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OBJECTIVE: To analyze the relationship between serum cystatin C (CysC), ß2-microglobulin (ß2-MG) and the efficacy of demethylation therapy in patients with acute myeloid leukemia (AML). METHODS: A prospective cohort study was conducted on 98 AML patients admitted to the Affiliated Hospital of Inner Mongolia Medical University from February 2019 to January 2022. All patients were treated with decitabine (DAC) + HAG regimen, 28 days as a course and treated for 3-4 courses. At the end of each course of treatment, the treatment effect of the patients was evaluated, and the patients who achieved complete remission (CR) transferred to consolidation therapy, while the patients who did not reach CR at the end of the course of treatment were considered as treatment failure. The examination items before treatment include routine blood parameters, serum CysC, and ß2-MG, and general clinical data of the patients were collected. According to the statistical results, logistic regression model was used to analyze the relationship between serum CysC, ß2-MG and the efficacy of demethylation therapy in AML patients. The ROC curves were drawn, and the predictive efficacy of serum CysC, ß2-MG on demethylation therapy in AML patients was evaluated by the area under the curve (AUC). RESULTS: Of the 98 AML patients enrolled in the study, 5 cases were excluded during the treatment period, and 93 cases finally completed the chemotherapy courses. Among them, 23 patients achieved CR after the initial induction chemotherapy (course 1-2), and 11 patients achieved CR after the re-induction chemotherapy (course 3-4). The success rate of demethylation therapy was 36.56 % (34/93). Compared with the patients in treatment success group, patients in treatment failure group had a higher proportion of intermediate- and adverse-risk, lower levels of platelet (PLT) and hemoglobin (Hb), and higher expression levels of serum CysC and ß2-MG, all of which were statistically significant (P < 0.05). Logistic regression analysis showed that high expression of serum CysC, ß2-MG and adverse-risk were independent risk factors for failure of demethylation treatment in AML patients (OR >1, P < 0.05). The ROC curves showed that the AUC values of serum CysC, ß2-MG alone and combined in predicting the efficacy of demethylation therapy in AML patients were 0.788, 0.785 and 0.834, respectively. CONCLUSION: The failure of demethylation therapy in AML patients is related to the high expression of serum CysC and ß2-MG, and detection of serum CysC and ß2-MG before treatment can predict the risk of demethylation therapy failure in AML patients.
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Cistatina C , Leucemia Mieloide Aguda , Microglobulina beta-2 , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/sangre , Estudios Prospectivos , Microglobulina beta-2/sangre , Cistatina C/sangre , Desmetilación , Inducción de Remisión , Decitabina , Masculino , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Persona de Mediana EdadRESUMEN
Colorectal cancer (CRC) is a common malignant tumor that occurs in the colon. Gut microbiota is a complex ecosystem that plays an important role in the pathogenesis of CRC. Our previous studies showed that the soluble dietary fiber of foxtail millet (FMB-SDF) exhibited significant antitumor activity in vitro. The present study evaluated the anticancer potential of FMB-SDF in the azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced mouse CRC models. The results showed that FMB-SDF could significantly alleviate colon cancer symptoms in mice. Further, we found that FMB-SDF consumption significantly altered gut microbiota diversity and the overall structure and regulated the abundance of some microorganisms in CRC mice. Meanwhile, KEGG pathway enrichment showed that FMB-SDF can also alleviate the occurrence of colon cancer in mice by regulating certain cancer-related signaling pathways. In conclusion, our findings may provide a novel approach for the prevention and biotherapy of CRC.
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Bacterias , Neoplasias Colorrectales , Fibras de la Dieta , Microbioma Gastrointestinal , Setaria (Planta) , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias Colorrectales/prevención & control , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/metabolismo , Ratones , Setaria (Planta)/química , Fibras de la Dieta/metabolismo , Fibras de la Dieta/farmacología , Humanos , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Bacterias/efectos de los fármacos , Bacterias/metabolismo , Masculino , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Extractos Vegetales/química , Azoximetano , Ratones Endogámicos C57BLRESUMEN
Short-chain fatty acids (SCFAs) are, the metabolic byproducts of intestinal microbiota that, are generated through anaerobic fermentation of undigested dietary fibers. SCFAs play a pivotal role in numerous physiological functions within the human body, including maintaining intestinal mucosal health, modulating immune functions, and regulating energy metabolism. In recent years, extensive research evidence has indicated that SCFAs are significantly involved in the onset and progression of Parkinson disease (PD). However, the precise mechanisms remain elusive. This review comprehensively summarizes the progress in understanding how SCFAs impact PD pathogenesis and the underlying mechanisms. Primarily, we delve into the synthesis, metabolism, and signal transduction of SCFAs within the human body. Subsequently, an analysis of SCFA levels in patients with PD is presented. Furthermore, we expound upon the mechanisms through which SCFAs induce inflammatory responses, oxidative stress, abnormal aggregation of alpha-synuclein, and the intricacies of the gut-brain axis. Finally, we provide a critical analysis and explore the potential therapeutic role of SCFAs as promising targets for treating PD.
