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The tumor suppressor gene BRCA1 associated protein-1 (BAP1) is frequently mutated in renal cell carcinoma (RCC). BAP1 loss-of-function mutations are associated with poor survival outcomes. However, personalized therapy for BAP1-mutated RCC is currently not available. Previously, we found that BAP1 loss renders RCC cells more sensitive to bromodomain and extra-terminal (BET) inhibitors, as demonstrated in both cell culture and xenografted nude mice models. Here, we demonstrate that BAP1 loss in murine RCC cells enhances sensitivity to BET inhibitors in ectopic and orthotopic allograft models. While BAP1 deletion suppresses RCC cell survival in vitro, it does not impede tumor growth in immunocompetent murine models. Thus, the effect of BAP1 loss on the interactions between tumor cells and host microenvironment plays a predominant role in RCC growth, highlighting the importance of utilizing immunocompetent animal models to assess the efficacy of potential anticancer therapies. Mechanistically, BAP1 deletion compromises DNA repair capacity, rendering RCC cells more vulnerable to DNA damage induced by BET inhibitors. Our results indicate that BET inhibitors show promise as targeted therapy for BAP1-deficient RCC.
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OBJECTIVES: To investigate the value of single-phase gonadotropin releasing hormone (GnRH) stimulation test in the diagnosis of central precocious puberty (CPP) in girls with different levels of body mass index (BMI). METHODS: A retrospective analysis was performed for the data of 760 girls with breast development before 7.5 years of age who attended the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2023. According to the results of GnRH stimulation test and clinical manifestations, they were divided into a CPP group (297 girls) and a non-CPP group (463 girls). According to the values of BMI, the girls were divided into a normal weight group (540 girls), an overweight group (116 girls), and an obese group (104 girls). The receiver operating characteristic (ROC) curve was used to investigate the value of single-phase GnRH stimulation test in the diagnosis of CPP in girls with different levels of BMI. RESULTS: Luteinizing hormone (LH)/follicle-stimulating hormone at 30 minutes after GnRH stimulation had an area under the curve (AUC) of 0.985 in the diagnosis of CPP, which was higher than the AUC at 0, 60, and 90 minutes (P<0.05). LH at 30 minutes had a similar diagnostic value to LH at 60 minutes (P>0.05). LH at 30 minutes was negatively correlated with BMI and BMI-Z value (P<0.05).The AUC for diagnosing CPP in normal weight, overweight, and obese girls at 30 minutes LH was 0.952, 0.965, and 0.954, respectively (P<0.05). CONCLUSIONS: The 30-minute GnRH stimulation test has a good value in the diagnosis of CPP in girls with different levels of BMI and is expected to replace the traditional GnRH stimulation test, but the influence of BMI on LH level should be taken seriously.
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Índice de Massa Corporal , Hormônio Liberador de Gonadotropina , Hormônio Luteinizante , Puberdade Precoce , Humanos , Puberdade Precoce/diagnóstico , Puberdade Precoce/sangue , Feminino , Hormônio Liberador de Gonadotropina/sangue , Criança , Estudos Retrospectivos , Hormônio Luteinizante/sangue , Hormônio Foliculoestimulante/sangue , Curva ROC , Pré-EscolarRESUMO
Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromodomain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP identified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to unrestrained YAP function.
