes without saying that the effect of methylation on tumors is a significant aspect of epigenetics. Among the methylation modifications, DNA methylation is an important part, which plays a regulatory role in tumor-related genes. Ten-eleven translocation 2 (TET2) is a highly influential protein involved in the modification of DNA methylation. Its primary role is associated with the suppression of tumor development, making it a significant player in cancer research. However, TET2 is frequently mentioned in hematological diseases, its role in solid tumors has received little attention. Studying the changes of TET2 in solid tumors and the regulatory mechanism will facilitate its investigation as a clinical target for targeted therapy and may also provide directions for clinical treatment of malignant tumors.
Assuntos
Metilação de DNA , Proteínas de Ligação a DNA , Dioxigenases , Epigênese Genética , Neoplasias , Proteínas Proto-Oncogênicas , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genéticaRESUMO
The heterogeneous nature of tumors presents a considerable obstacle in addressing imatinib resistance in advanced cases of gastrointestinal stromal tumors (GIST). To address this issue, we conducted single-cell RNA-sequencing in primary tumors as well as peritoneal and liver metastases from patients diagnosed with locally advanced or advanced GIST. Single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Immunohistochemistry and multiplex immunofluorescence staining were used to further validate it. This analysis revealed unique tumor evolutionary patterns, transcriptome features, dynamic cell-state changes, and different metabolic reprogramming. The findings indicate that in imatinib-resistant TME, tumor cells with activated immune and cytokine-mediated immune responses interacted with a higher proportion of Treg cells via the TIGIT-NECTIN2 axis. Future immunotherapeutic strategies targeting Treg may provide new directions for the treatment of imatinib-resistant patients. In addition, IDO1+ dendritic cells (DC) were highly enriched in imatinib-resistant TME, interacting with various myeloid cells via the BTLA-TNFRSF14 axis, while the interaction was not significant in imatinib-sensitive TME. Our study highlights the transcriptional heterogeneity and distinct immunosuppressive microenvironment of advanced GIST, which provides novel therapeutic strategies and innovative immunotherapeutic agents for imatinib resistance.
Assuntos
Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Microambiente Tumoral , Evolução Biológica , CitocinasRESUMO
BACKGROUND AND AIMS: Radiotherapy is widely applied for lung adenocarcinoma (LUAD), while individualized differences led to different outcomes. This study aimed to establish a multi-gene risk scoring model to predict the benefits of LUAD patients from radiotherapy, based on different types of cell death respectively. RESULTS: Other than autophagy, pyroptosis, ferroptosis and Immunogenic cell death (ICD), the LUAD prognostic model based on apoptosis had the best performance, and the area under curves (AUCs) of the receiver operating curve (ROC) for 1-, 3-, and 5-year OS were 0.700,0.736,0.723,respectively. Such genes were involved as SLC7A5, EXO1, ABAT, NLRP1 and GAR1. Then patients were divided into high and low risk groups by the median apoptosis-LUAD risk score. For patients in the high-risk group, i.e., the radiotherapy-tolerant group, we screened adjuvant chemotherapy and found that besides the conventional first-line chemotherapy regimen, drugs such as Fludarabine, Pevonedistat, and Podophyllotoxin Bromide may also have potential therapeutic value. CONCLUSION: The multi-gene risk scoring model based on apoptosis might predict the radiotherapy benefits of LUAD patients and for those radioresistant patients classified by the model we also provided effective adjuvant chemicals, which would be used to guide clinical treatment.