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Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/microbiología , Microbioma Gastrointestinal/fisiología , Ácidos Grasos Volátiles/metabolismo , Eje Cerebro-Intestino/fisiología , Estrés Oxidativo/fisiologíaRESUMEN
Background: Breast cancer (BC) is a frequent disease in females. The heat shock 70 kDa protein 5 (HSPA5) has recently been discovered to have an important function in tumor growth. However, the biological significance of HSPA5 in BC is unknown. Material and Method. Firstly, The Cancer Genome Atlas (TCGA) database was applied to analyze the expressions of HSPA5 in different cancer types, especially in BC. Then, the LinkedOmics database was used to screen genes coexpressed with HSPA5 in BC, presented by protein-protein interaction (PPI) and analyzed by functional enrichment analyses. Next, the Kaplan-Meier plotter was adopted to study the prognostic significance of HSPA5 and the relation between HSPA5 expression and different clinical factors in BC. Finally, the Tumor Immune Estimation Resource (TIMER) method was adopted to explore the relation between immune infiltration and HSPA5 in BC. Result: HSPA5 was highly expressed in most cancers, including BC. Genes coexpressed with HSPA5 were mainly related to endoplasmic reticulum unfolded protein response, melanosome, thyroid hormone synthesis, N-glycan biosynthesis, and so on. In the survival analysis, high HSPA5 expression indicated a poor prognosis in BC, and the expression of HSPA5 in BC was elevated after the incidence of BC, changing with different clinical factors. In the immune infiltration, HSPA5 was positively correlated with most immune cells. Conclusion: HSPA5 is an oncogene in BC progression, and it is connected with the prognosis and the immune infiltration in BC. Our findings suggest that HSPA5 could be an immunotherapy target and a prognostic biomarker in BC.
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Neoplasias de la Mama , Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , Chaperón BiP del Retículo Endoplásmico , Femenino , Proteínas HSP70 de Choque Térmico , Humanos , Polisacáridos , PronósticoRESUMEN
Fine particulate matter (PM) is a leading environmental cause for the increased morbidity and mortality of atherosclerosis (AS) worldwide, but little is known about the toxic component and disturbance of PM exposure on foam cell formation, a crucial pathological process in AS. Airborne magnetite nanoparticles (NPs) have been reported to be detected in human serum, which inevitably encounter with macrophages in atherosclerotic plaques, thus throwing potential disturbance on the formation of macrophage-derived foam cells. Here we comprehensively unveiled that the environmental concentrations of PM exposure triggered and potentiated the formation of macrophage-derived foam cells using both real-ambient PM-exposed mice and AS mice models, including high-fat diet-fed mice and apolipoprotein E-deficient mice. The in vitro model further defined the dose-dependent response of PM treatment on foam cell formation. Interestingly, airborne magnetite NPs rather than nonmagnetic NPs at the same concentration were demonstrated to be the key toxic component of PM in the promoted foam cell formation. Furthermore, magnetite NPs exposure led to abnormal cholesterol accumulation in macrophages, which was attributed to the attenuation of cholesterol efflux and enhancement of lipoprotein uptake, but independent of cholesterol esterification. The in-depth data revealed that magnetite NPs accelerated the protein ubiquitination and subsequent degradation of SR-B1, a crucial transporter of cholesterol efflux. Collectively, these findings for the first time identified magnetite NPs as one key toxic component of PM-promoted foam cell formation, and provided new insight of abnormal cholesterol metabolism into the pathogenesis of PM-induced AS.