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Melanoma , Proteínas Nucleares , Animais , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas B-raf/genética , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias UveaisRESUMO
Rapalogs (everolimus and temsirolimus) are allosteric mTORC1 inhibitors and approved agents for advanced clear cell renal cell carcinoma (ccRCC), although only a subset of patients derive clinical benefit. Progress in genomic characterization has made it possible to generate comprehensive profiles of genetic alterations in ccRCC; however, the correlations between recurrent somatic mutations and rapalog efficacy remain unclear. Here, we demonstrate by using multiple patient-derived ccRCC cell lines that compared to PTEN-proficient cells, PTEN-deficient cells exhibit hypersensitivity to rapalogs. Rapalogs inhibit cell proliferation by inducing G0/G1 arrest without inducing apoptosis in PTEN-deficient ccRCC cell lines. Using isogenic cell lines generated by CRISPR/Cas9, we validate the correlation between PTEN loss and rapalog hypersensitivity. In contrast, deletion of VHL or chromatin-modifying genes (PBRM1, SETD2, BAP1, or KDM5C) fails to influence the cellular response to rapalogs. Our mechanistic study shows that ectopic expression of an activating mTOR mutant (C1483F) antagonizes PTEN-induced cell growth inhibition, while introduction of a resistant mTOR mutant (A2034V) enables PTEN-deficient ccRCC cells to escape the growth inhibitory effect of rapalogs, suggesting that PTEN loss generates vulnerability to mTOR inhibition. PTEN-deficient ccRCC cells are more sensitive to the inhibitory effects of temsirolimus on cell migration and tumor growth in zebrafish and xenograft mice, respectively. Of note, PTEN protein loss as detected by immunohistochemistry is much more frequent than mutations in the PTEN gene in ccRCC patients. Our study suggests that PTEN loss correlates with rapalog sensitivity and could be used as a marker for ccRCC patient selection for rapalog therapy.
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Carcinoma de Células Renais , Neoplasias Renais , Animais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Inibidores de MTOR , Camundongos , Mutação , PTEN Fosfo-Hidrolase/genética , Serina-Treonina Quinases TOR/metabolismo , Proteínas Supressoras de Tumor/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-ZebraRESUMO
The tumor suppressor gene BAP1 encodes a widely expressed deubiquitinase for histone H2A. Both hereditary and acquired mutations are associated with multiple cancer types, including cutaneous melanoma (CM), uveal melanoma (UM), and clear cell renal cell carcinoma (ccRCC). However, there is no personalized therapy for BAP1-mutant cancers. Here, we describe an epigenetic drug library screening to identify small molecules that exert selective cytotoxicity against BAP1 knockout CM cells over their isogenic parental cells. Hit characterization reveals that BAP1 loss renders cells more vulnerable to bromodomain and extraterminal (BET) inhibitor-induced transcriptional alterations, G1/G0 cell cycle arrest and apoptosis. The association of BAP1 loss with sensitivity to BET inhibitors is observed in multiple BAP1-deficient cancer cell lines generated by gene editing or derived from patient tumors as well as immunodeficient xenograft and immunocompetent allograft murine models. We demonstrate that BAP1 deubiquitinase activity reduces sensitivity to BET inhibitors. Concordantly, ectopic expression of RING1A or RING1B (H2AK119 E3 ubiquitin ligases) enhances sensitivity to BET inhibitors. The mechanistic study shows that the BET inhibitor OTX015 exerts a more potent suppressive effect on the transcription of various proliferation-related genes, especially MYC, in BAP1 knockout cells than in their isogenic parental cells, primarily by targeting BRD4. Furthermore, ectopic expression of Myc rescues the BET inhibitor-sensitizing effect induced by BAP1 loss. Our study reveals new approaches to specifically suppress BAP1-deficient cancers, including CM, UM, and ccRCC.
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Carcinoma de Células Renais , Neoplasias Renais , Melanoma , Neoplasias Cutâneas , Animais , Carcinoma de Células Renais/tratamento farmacológico , Proteínas de Ciclo Celular , Humanos , Neoplasias Renais/genética , Melanoma/genética , Camundongos , Proteínas Nucleares , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais , Melanoma Maligno CutâneoRESUMO
Heatstroke is a life-threatening illness that is characterised by a core body temperature >40°C and central nervous system dysfunction. Acute kidney injury (AKI) is a common complication of heatstroke, and the mitochondrial apoptotic pathway has been demonstrated to be one of the leading causes of tissue damage and cell death in AKI. Curcumin is a phenol that is extracted from turmeric and demonstrates anti-apoptotic properties. To test if curcumin can protect the kidney from injury caused by heat stress, the effect of curcumin administration on renal injury and apoptosis of renal tissue was examined in a rat model of dry-heat environment. A total of 50 Sprague-Dawley rats were randomly divided into five groups (n=10): Standard temperature control, dry-heat control and curcumin treatment groups (50, 100 and 200 mg/kg groups). After exposure to a dry-heat environment for 150 min, the rats were anesthetized and euthanized. Blood, urine and renal tissue were collected to quantify the expression of specific mitochondrial apoptosis-related molecules. Curcumin pre-treatment decreased blood urea nitrogen and serum creatinine, urinary kidney injury molecule-1, and neutrophil gelatinase-associated lipocalin levels compared with the dry-heat control group. Curcumin was also revealed to downregulate c-Jun N-terminal kinases (JNK), cytochrome c, caspase-3 and caspase-9 expression upon treatment with 100 and 200 mg/kg curcumin, which may result in inhibition of the mitochondrial apoptotic pathway in renal cells. The current study revealed that Curcumin may to have potential for preventing heatstroke-induced AKI.
