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Acute graft-versus-host disease (aGvHD) is considered a result of "cytokine storm." Targeted therapeutic interventions on cytokines via ubiquitination regulatory pathways may provide a potential approach for aGvHD treatment. Ubiquitin-specific peptidase 11 (USP11) has been reported to play key roles in a variety of physiopathological processes by regulating the stability and function of several vital protein molecules. However, its role in aGvHD remains unclear. In this study, we identified USP11 was associated with aGvHD in patients. In the aGvHD mouse model, the colon and liver were more seriously affected in recipient mice who received USP11 wt bone marrow (BM) cells and eased after the donor was treated with a USP11 inhibitor or received USP11 ko BM cells. In mouse models, IL-6 was identified as a major effecter in accelerating aGvHD induced by USP11. In the cell model, IL-6 mRNA transcript was affected by USP11. In addition, USP11 also inhibited IL-6 degradation by affecting IL-6 ubiquitination. Furthermore, the positive correlation between USP11 and IL-6 was confirmed in the GvHD patients' samples. Collectively, all results indicated that USP11 played a critical role in the onset and progression of aGvHD. USP11 might be a potential target for aGvHD treatment.
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Enfermedad Injerto contra Huésped , Interleucina-6 , Animales , Ratones , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Citocinas/uso terapéutico , Enfermedad AgudaRESUMEN
Organoid culture is a promising biomedical technology that requires specialized growth factors. Recently, a recombinant L-WRN cell line has been extensively used to generate conditioned medium (L-CM) for organoid culture. Nevertheless, methods for evaluating the stability of the L-WRN cells have been limited. In this study, a novel proteomics-based approach was developed to analyze the secretome of the cells. Serum-free L-CM was lyophilized, precipitated by trichloroacetic acid, and desalted prior to analysis by liquid chromatography-tandem mass spectrometry. Data-dependent acquisition (DDA) was conducted for the untargeted secretome profiling of the cells, and parallel reaction monitoring (PRM) was applied for the targeted quantification of the Wnt3A, R-spondin3, and noggin proteins (WRNs). This study also compared the performance of two types of PRM methods, namely MS1-independent PRM and MS1-dependent PRM, that can be executed on an Orbitrap instrument. The results showed that the growth of mouse intestinal organoids was closely related to the use of L-CM. The composition of L-CM could be markedly affected by the medium collection scheme. A total of 1725, 2302, and 2681 proteins were identified from the L-CM collected on day 5, day 9, and day 13, respectively. The MS1-independent PRM outperformed the MS1-dependent PRM and effectively quantified the WRNs with high repeatability and specificity. In conclusion, by integrating untargeted and targeted proteomics, this study develops a mass spectrometry-based method for the secretome analysis and quality control of the L-WRN cells. The methodology and findings of the present work will benefit future studies on organoids and secretomes.
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Proteómica , Secretoma , Animales , Ratones , Proteómica/métodos , Cromatografía Liquida , Espectrometría de Masas/métodos , Línea Celular , Helicasa del Síndrome de WernerRESUMEN
BACKGROUND: Fasting is known to influence the immune functions of leukocytes primarily by regulating their mobilization and redistribution between the bone marrow and the peripheral tissues or circulation, in particular via relocalization of leukocytes back in the bone marrow. However, how the immune system responds to the increased risk of invasion by infectious pathogens with fewer leukocytes in the peripheral blood during fasting intervention remains an open question. RESULTS: We used proteomic, biochemical and flow cytometric tools to evaluate the impact of short-term intensive fasting (STIF), known as beego, on red blood cells by profiling the cells from the STIF subjects before and after 6 days of fasting and 6 days of gradual refeeding. We found that STIF, by triggering the activation of the complement system via the complement receptor on the membrane of red blood cells, boosts fairly sustainable function of red blood cells in immune responses in close relation to various pathogens, including viruses, bacteria and parasites, particularly with the pronounced capacity to defend against SARS-CoV-2, without compromising their oxygen delivery capacity and viability. CONCLUSION: STIF fosters the immune function of red blood cells and therefore, it may be considered as a nonmedical intervention option for the stronger capacity of red blood cells to combat infectious diseases.