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Aterosclerosis , Nanopartículas de Magnetita , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Aterosclerosis/inducido químicamente , Aterosclerosis/metabolismo , Colesterol/metabolismo , Óxido Ferrosoférrico/metabolismo , Células Espumosas/patología , Homeostasis , Humanos , Lipoproteínas LDL/metabolismo , Nanopartículas de Magnetita/toxicidad , Ratones , Material Particulado/metabolismo , Material Particulado/toxicidadRESUMEN
Hepatitis C is a serious infectious disease caused by the hepatitis C virus (HCV). HCV genotypes (GT) and subtypes are closely related to geographical distribution. Studies on the distribution of HCV genotypes can help to understand the regional epidemiology and genotype distribution and provide benefits in the treatment for hepatitis C. To provide information about the distribution of HCV genotypes as well as improved prevention and treatment of hepatitis C, we aimed to classify the distribution of HCV genotypes among Mongolian and Han patients with hepatitis C in Inner Mongolia over the past 5 years. Peripheral blood samples of patients with HCV were collected for gene sequencing. To analyze the HCV genotype distribution and possible influencing factors, we determined the viral load and ratios of various genotypes. We found that the most prevalent genotype in Inner Mongolia was 1b, followed by GT2a, GT3a, GT3b, and GT6a. The prevalence of HCV among Mongolian patients was significantly higher than the prevalence in their Han counterparts (χ2â =â 16.64, Pâ =â .000). There was no significant difference in viral load according to sex among HCV genotypes. However, the viral load of GT 1b was significantly higher than that of GT 2a (Fâ =â 3.51, Pâ =â .008). The viral load of GT 1b among ethnic Mongolians was significantly higher than that among Han patients (tâ =â 2.28, Pâ =â .044). The present study's findings can serve as a basis for developing a personalized treatment for hepatitis C among patients in Inner Mongolia.
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Hepacivirus , Hepatitis C , Pueblo Asiatico , Genotipo , Hepacivirus/genética , Hepatitis C/epidemiología , Humanos , Prevalencia , Carga ViralRESUMEN
Atmospheric PM2.5 exposure greatly contributes to the incidence of and mortality from cardiovascular disease (CVD). Owing to the crucial role of vascular calcification in the progression of CVD, it is imperative to elucidate the effects of PM2.5 on vascular calcification to understand the toxic mechanisms of haze-induced CVD. However, the effects of PM2.5 exposure on vascular calcification and the underlying molecular mechanisms are still unclear. In this work, the in vitro and in vivo models were used to illuminate the effects of PM2.5 on vascular calcification. We found that PM2.5 promoted the deposition of hydroxyapatite in calcifying vascular cells. Moreover, hydroxyapatite deposition was significantly enhanced by 3.5 times compared with those in the control group in aortas of ApoE-/- mice after exposure winter PM2.5 (1.5 mg/kg b.w.), accompanied by activation of the OPG/RANKL pathway and inï¬ammatory cytokines' expressions. Moreover, PM2.5-induced reactive oxygen species (ROS) generation was observed. NAC, an ROS inhibitor, observably alleviated the promotion effects of PM2.5 on vascular calcification. Furthermore, rutin effectively prevented vascular calcification by regulating the OPG/RANKL pathway. Our results suggest that PM2.5 play an important role in the occurrence and development of vascular calcification, and that rutin has an antagonistic effect on it.
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Phyllodes tumors (PTs) are rare but complex fibroepithelial lesions of the breast. The present report describes an unusual case of a giant malignant PT with a rich blood supply treated with dominant blood supply internal thoracic artery interventional embolization before surgery. A 41-year-old woman without underlying systemic disease presented with a tumor >20 cm in diameter growing rapidly in the left breast. Radiological results indicated a giant circular tumor with a clear boundary occupying the whole breast, possible invasion of the major pectoralis muscle and several enlarged lymph nodes in the left axillary region. Computed tomography angiography showed a large mass with a rich and powerful blood vessel supply and preoperative interventional embolization was performed to block the internal thoracic artery. Three days after artery embolization, mastectomy and grade I axillary lymph node dissection were performed. The giant tumor measured 17x16x11 cm. The surgery successfully treated the pain and tumor necrosis and the patient received chemotherapy and local radiotherapy. No recurrence was found at the 14-month follow-up.