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OBJECTIVE: Moxifloxacin (MFX) shows good in vitro activity against Mycobacterium abscessus and can be a possible antibiotic therapy to treat M. abscessus infection; however, other studies have shown a lower or no activity. We aimed to evaluate MFX activity against M. abscessus using zebrafish (ZF) model in vivo. METHODS: A formulation of M. abscessus labeled with CM-Dil was micro-injected into ZF. Survival curves were determined by recording dead ZF every day. ZF were lysed, and colony-forming units (CFUs) were enumerated. Bacteria dissemination and fluorescence intensity in ZF were analyzed. Inhibition rates of MFX and azithromycin (AZM, positive control) were determined and compared. RESULTS: Significantly increased survival rate was observed with different AZM concentrations. However, increasing MFX concentration did not result in a significant decrease in ZF survival curve. No significant differences in bacterial burdens by CFU loads were observed between AZM and MFX groups at various concentrations. Bacterial fluorescence intensity in ZF was significantly correlated with AZM concentration. However, with increasing MFX concentration, fluorescence intensity decreased slightly when observed under fluorescence microscope. Transferring rates at various concentrations were comparable between the MFX and AZM groups, with no significant difference. CONCLUSION: MFX showed limited efficacy against M . abscessus in vivo using ZF model. Its activity in vivo needs to be confirmed.
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Antibacterianos/farmacologia , Moxifloxacina/farmacologia , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mycobacterium abscessus/efeitos dos fármacos , Peixe-Zebra , Animais , Modelos Animais de DoençasRESUMO
The effect of microRNA (miRNA) and targeted mRNA on signal transduction is not fully understood in myelodysplastic syndromes (MDS). Here, we tried to identify the miRNAs-regulated pathways through a combination of miRNA and mRNA microarray in CD34+ cells from MDS patients. We identified 34 differentially expressed miRNAs and 1783 mRNAs in MDS. 25 dysregulated miRNAs and 394 targeted mRNAs were screened by a combination of Pearson's correlation analysis and software prediction. Pathway analysis showed that several pathways such as Notch, PI3K/Akt might be regulated by those miRNA-mRNAs pairs. Through a combination of Pathway and miRNA-Gene or GO-Network analysis, miRNAs-regulated pathways, such as miR-195-5p/DLL1/Notch signaling pathway, were identified. Further qRT-PCR showed that miR-195-5p was up-regulated while DLL1 was down-regulated in patients with low-grade MDS compared with normal controls. Luciferase assay showed that DLL1 was a direct target of miR-195-5p. Overexpression of miR-195-5p led to increased cell apoptosis and reduced cell growth through inhibition of Notch signaling pathway. In conclusion, alteration expression of miRNAs and targeted mRNAs might have an important impact on cancer-related cellular pathways in MDS. Inhibition of Notch signaling pathway by miR-195-5p-DLL1 axis contributes to the excess apoptosis in low-grade MDS.