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Cultured keratinocytes are desirable models for biological and medical studies. However, primary keratinocytes are difficult to maintain, and there has been little research on lingual keratinocyte culture. Here, we investigated the effect of Y-27632, a Rho kinase (ROCK) inhibitor, on the immortalization and characterization of cultured rat lingual keratinocyte (RLKs). Three Y-27632-supplemented media were screened for the cultivation of RLKs isolated from Sprague-Dawley rats. Phalloidin staining and TUNEL assay were applied to visualize cytoskeleton dynamics and cell apoptosis following Y-27632 removal. Label-free proteomics, RT-PCR, calcium imaging, and cytogenetic studies were conducted to characterize the cultured cells. Results showed that RLKs could be conditionally immortalized in a high-calcium medium in the absence of feeder cells, although they did not exhibit normal karyotypes. The removal of Y-27632 from the culture medium led to reversible cytoskeletal reorganization and nuclear enlargement without triggering apoptosis, and a total of 239 differentially expressed proteins were identified by proteomic analysis. Notably, RLKs derived from the non-taste epithelium expressed some molecular markers characteristic of taste bud cells, yet calcium imaging revealed that they rarely responded to tastants. Collectively, we established a high-calcium and feeder-free culture method for the long-term maintenance of RLKs. Our results shed some new light on the immortalization and differentiation of lingual keratinocytes.
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Amidas/farmacología , Calcio/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/farmacología , Quinasas Asociadas a rho/antagonistas & inhibidores , Animales , Técnicas de Cultivo de Célula , Células Cultivadas , RatasRESUMEN
Isochromosome 20q- (i(20q-)), as a rare reproducible chromosomal anomaly formed on the basis of 20q-, has not been commonly reported. Due to the rarity of this karyotypic anomaly, the bone marrow morphological characteristics of the patients with i(20q-) have not been clarified until now. In this study, the bone marrow cell morphology from MDS patients with isolated i(20q-), isolated 20q-, and normal karyotype was retrospectively compared and statistically analyzed. The results indicated that the isolated i(20q-) was mostly detected in MDS-MLD patients. The frequency and proportion dysplasia of cytoplasmic vacuolization in erythoid cells and small or unusually large size in myeloid cells of isolated i(20q-) MDS patients were significantly higher than those of normal karyotype MDS patients respectively (P < 0.05); the frequency and proportion dysplasia of decreased granules/agranularity in myeloid cells of isolated i(20q-) MDS patients were higher than those of isolated 20q- MDS patients (P < 0.05). The incidence of some specific morphological manifestations, such as deeply lobulated and hyperlobulated megakaryocytes and hypogranular and vacuolized eosinophils, may be an important morphological implication for the anomaly of isolated i(20q-). These morphological features of dysplasia may be helpful in distinguishing MDS with isolated i(20q-) from those with isolated 20q- and normal karyotype.
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Células de la Médula Ósea/ultraestructura , Deleción Cromosómica , Cromosomas Humanos Par 20/ultraestructura , Isocromosomas , Síndromes Mielodisplásicos/genética , Cariotipo Anormal , Adulto , Anciano , Anciano de 80 o más Años , Linaje de la Célula , Núcleo Celular/ultraestructura , Estudios de Cohortes , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/patología , Estudios Retrospectivos , Vacuolas/ultraestructura , Adulto JovenAsunto(s)
Antígenos CD19 , Leucemia Mieloide Aguda , Antígenos CD34 , Humanos , Macrólidos/farmacología , Células MadreRESUMEN
BACKGROUND: This study was conducted to determine the antineoplastic activities of 5-aza-2'-deoxycytidine (decitabine; DAC) and all-trans retinoic acid (ATRA), administered either alone or in combination, on in vitro cultured SHI-1 cells as well as their effects on the expression of the tumor suppressor gene p16(INK4a) (p16) and the retinoic acid receptor (RAR)-ß. METHODS: Cell growth inhibition, differentiation and apoptosis were determined in SHI-1 cells treated with DAC and/or ATRA, and the combination index of the two compounds was calculated. Methylation of the p16 and RAR-ß genes in SHI-1 cells was detected by methylation-specific polymerase chain reaction (PCR). Real-time quantitative reverse transcriptase PCR was used to detect mRNA expression of the p16 and RAR-ß genes, and Western blot analysis was performed for protein expression. RESULTS: The drug combination had a synergistic effect on growth inhibition, differentiation and apoptosis of SHI-1 cells, and the effects of DAC and ATRA were dependent on time. DAC, either alone or in combination with ATRA, induced demethylation of the genes p16 and RAR-ß, whereas ATRA alone had no effect on methylation. The RAR-ß gene was reexpressed following DAC-ATRA combination treatment, and both agents had no effect on p16 expression. CONCLUSION: The results revealed that DAC used in combination with ATRA has significant clinical potential in the treatment of acute monocytic leukemia.