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Tetrabromobisphenol A (TBBPA), an emerging organic pollutant widely detected in human samples, has a positive correlation with the development of endometrial cancer (EC), but its underlying mechanisms have not yet been fully elucidated. Tumor-associated macrophages (TAM), one of the most vital components in tumor microenvironment (TME), play regulatory roles in the progression of EC. Consequently, this study mainly focuses on the macrophage polarization in TME to unveil the influence of TBBPA on the progression of EC and involved mechanisms. Primarily, low doses of TBBPA treatment up-regulated M2-like phenotype biomarkers in macrophage. The data from in vitro co-culture models suggested TBBPA-driven M2 macrophage polarization was responsible for the EC deterioration. Results from in vivo study further confirmed the malignant proliferation of EC promoted by TBBPA. Mechanistically, TBBPA-mediated miR-19a bound to the 3'-UTR regions of SOCS1, resulting in down-regulation of SOCS1 followed by the phosphorylation of JAK and STAT6. The present study not only revealed for the first time the molecular mechanism of TBBPA-induced EC's deterioration based on macrophage polarization, but also established co-culture models, thus providing a further evaluation method for the exploration of environmental pollutants-induced tumor effects from the role of TME.
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Neoplasias Endometriales , Macrófagos , Línea Celular Tumoral , Técnicas de Cocultivo , Femenino , Humanos , Bifenilos Polibrominados , Microambiente TumoralRESUMEN
PURPOSE: To detect the methylation of Dickkopf-associated protein 1 (DKK-1) gene promoter in cervical exfoliated cells and to study its clinical significance in cervical squamous cell carcinoma (CSCC) and its relationship with high-risk HPV infection. METHODS: Methylation-specific PCR (MSP) was utilized to detect the methylation of DKK-1 gene promoter in cervical exfoliated cells from 40 patients with CSCC and 40 patients with chronic cervicitis in the Affiliated Hospital of Inner Mongolia Medical University. The methylation rate of DKK-1 gene promoter in different clinicopathological factors and its relationship with high-risk HPV infection was compared, and different detection methods were compared. RESULT: The degree of methylation of DKK-1 gene promoter in CSCC group was significantly higher than that in cervicitis group (P < 0.05). In CSCC group, the degree of methylation was significantly different in high-risk HPV infection, histological differentiation, tumor size, lymph node metastasis and the International Federation of Gynecology and Obstetrics (FIGO) staging (all P < 0.05). The degree of methylation is not related to the type of high-risk HPV infection (P > 0.05). The one-year survival rate of CSCC patients with high-risk HPV positive and DKK-1 gene promoter methylation is relatively low, only 74.1%. The sensitivity, specificity and accuracy of DKK-1 gene methylation combined with high-risk HPV detection were 96.7%, 78.0% and 85.0%, respectively. CONCLUSION: Methylation of DKK-1 gene promoter in cervical exfoliated cells of patients with CSCC is related to high-risk HPV infection and different clinicopathological factors, but the degree of methylation of DKK-1 gene is not related to the type of high-risk HPV infection. It may become an indicator different from HPV typing detection, which may play a shunt role in suggesting whether further invasive cervical examination is needed and reduce cervical invasive examination and overtreatment. It may be related to the survival rate of patients, which can be used to estimate the development and prognosis of CSCC and may play a good role in early warning in follow-up monitoring of CSCC after treatment. DKK1 gene methylation combined with HPV detection can improve the sensitivity, specificity and accuracy of diagnosis, which may improve the detection rate of early CSCC and make up for the deficiency of HPV and TCT detection. That may become a non-invasive screening method for CSCC.
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Carcinoma de Células Escamosas/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Infecciones por Papillomavirus/genética , Neoplasias del Cuello Uterino/genética , Cervicitis Uterina/genética , Adulto , Anciano , Secuencia de Bases , Metilación de ADN , Femenino , Humanos , Metilación , Persona de Mediana Edad , Infecciones por Papillomavirus/complicaciones , Reacción en Cadena de la Polimerasa , EmbarazoRESUMEN
High-risk B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive disease, often characterized by resistance to chemotherapy. A frequent feature of high-risk B-ALL is loss of function of the IKAROS (encoded by the IKZF1 gene) tumor suppressor. Here, we report that IKAROS regulates expression of the BCL2L1 gene (encodes the BCL-XL protein) in human B-ALL. Gain-of-function and loss-of-function experiments demonstrate that IKAROS binds to the BCL2L1 promoter, recruits histone deacetylase HDAC1, and represses BCL2L1 expression via chromatin remodeling. In leukemia, IKAROS' function is impaired by oncogenic casein kinase II (CK2), which is overexpressed in B-ALL. Phosphorylation by CK2 reduces IKAROS binding and recruitment of HDAC1 to the BCL2L1 promoter. This results in a loss of IKAROS-mediated repression of BCL2L1 and increased expression of BCL-XL. Increased expression of BCL-XL and/or CK2, as well as reduced IKAROS expression, are associated with resistance to doxorubicin treatment. Molecular and pharmacological inhibition of CK2 with a specific inhibitor CX-4945, increases binding of IKAROS to the BCL2L1 promoter and enhances IKAROS-mediated repression of BCL2L1 in B-ALL. Treatment with CX-4945 increases sensitivity to doxorubicin in B-ALL, and reverses resistance to doxorubicin in multidrug-resistant B-ALL. Combination treatment with CX-4945 and doxorubicin show synergistic therapeutic effects in vitro and in preclinical models of high-risk B-ALL. Results reveal a novel signaling network that regulates chemoresistance in leukemia. These data lay the groundwork for clinical testing of a rationally designed, targeted therapy that combines the CK2 inhibitor, CX-4945, with doxorubicin for the treatment of hematopoietic malignancies.