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Biologia Computacional/métodos , Perfilação da Expressão Gênica/métodos , MicroRNAs/genética , Síndromes Mielodisplásicas/genética , RNA Mensageiro/genética , Transdução de Sinais/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Células HEK293 , Humanos , Células K562 , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Adulto JovemRESUMO
OBJECTIVE: This study aims to assess the status of successful aging (SA) in longevity areas in China and explore multiple factors associated with SA among the young-old and oldest-old. METHODS: A total of 2296 elderly people aged 65 and older were interviewed in the longevity areas sub-sample of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) in 2012. Baseline assessments included a researcher-administered questionnaire, physical examination, and laboratory testing. A logistic regression model was used to identify factors associated with SA. RESULTS: The prevalence of SA was 38.81% in the CLHLS in 2012. There were significant differences between ages groups, with SA compromising 56.85% among â65 years group and 20.31% among â100 years group (χ2trend=126.73, P<0.01). The prevalence of SA among females was 33.59%, which was significantly lower than that among males (45.58%) (χ2gender=33.65, P<0.05). In the regression analysis, having anemia (OR=0.744, 95% CI: 0.609-0.910), poor lifestyle (OR=0.697, 95% CI: 0.568-0.854), poor sleep quality (OR=0.558, 95% CI: 0.456-0.682), and central obesity (OR=0.684, 95% CI: 0.556-0.841) were the main factors associated with SA. The promoting SA rate decreased as age increased, and the group of 65-79 years had higher odds than the other age group. CONCLUSION: Preventing central obesity, improving sleep quality and promoting healthy lifestyle may contribute to achieve SA among the elderly.
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Envelhecimento , Anemia/epidemiologia , Estilo de Vida , Obesidade/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , China/epidemiologia , Feminino , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Obesidade/etiologia , Prevalência , Fatores de Risco , Transtornos do Sono-Vigília/etiologiaRESUMO
The role of EZH2 in cancer is complex and may vary depending on cancer type or stage. We examined the effect of altered EZH2 levels on H3K27 methylation, HOX gene expression, and malignant phenotype in myelodysplastic syndrome (MDS) cell lines and an in vivo xenograft model. We also studied links between EZH2 expression and prognosis in MDS patients. Patients with high-grade MDS exhibited lower levels of EZH2 expression than those with low-grade MDS. Low EZH2 expression was associated with high percentages of blasts, shorter survival, and increased transformation of MDS into acute myeloid leukemia (AML). MDS patients frequently had reductions in EZH2 copy number. EZH2 knockdown increased tumor growth capacity and reduced H3K27me3 levels in both MDS-derived leukemia cells and in a xenograft model. H3K27me3 levels were reduced and HOX gene cluster expression was increased in MDS patients. EZH2 knockdown also increased HOX gene cluster expression by reducing H3K27me3, and H3K27 demethylating agents increased HOX gene cluster expression in MDS-derived cell lines. These findings suggest genomic loss of EZH2 contributes to overexpression of the HOX gene clusters in MDS through epigenetic modifications.
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Metilação de DNA , Epigênese Genética/genética , Genes Homeobox/genética , Leucemia Mieloide Aguda/genética , Família Multigênica , Síndromes Mielodisplásicas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Western Blotting , Adesão Celular , Movimento Celular , Proliferação de Células , Imunoprecipitação da Cromatina , Feminino , Citometria de Fluxo , Seguimentos , Perfilação da Expressão Gênica , Genômica/métodos , Histonas/genética , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
The standardized hypertension management provided by primary health care workers is an important part of China's recent health care reform efforts. Investigating 5,116 hypertensive patients from a cross-sectional survey conducted by the Chinese Center for Disease Control and Prevention in 2012, this study found that adherence to standardized hypertension management is associated with positive effects on hypertension- related knowledge, healthy lifestyle behavior, antihypertensive medical treatments, and blood pressure control. It will be necessary to provide primary health care workers with sufficient training and reasonable incentives to ensure the implementation and effectiveness of hypertension management.