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Leucemia Monocítica Aguda/tratamiento farmacológico , Receptores de Ácido Retinoico/biosíntesis , Azacitidina/agonistas , Azacitidina/análogos & derivados , Azacitidina/farmacología , Línea Celular Tumoral , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Decitabina , Humanos , Leucemia Monocítica Aguda/metabolismo , Leucemia Monocítica Aguda/patología , Tretinoina/agonistas , Tretinoina/farmacologíaRESUMEN
The polycomb group BMI1 is proved to be crucial in malignant myeloid progression. However, the underlying mechanism of the action of BMI1 in myeloid malignant progression was not well characterized. In this study, we found that the patients of both myelodysplastic syndromes and chronic myeloid leukaemia with BMI1 overexpression had a higher risk in malignant myeloid progression. In vitro gene transfection studies showed that BMI1 inhibited cell myeloid and erythroid differentiation induced by 12-O-tetradecanoyl phorbol-13-acetate (TPA) and histone deacetylase inhibitor sodium butyrate respectively. BMI1 also resisted apoptosis induced by arsenic trioxide. Moreover, the transcript levels of Runx1 and Pten were down-regulated in Bmi1-transfected cells in company with histone deacetylation modification. By using chromatin immunoprecipitation (ChIP) collaborated with secondary generation sequencing and verified by ChIP-PCR, we found that BMI1 directly bound to the promoter region of Zmym3, which encodes a component of histone deacetylase-containing complexes. In addition, as one of the downstream target genes of this complex, c-fos was activated with increasing histone acetylation when ZMYM3 was suppressed in the Bmi1-transfected cells. These results suggested that BMI1 may reprogramme the histone acetylation profile in multiple genes through either indirect or direct binding effects which probably contributes to the malignant progression of myeloid progenitor cells.
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Regulación Neoplásica de la Expresión Génica , Histonas/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Síndromes Mielodisplásicos/patología , Proteínas Nucleares/genética , Complejo Represivo Polycomb 1/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Acetilación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/efectos de los fármacos , Western Blotting , Ácido Butírico/farmacología , Estudios de Casos y Controles , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Inmunoprecipitación de Cromatina , Femenino , Citometría de Flujo , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismo , Proteínas Nucleares/metabolismo , Complejo Represivo Polycomb 1/genética , Unión Proteica , Proteínas Proto-Oncogénicas c-fos/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/farmacología , Adulto JovenRESUMEN
Lung cancer is intricately associated with genetic susceptibility, leading to familial clustering among affected individuals. This cross-sectional study aimed to assess the knowledge, attitude, and practice (KAP) toward lung cancer risk among the offspring of lung cancer patients. This study was conducted at Guangdong Provincial People's Hospital between April 2023 and August 2023. Participants' demographic characteristics and KAP toward lung cancer risk were collected through questionnaires. A total of 481 valid questionnaires were enrolled, with 243 (50.52%) males, and 242 (50.31%) aged > 40 years old. The mean scores for knowledge, attitude, and practice were 8.54 ± 2.60 (range: 0-13), 25.93 ± 3.16 (range: 7-35), and 17.47 ± 4.30 (range: 5-25), respectively. Structural equation modeling indicated that knowledge exerted a negative direct effect on attitude (ß = - 0.417, P = 0.006) but a positive direct effect on practice (ß = 0.733, P = 0.025). Additionally, attitudes displayed a negative direct effect on practice (ß = - 1.707, P = 0.002). In conclusion, offspring of lung cancer patients exhibited insufficient knowledge, positive attitude, and suboptimal practice toward lung cancer risk.