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Quinasa de la Caseína II/genética , Resistencia a Antineoplásicos , Regulación Leucémica de la Expresión Génica , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteína bcl-X/genética , Animales , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
Increasing epidemiological evidences have revealed the association between ambient fine particulate matter (PM2.5) pollution and cardiovascular disease's morbidity and mortality. However, how seasonal PM2.5 exposure influence cardiac function and the underlying mechanism converged in energy metabolic remodeling remain to be elucidated. This study focused on seasonal PM2.5-induced cardiac dysfunction and metabolic remodeling, and the toxicity differences of PM2.5 samples from different sampling seasons and different exposure dosages were discussed. The results showed that seasonal haze caused cardiac dysfunctions, including decreases in heart rate (HR) and heart rate variability (HRV), abnormal changes in hemodynamic and echocardiographic parameters. Concurrently, the energy production in myocardial tissues was evidently disturbed. In particular, low dose of PM2.5 exposure notably induced the elevation of beta oxidation (ß-oxidation) and tricarboxylic acid cycle (TCA cycle) as the compensation for the disturbed energy metabolism in animals, whereas high dose of PM2.5 exposure attenuated this process and the glycolysis levels were strikingly promoted, thus causing the reduced energy production and cardiac dysfunction. Comparatively, winter PM2.5 exposure caused more severe cardiac toxicity than did summer haze samples, possibly due to the existence of different components and pollutant levels in seasonal hazes. The findings on seasonal PM2.5 induced cardiac dysfunction and myocardial metabolic remodeling provided new insights into cardiovascular disease risks from haze exposure.
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Contaminantes Atmosféricos/análisis , Cardiopatías , Animales , Frecuencia Cardíaca , Tamaño de la Partícula , Material Particulado/análisis , Estaciones del AñoRESUMEN
Tetrabromobisphenol A (TBBPA) and its derivatives are the common flame-retardants that may increase the risk of development of many types of cancers, including liver cancer. However, the effects of TBBPA in the development and progression of liver cancer remains unknown. This study investigated the potential effects of TBBPA on a metastatic phenotype of hepatocellular carcinoma cell line-HepG2. Our results revealed that TBBPA significantly promoted the migration and invasion via affecting the number and distribution of lysosomes in HepG2 cells in a dose-dependent manner. Moreover, TBBPA decreased the intracellular protein levels of Beta-Hexosaminidase (HEXB), Cathepsin B (CTSB) and Cathepsin D (CTSD) while increased the extracellular CTSB and CTSD. It entailed that TBBPA exposure could promote the lysosomal exocytosis in cancer cells. The reversal results were obtained after adding lysosomal exocytosis inhibitor vacuolin-1. Docking results suggested that TBBPA could bind to TRPML1. It was consistent with the binding position of agonist ML-SA1. TRPML1 knockdown significantly decreased the invasion and migration, and the results were reversed when TBBPA was added. The results were indicated that TRPML1 was critical in lysosomal exocytosis. In addition, our results showed that TBBPA-TRPML1 complex regulated the calcium-mediated lysosomal exocytosis, thereby promoting the metastasis in liver cancer cells. It was expected that our data could provide important basis for understanding the molecular mechanism(s) of TBBPA promoting invasion and migration of hepatoma cells and give rise to profound concerns of TBBPA exposure on human health.