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Fidelidade a Diretrizes/estatística & dados numéricos , Conhecimentos, Atitudes e Prática em Saúde , Estilo de Vida Saudável , Hipertensão/psicologia , Hipertensão/terapia , Cooperação do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , China , Estudos Transversais , Feminino , Reforma dos Serviços de Saúde/legislação & jurisprudência , Pesquisas sobre Atenção à Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/psicologia , Cooperação do Paciente/estatística & dados numéricosRESUMO
The progressive mechanism underlying myelodysplastic syndrome remains unknown. Here we identify ROBO1 and ROBO2 as novel progression-related somatic mutations using whole-exome and targeted sequencing in 6 of 16 (37.5%) paired MDS patients with disease progression. Further deep sequencing detects 20 (10.4%) patients with ROBO mutations in a cohort of 193 MDS patients. In addition, copy number loss and loss of heterogeneity (LOH) of ROBO1 and ROBO2 are frequently observed in patients with progression or carrying ROBO mutations. In in vitro experiments, overexpression of ROBO1 or ROBO2 produces anti-proliferative and pro-apoptotic effects in leukaemia cells. However, this effect was lost in ROBO mutants and ROBO-SLIT2 signalling is impaired. Multivariate analysis shows that ROBO mutations are independent factors for predicting poor survival. These findings demonstrate a novel contribution of ROBO mutations to the pathogenesis of MDS and highlight a key role for ROBO-SLIT2 signalling in MDS disease progression.
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Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Síndromes Mielodisplásicas/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Receptores Imunológicos/genética , Idoso , Western Blotting , Linhagem Celular Tumoral , Ensaio de Unidades Formadoras de Colônias , Progressão da Doença , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Transdução de Sinais , Proteínas RoundaboutRESUMO
Malignant clonal cells purification can greatly benefit basic and clinical studies in myelodysplastic syndrome (MDS). In this study, we investigated the potential of using type 1 insulin-like growth factor receptor (IGF-IR) as a marker for purification of malignant bone marrow clonal cells from patients with MDS. The average percentage of IGF-IR expression in CD34+ bone marrow cells among 15 normal controls was 4.5%, 70% of which also express the erythroid lineage marker CD235a. This indicates that IGF-IR mainly express in erythropoiesis. The expression of IGF-IR in CD34+ cells of 55 MDS patients was significantly higher than that of cells from the normal controls (54.0 vs. 4.5%). Based on the pattern of IGF-IR expression in MDS patients and normal controls, sorting of IGF-IR-positive and removal of CD235a-positive erythroid lineage cells with combination of FISH detection were performed on MDS samples with chromosomal abnormalities. The percentage of malignant clonal cells significantly increased after sorting. The enrichment effect was more significant in clonal cells with a previous percentage lower than 50%. This enrichment effect was present in samples from patients with +8, 5q-/-5, 20q-/-20 or 7q-/-7 chromosomal abnormalities. These data suggest that IGF-IR can be used as a marker for MDS bone marrow clonal cells and using flow cytometry for positive IGF-IR sorting may effectively purify MDS clonal cells.
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Biomarcadores Tumorais/metabolismo , Medula Óssea/patologia , Células-Tronco Hematopoéticas/metabolismo , Síndromes Mielodisplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Receptor IGF Tipo 1/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/genética , Antígenos CD34/metabolismo , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Células Cultivadas , Aberrações Cromossômicas , Feminino , Citometria de Fluxo/métodos , Células-Tronco Hematopoéticas/classificação , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/metabolismo , Células-Tronco Neoplásicas/classificação , Células-Tronco Neoplásicas/patologia , Receptor IGF Tipo 1/genéticaRESUMO
Chromosome 7 abnormalities are the most common cytogenetic alterations found in myeloid malignancies. Myeloid malignancies exhibiting monosomy 7/del (7q) have been confirmed to associate with high susceptibility to infections, poor response to chemotherapy, and short survival time, so speculating that chromosome 7 has important tumor suppressor genes. Commonly deleted segments (such as 7q22) of chromosome 7 have been identified by FISH and other technologies. Genes (EZH2, MLL5, DOCK4, SAMD9L/SAMD9) located in commonly deleted segments of 7q have been cloned and characterized along with the advance of molecular biology.This review summaries the current advancement about myeloid malignancies associated with monosomy7/del(7q).