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Conocimientos, Actitudes y Práctica en Salud , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/epidemiología , Masculino , Femenino , Estudios Transversales , Adulto , Persona de Mediana Edad , Encuestas y Cuestionarios , Predisposición Genética a la Enfermedad , Anciano , Factores de RiesgoRESUMEN
Capsaicinoids are the pungent compounds in chili peppers. The present study investigated the effect of capsaicinoids on obesity in mice induced by a high-fat-high-fructose diet. Thirty-two male C57BL/6J mice were randomly divided into four groups (n = 8) and fed one of the following diets, namely, a low-fat diet (LFD), a high-fat-high-fructose diet (HFF), an HFF + 0.015% capsaicinoids (LCP), and an HFF + 0.045% capsaicinoids (HCP), for 12 weeks. Results showed that capsaicinoids significantly reversed HFF-induced obesity. Supplementation with capsaicinoids improved glucose tolerance, reduced plasma lipids, and attenuated inflammation. Capsaicinoids also reduced hepatic lipid accumulation by upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In addition, capsaicinoids enhanced the production of fecal short-chain fatty acids (SCFAs) and increased the fecal excretion of lipids. Gut microbiota analysis revealed that capsaicinoids decreased the Firmicutes/Bacteroidetes ratio and beneficially reconstructed the microbial community. However, the effects of capsaicinoids on intestinal villus length and lipid tolerance were negligible. In conclusion, capsaicinoids effectively attenuated HFF-induced obesity and metabolic syndrome by favorably modulating lipid metabolism, improving SCFA production, and reshaping gut microbial structure.
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Capsaicina , Dieta Alta en Grasa , Suplementos Dietéticos , Fructosa , Microbioma Gastrointestinal , Ratones Endogámicos C57BL , Obesidad , Animales , Masculino , Obesidad/metabolismo , Obesidad/tratamiento farmacológico , Ratones , Dieta Alta en Grasa/efectos adversos , Capsaicina/farmacología , Fructosa/efectos adversos , Microbioma Gastrointestinal/efectos de los fármacos , Capsicum/química , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Ácidos Grasos Volátiles/metabolismoRESUMEN
Phytosterols are structurally similar to cholesterol but they are much less absorbed (<2%) than cholesterol (>50%) in the intestine. We hypothesize that phytosterols are poor substrates of intestinal acyl-CoA: cholesterol acyltransferase 2 (ACAT2), and thus minimal phytosterol esters are formed and packed into chylomicrons, leading to their low absorption. Two isotope tracing models, including a radioactive hamster microsomal ACAT2 reaction model and a differentiated Caco-2 cell model, were established to examine the specificity of ACAT2 to various sterols, including cholesterol, sitosterol, stigmasterol, and campesterol. Both models consistently demonstrated that only cholesterol but not phytosterols could be efficiently esterified by ACAT2 in a time- and dose-dependent manner. Molecular docking further suggested that unfavorable interactions existed between ACAT2 and phytosterols. In conclusion, phytosterols are poor substrates of ACAT2 and thus minimally absorbed. This work provides a theoretical basis for the use of phytosterol-based supplements in treating dyslipidemia and preventing heart diseases.
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Colesterol , Fitosteroles , Fitosteroles/metabolismo , Fitosteroles/química , Humanos , Animales , Células CACO-2 , Colesterol/metabolismo , Colesterol/química , Cricetinae , Esterol O-Aciltransferasa/metabolismo , Esterol O-Aciltransferasa/química , Absorción Intestinal , Esterol O-Aciltransferasa 2/metabolismo , Esterol O-Aciltransferasa 2/química , Simulación del Acoplamiento MolecularRESUMEN
The application of plant sterols in the treatment of hypercholesterolemia is promising. We hypothesize that plant sterols can reduce blood cholesterol because they have a side chain of at least three branches. Three cholesterol analogues were synthesized: CA0 (no side chain), CA3 (a 3carbon chain with one branch), and CA14 (a 14carbon side chain with two branches), and then compared their effect on blood cholesterol with that of ß-sitosterol. Structurally, ß-sitosterol has a 10carbon side chain with three branches. Results demonstrated that ß-sitosterol could effectively reduce plasma total cholesterol (TC) by 20.3%, whereas CA0, CA3 and CA14 did not affect plasma TC in hypercholesterolemia hamsters. ß-Sitosterol was absent in the plasma and liver, indicating it was not absorbed. We concluded that ß-sitosterol with three branches had plasma TC-lowering activity. In contrast, cholesterol analogues with a side chain of two or fewer branches did not affect plasma cholesterol.