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Carcinoma Hepatocelular/patología , Exocitosis/efectos de los fármacos , Retardadores de Llama/toxicidad , Neoplasias Hepáticas/patología , Lisosomas/efectos de los fármacos , Bifenilos Polibrominados/toxicidad , Calcio/metabolismo , Carcinoma Hepatocelular/metabolismo , Movimiento Celular/efectos de los fármacos , Células Hep G2 , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Humanos , Neoplasias Hepáticas/metabolismo , Invasividad Neoplásica , Canales de Potencial de Receptor Transitorio/fisiologíaRESUMEN
Atmospheric particulate matter (PM2.5) is associated with the morbidity and mortality of cardiovascular diseases. However, whether PM2.5 penetrates into the cells and the potential mechanisms are unknown. Hence, the study firstly indicated that PM2.5 could penetrate into the HUVEC cells, and phagocytosis, micropinocytosis, caveolin as well as clathrin mediated the internalization of PM2.5 into HUVEC cells. Particularly, the components of PM2.5-Metal, PAHs and WSC could enter into HUVEC cells mainly via the micropinocytosis, clathrin and caveolin mediated endocytosis, respectively. The current data of environmental assessments indicated that PM2.5-Metal were extremely harmful to the ecological environment and human health. Moreover, accompanying with mitochondrial fusion gene Mfn1 was increased and fission genes Opa1 and Drp1 were decreased, and the lysosome related genes LAMP2 and LAMP3 were decreased, the phenomenon that the morphology of mitochondrial and lysosome injured was observed in HUVEC cells treated with PM2.5 and/or PM2.5-Metal. These data suggest that PM2.5 and its main components depend on different endocytosis penetrate into HUVEC cells and cause the mitochondrial and lysosomal damages. Thereby, our study provides the potential mechanism of haze particles penetration into HUVEC cells and damage to organelles.
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Contaminantes Atmosféricos/toxicidad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Material Particulado/toxicidad , Contaminantes Atmosféricos/análisis , Células Endoteliales de la Vena Umbilical Humana/patología , Células Endoteliales de la Vena Umbilical Humana/ultraestructura , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Dinámicas Mitocondriales/efectos de los fármacos , Dinámicas Mitocondriales/genética , Orgánulos/efectos de los fármacos , Orgánulos/patología , Tamaño de la Partícula , Material Particulado/análisisRESUMEN
BACKGROUND: Hemophilia A, a bleeding disorder resulting from F8 mutations, can only be cured by gene therapy. A promising strategy is CRISPR-Cas9-mediated precise insertion of F8 in hepatocytes at highly expressed gene loci, such as albumin (Alb). Unfortunately, the precise in vivo integration efficiency of a long insert is very low (~ 0.1%). RESULTS: We report that the use of a double-cut donor leads to a 10- to 20-fold increase in liver editing efficiency, thereby completely reconstituting serum F8 activity in a mouse model of hemophilia A after hydrodynamic injection of Cas9-sgAlb and B domain-deleted (BDD) F8 donor plasmids. We find that the integration of a double-cut donor at the Alb locus in mouse liver is mainly through non-homologous end joining (NHEJ)-mediated knock-in. We then target BDDF8 to multiple sites on introns 11 and 13 and find that NHEJ-mediated insertion of BDDF8 restores hemostasis. Finally, using 3 AAV8 vectors to deliver genome editing components, including Cas9, sgRNA, and BDDF8 donor, we observe the same therapeutic effects. A follow-up of 100 mice over 1 year shows no adverse effects. CONCLUSIONS: These findings lay the foundation for curing hemophilia A by NHEJ knock-in of BDDF8 at Alb introns after AAV-mediated delivery of editing components.