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Deleção Cromossômica , Leucemia Mieloide/genética , Cromossomos Humanos Par 7 , Humanos , Transtornos MieloproliferativosRESUMO
Rigosertib has demonstrated therapeutic activity for patients with high-risk myelodysplastic syndrome (MDS) in clinical trials. However, the role of rigosertib in MDS has not been thoroughly characterized. In this study, we found out that rigosertib induced apoptosis, blocked the cell cycle at the G2/M phase and subsequently inhibited the proliferation of CD34+ cells from MDS, while it minimally affected the normal CD34+ cells. Further studies showed that rigosertib acted via the activation of the P53 signaling pathway. Bioinformatics analysis based on gene expression profile and flow cytometry analysis revealed the abnormal activation of the Akt-PI3K, Jak-STAT and Wnt pathways in high-grade MDS, while the p38 MAPK, SAPK/JNK and P53 pathways were abnormally activated in low-grade MDS. Rigosertib could markedly inhibit the activation of the Akt-PI3K and Wnt pathways, whereas it activated the SAPK/JNK and P53 pathways in high-grade MDS. A receptor tyrosine kinase phosphorylation array demonstrated that rigosertib could increase the activation of RET and PDGFR-ß while reducing the activation of Tie2 and VEGFR2 in MDS cells. Taken together, these data indicate that rigosertib is a selective and promising anti-tumor agent that could ameliorate multiple dysregulated signaling transduction pathways in high-grade MDS.
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Antineoplásicos/farmacologia , Glicina/análogos & derivados , Síndromes Mielodisplásicas/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Sulfonas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Linhagem Celular , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glicina/farmacologia , Humanos , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição STAT , Transcriptoma/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Abnormal immunophenotypes of hematopoietic cells can be detected by flow cytometry (FCM) to assist the diagnosis of myelodysplastic syndromes (MDS). We previously established a FCM scoring system for the diagnosis of low-grade MDS. In this study, additional valuable antigens were involved in an updated FCM scoring system (u-FCMSS) for all MDS subtypes. The u-FCMSS showed better sensitivity and specificity (89.4% and 96.5%) in distinguishing MDS from non-clonal cytopenia diseases. Validation analysis of u-FCMSS exhibited comparable sensitivity and specificity (86.7% and 93.3%) and high agreement rate (88.9%) of FCM diagnosis with morphological diagnosis at optimal cut-off (score 3). The distribution of FCM scores in different disease stages was also analyzed. The results suggested that early scoring from abnormal expression of mature myeloid/lymphoid antigens and advanced scoring from abnormal expression of stem/progenitor antigens expression constituted the majority of FCM scores of low-grade and high-grade MDS, respectively. High early scoring was generally accompanied by low IPSS-R score and superior survival, whereas high advanced scoring was accompanied by high IPSS-R score and inferior survival. In addition, the low-risk MDS patients with high early scoring and low advanced scoring were revealed as candidates for immunosuppressive therapy, whereas those with high advanced scoring and low early scoring may be more suitable for decitabine treatment. In conclusion, the u-FCMSS is a useful tool for diagnosis, prognosis and treatment selection in MDS. Differences in classes of antigens expressed and in distribution of FCM scores may reflect distinctive stage characteristics of MDS during disease progression.
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Antígenos CD34/metabolismo , Citometria de Fluxo/métodos , Imunofenotipagem/métodos , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Sangue , Estudos de Coortes , Progressão da Doença , Feminino , Regulação da Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Prognóstico , Células-Tronco/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
Effects of pressure on glucose-ammonium sulphite solutions were investigated. The reactant (i.e. glucose), intermediate products content, and browning intensity of advanced stages were tested using an UV-Vis spectrophotometer and a high performance liquid chromatograph to gain a better understanding of the influence of pressure on the glucose-ammonium model Maillard reaction system. This study indicates that pressure could promote the first step of the reaction, i.e. condensation reaction between SO(3)(2-)/ammonium and glucose, but inhibit the increase of A(294), A(420) and 5-hydroxymethyl-2-furaldehyde content. The mechanism of inhibiting the glucose-ammonium model Maillard reaction might be that pressure increases dissociative SO(3)(2-) content in solutions and inhibits the degradation of the Amadori rearrangement product.