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Trimethylamine-N-oxide (TMAO) is a risk factor for atherosclerosis. As a natural phenolic acid, protocatechuic acid (PCA) is abundant in various plant foods. The present study investigated the effect of PCA on TMAO-aggravated atherosclerosis in ApoE-/- mice. The mice were randomly divided into five groups and fed one of the following five diets for 12 weeks: namely a low-fat diet (LFD), a western diet (WD), a WD + 0.2% TMAO diet (WDT), a WDT + 0.5% PCA diet (WDT + LPCA), and a WDT + 1.0% PCA diet (WDT + HPCA). Results demonstrated that dietary TMAO exacerbated the development of atherosclerosis by eliciting inflammation and disturbing lipid metabolism. The diet with PCA at 1% reduced TMAO-induced aortic plaque by 30% and decreased the levels of plasma pro-inflammatory cytokines. PCA also improved lipid metabolism by up-regulating the hepatic gene expression of peroxisome proliferator-activated receptor alpha (PPARα). In addition, PCA supplementation enhanced fecal excretion of fatty acids and decreased hepatic fat accumulation. PCA supplementation favorably modulated gut microbiota by increasing the α-diversity with an increase in the abundance of beneficial genera (Rikenella, Turicibacter, Clostridium_sensu_stricto and Bifidobacterium) and a decrease in the abundance of the harmful Helicobacter genus. In summary, PCA could alleviate the TMAO-exacerbated atherosclerosis and inflammation, improve the lipid metabolism, and modulate gut microbiota.
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Aterosclerosis , Microbioma Gastrointestinal , Hidroxibenzoatos , Ratones , Animales , Metabolismo de los Lípidos , Ratones Endogámicos C57BL , Aterosclerosis/metabolismo , Metilaminas , Inflamación/tratamiento farmacológico , Dieta con Restricción de GrasasRESUMEN
Background: Significant progress has been achieved in the management of multiple myeloma (MM) by implementing high-dose therapy and stem cell transplantation. Moreover, the prognosis of patients has been enhanced due to the introduction of novel immunomodulatory drugs and the emergence of new targeted therapies. However, predicting the survival rates of patients with multiple myeloma is still tricky. According to recent researches, platelets have a significant impact in affecting the biological activity of tumors and are essential parts of the tumor microenvironment. Nonetheless, it is still unclear how platelet-related genes (PRGs) connect to the prognosis of multiple myeloma. Methods: We analyzed the expression of platelet-related genes and their prognostic value in multiple myeloma patients in this study. We also created a nomogram combining clinical metrics. Furthermore, we investigated disparities in the biological characteristics, immunological microenvironment, and reaction to immunotherapy, along with analyzing the drug susceptibility within diverse risk groups. Results: By using the platelet-related risk model, we were able to predict patients' prognosis more accurately. Subjects in the high-risk cohort exhibited inferior survival outcomes, both in the training and validation datasets, as compared to those in the low-risk cohort (p < 0.05). Moreover, there were differences in the immunological microenvironments, biological processes, clinical features, and chemotherapeutic drug sensitivity between the groups at high and low risk. Using multivariable Cox regression analyses, platelet-related risk score was shown to be an independent prognostic influence in MM (p < 0.001, hazard ratio (HR) = 2.001%, 95% confidence interval (CI): 1.467-2.730). Furthermore, the capacity to predict survival was further improved when a combined nomogram was utilized. In training cohort, this outperformed the predictive value of International staging system (ISS) alone from a 5-years area under curve (AUC) = 0.668 (95% CI: 0.611-0.725) to an AUC = 0.721 (95% CI: 0.665-0.778). Conclusion: Our study revealed the potential benefits of PRGs in terms of survival prognosis of MM patients. Furthermore, we verified its potential as a drug target for MM patients. These findings open up novel possibilities for prognostic evaluation and treatment choices for MM.