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Reparación del ADN por Unión de Extremidades , Factor VIII/genética , Técnicas de Sustitución del Gen , Terapia Genética/métodos , Hemofilia A/terapia , Albúminas/genética , Animales , Codón de Terminación , RatonesRESUMEN
Health risks have been closely related to increased exposure of fine particulate matter (PM2.5) in general population. Immune system is considered to be a most vulnerable target for airborne pollutants. PM2.5 could make some serious damages to the body organs by inducing immunotoxicity. However, the underlying molecular mechanisms are still unclear. The purpose of this study is aimed to elucidate the possible mechanisms of PM2.5-mediated immunotoxicity on spleen organ by using SD rat models. This research demonstrated that the spleen structure damage induced by PM2.5 treatment was more pronounced in winter than in summer. Mechanistically, TUNEL staining show a considerable increase in spleen apoptosis by summer and winter PM2.5 exposures compared with control. However, winter PM2.5 exposure caused more toxicity in the spleen than summer PM2.5 exposure. Furthermore, our results illustrated that PM2.5 triggered oxidative stress and ERS in spleen tissues of SD rats, and lead to apoptosis via upregulation of CHOP and caspase-12. Likewise, the protein levels of LC3 were significantly increased and p62 was decreased by PM2.5 exposure, thereby activated the autophagy of spleen in SD rats in a concentration-dependent manner. In conclusion, this study supported that PM2.5 mediated the immunotoxicity by the occurrence of stimulation of ERS and autophagy in SD rats. Taken together, these findings suggest PM2.5 as potential agent of immunotoxicity that needs an urgent attention. Graphical abstract Graphical abstract contains poor quality of text inside the artwork. Please do not re-use the file that we have rejected or attempt to increase its resolution and re-save. It is originally poor, therefore, increasing the resolution will not solve the quality problem. We suggest that you provide us the original format. We prefer replacement figures containing vector/editable objects rather than embedded images. Preferred file formats are eps, ai, tiff and pdf.Thanks you attention. We will provide tiff format image.
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Contaminantes Atmosféricos/toxicidad , Sistema Inmunológico/efectos de los fármacos , Material Particulado/toxicidad , Contaminantes Atmosféricos/análisis , Animales , Apoptosis , Autofagia , Etiquetado Corte-Fin in Situ , Masculino , Estrés Oxidativo , Material Particulado/análisis , Ratas , Ratas Sprague-Dawley , Estaciones del Año , BazoRESUMEN
Leukemia is a group of progressive hematologic malignancies derived from stem cells in bone marrow which causes a large number of cancer deaths. Even with treatment such as traditional chemotherapy, targeted therapy, and allogeneic stem cell transplantation (allo-HSCT), many patients suffer from relapse/refractory disease, and the overall survival is dismal. Leukemic stem cells (LSCs) are induced by gene mutations and undergo an aberrant and poorly regulated proliferation process which is involved in the evolution, relapse, and drug-resistance of leukemia. Emerging studies demonstrate that CD123, the interleukin 3 receptor alpha (IL-3Rα), is highly expressed in LSCs, while not normal hematopoietic stem cells (HSCs), and associates with treatment response, minimal residual disease (MRD) detection and prognosis. Furthermore, CD123 is an important marker for the identification and targeting of LSCs for refractory or relapsed leukemia. Anti-CD123 target-therapies in pre-clinical studies and clinical trials confirm the utility of anti-CD123 neutralizing antibody-drugs, CD3×CD123 bispecific antibodies, dual-affinity retargeting (DART), and anti-CD123 chimeric antigen receptor-modified T-cell (CAR-T) therapies in progress. This review summarizes the most recent progress on the study of CD123 biology and the development of novel CD123-targeted therapies.
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Antineoplásicos Inmunológicos/uso terapéutico , Subunidad alfa del Receptor de Interleucina-3/análisis , Leucemia/diagnóstico , Leucemia/terapia , Animales , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/antagonistas & inhibidores , Humanos , Inmunoterapia Adoptiva , Subunidad alfa del Receptor de Interleucina-3/antagonistas & inhibidoresRESUMEN
OBJECTIVES: To characterize the clinical and pathologic features of mantle cell lymphoma with mantle zone growth pattern (MCL-MZGP). METHODS: The clinicopathologic data from 35 cases of MCL-MZGP obtained in 12 centers were analyzed. RESULTS: The patients with MCL-MZGP typically sought treatment at high clinical stages (81%). Intriguingly, 40% (14/35) of cases were incidentally noted. The lymph nodes with MCL-MZGP showed preserved architecture and expanded mantles containing lymphoma cells with classic or small cell cytology. MCL-MZGP was positive for BCL2 (96%, bright), CD5 (82%, moderate), cyclin D1 (100%), and SOX11 (89%). Clinically, our study revealed no significant difference in the overall survival between patients managed with observation alone and those who received chemotherapy. CONCLUSIONS: MCL-MZGP was often incidentally identified and resembled reactive mantles. Therefore, recognition of this unusual morphology emphasizes the utility of cyclin D1 immunostain in the cases with suspicious morphology. However, the clinical significance of these findings is still unclear.