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Purpose: To assess the prognostic significance of ß2-microglobulin decline index (ß2M DI) in multiple myeloma (MM). Methods: 150 MM patients diagnosed with MM were enrolled in this study. Cox proportional hazards model was used to analyze the uni- and multivariate prognosis in training cohort (n=105). A new combined prognostic model containing ß2M DI was built up based on the data in training cohort. The validation group was used to verify the model. Results: ß2M DI showed significant correlation with prognosis in both uni- and multivariate analyses and had a good correlation with complete response (CR) rate and deep remission rate. The ROC and calibration curves in validation cohort (n=45) indicated a good predictive performance of the new model. Based on the median risk score of the training group, we classified patients into high- and low- risk groups. In both training and validation groups, patients in the low-risk group had longer overall survival (OS) time than that in the high-risk group (p<0.05). Conclusion: ß2M DI is a good predictive index for predicting treatment response and survival time in MM patients. The prognostic model added with ß2M DI showed a better correlation with OS.
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This study aimed to determine the clinical characteristics and prognostic significance of the meningioma 1 (MN1) gene and MN1-associated microRNA expression in Chinese adult de novo acute myeloid leukemia (AML) patients. The expression level of MN1, microRNA-20 (miR-20a), and microRNA-181b (miR-181b) in bone marrow mononuclear cells was measured in 158 newly diagnosed AML patients and 20 cases of normal healthy donors by real-time quantitative reverse transcriptase polymerase chain reaction. All AML patients significantly overexpressed MN1 at the level of 0.01983 (P < 0.001) compared with normal controls. High MN1 expression was associated with spleen involvement (P = 0.037), NPM1 wild type (P = 0.001), lower miR-20a expression levels (P = 0.015), and higher miR-181b expression levels (P = 0.035). MiR-20a (P = 0.029) and miR-181b (P = 0.017) overexpressed in the bone marrow cells of patients with certain subtypes of AML compared with healthy donors. High MN1 expressers had lower complete remission (CR) rates and shorter overall survival (OS) within the Southwest Oncology Group classification. In multivariable models, high MN1 expression was associated with worse CR rates (P = 0.01), relapse-free survival (RFS; P = 0.02), and OS (P = 0.02); high miR-20a expression was associated with higher CR rates (P = 0.008) and longer OS (P = 0.04), whereas high miR-181b expression was associated with lower CR rates (P = 0.03), and shorter RFS (P = 0.045) and OS (P = 0.017). High MN1 expression confers worse prognosis in Chinese adult patients with de novo AML. MN1 gene and MN1-associated microRNAs provide clinical prognosis of AML patients and may refine their molecular risk classification.
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Regulación Leucémica de la Expresión Génica , Leucemia Mieloide/genética , MicroARNs/genética , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Proteínas Supresoras de Tumor/genética , Enfermedad Aguda , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Idarrubicina/administración & dosificación , Leucemia Mieloide/tratamiento farmacológico , Leucemia Mieloide/metabolismo , Leucemia Mieloide/cirugía , Masculino , MicroARNs/análisis , MicroARNs/biosíntesis , Persona de Mediana Edad , Proteínas de Neoplasias/análisis , Proteínas de Neoplasias/biosíntesis , Nucleofosmina , Trasplante de Células Madre de Sangre Periférica , Pronóstico , ARN Neoplásico/análisis , ARN Neoplásico/biosíntesis , Reacción en Cadena en Tiempo Real de la Polimerasa , Análisis de Supervivencia , Transactivadores , Trasplante Autólogo , Resultado del Tratamiento , Proteínas Supresoras de Tumor/análisis , Proteínas Supresoras de Tumor/biosíntesis , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.
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Empalme Alternativo , Cromosomas Humanos Par 21 , Cromosomas Humanos Par 8 , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Leucemia Mieloide Aguda/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Secuencia de Aminoácidos , Animales , Línea Celular , Subunidad alfa 2 del Factor de Unión al Sitio Principal/análisis , Subunidad alfa 2 del Factor de Unión al Sitio Principal/química , Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Modelos Animales de Enfermedad , Exones , Humanos , Células Jurkat , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Transgénicos , Datos de Secuencia Molecular , Trasplante de Neoplasias , Proteínas de Fusión Oncogénica/análisis , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Proteína 1 Compañera de Translocación de RUNX1 , Retroviridae/genéticaRESUMEN
Both cholesterol and oxidized cholesterol (OXC) are present in human diets. The incidence of inflammatory bowel diseases (IBDs) is increasing in the world. The present study was to investigate the mechanism by which OXC promotes colitis using C57BL/6 mice as a model. Results shown that more severe colitis was developed in OXC-treated mice with the administration of dextran sulfate sodium (DSS) in water. Direct effects of short-term OXC exposure on gut barrier or inflammation were not observed in healthy mice. However, OXC exposure could cause gut microbiota dysbiosis with a decrease in the relative abundance of short-train fatty acids (SCFAs)-producing bacteria (Lachnospiraceae_NK4A136_group and Blautia) and an increase in the abundance of some potential harmful bacteria (Bacteroides). OXC-induced symptoms of colitis were eliminated when mice were administered with antibiotic cocktails, indicating the promoting effect of OXC on DSS-induced colitis was mediated by its effect on gut microbiota. Moreover, bacteria-depleted mice colonized with gut microbiome from OXC-DSS-exposed mice exhibited a severe colitis, further proving the gut dysbiosis caused by OXC exposure was the culprit in exacerbating the colitis. It was concluded that dietary OXC exposure increased the susceptibility of colitis in mice by causing gut microbiota dysbiosis.
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Colitis , Microbioma Gastrointestinal , Humanos , Ratones , Animales , Disbiosis/inducido químicamente , Ratones Endogámicos C57BL , Colitis/inducido químicamente , Colitis/microbiología , Bacterias , Colesterol/toxicidad , Colon , Sulfato de Dextran/toxicidadRESUMEN
OBJECTIVE: To detect the relative expression of IGLL1 (immunoglobulin lambda-like polypeptide 1) mRNA in bone marrow of children with T-cell acute lymphoblastic leukemia (T-ALL), and analyze its correlation with the clinical characteristics and prognosis of the patients, so as to clarify the clinical significance of IGLL1 in pediatric T-ALL patients. METHODS: A total of 56 pediatric T-ALL patients hospitalized in Children's Hospital of Soochow University from June 2012 to December 2017 and treated with CCLG-ALL 2008 regimen were selected. Transcriptome sequencing technology was used to detect the transcription level of IGLL1 gene in children with T-ALL. According to 25% of the IGLL1 transcription level (cutoff value:448), the enrolled children were divided into IGLL1 low expression group (17 cases) and IGLL1 high expression group (39 cases). Combined with clinical data, the correlation between the expression level of IGLL1 and prognosis of the patients was analyzed. RESULTS: The comparative analysis showed that the transcription level of IGLL1 was not correlated with the clinical characteristics of the patients, such as sex, age, bone marrow blast, white blood cell (WBC) count at initial diagnosis. The 5-year OS rate of patients with high IGLL1 expression was significantly higher than that of patients with low IGLL1 expression (76.9%±6.7% vs 47.1%±12.1%, P =0.018). Further comparison of relapse-free survival (RFS) rate between the two groups showed that the 5-year RFS rate of patients with high IGLL1 expression was higher than that of patients with low IGLL1 expression, but the difference between the two groups was not statistically significant (P =0.095). Multivariate COX analysis was conducted on common clinical prognostic factors (age, sex, WBC count at diagnosis, prednisone response on the 7th day, bone marrow response on the 15th day after treatment) and IGLL1 expression level, and the results showed that IGLL1 expression (P =0.012) and prednisone response (P =0.017) were independent risk factors for overall survival in pediatric T-ALL patients. CONCLUSION: In pediatric T-ALL, the OS rate of children with high expression of IGLL1 gene was significantly higher than that of children with low expression of IGLL1 gene, and the expression level of IGLL1 gene was an independent factor affecting the survival of children with T-ALL, which suggests that IGLL1 is a marker of good clinical prognosis of children with T-ALL.