RESUMEN
OBJECTIVES: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress. METHODS: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo. RESULTS: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models. DISCUSSION: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.
Asunto(s)
Progresión de la Enfermedad , Homeostasis , Metilenotetrahidrofolato Deshidrogenasa (NADP) , Estrés Oxidativo , Neoplasias Gástricas , Animales , Humanos , Ratones , Aminohidrolasas/metabolismo , Aminohidrolasas/genética , Línea Celular Tumoral , Metilenotetrahidrofolato Deshidrogenasa (NADP)/metabolismo , Metilenotetrahidrofolato Deshidrogenasa (NADP)/genética , Enzimas Multifuncionales/metabolismo , Enzimas Multifuncionales/genética , Oxidación-Reducción , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Low birth weight (LBW) might be a risk factor for acquiring lower respiratory tract infections (LRTIs) associated with disease related complications in early childhood. HFMD, a frequent viral infection in southern China, is a leading cause of lower respiratory tract infections in children. We analyzed whether LBW is a risk factor for children with HFMD to develop lower respiratory tract infections. METHODS: A total of 298 children with HFMD, admitted to a hospital in Qingyuan city, Guangdong province, were recruited. Demographic data and clinical parameters such as serum glucose level and inflammatory markers including peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate were routinely collected on admission. Birth weight data were derived from birth records. RESULTS: Mean birth weight (BW) was 167 g lower in patients with HFMD and LRTIs as compared to patients with solely HFMD (p = 0.022) and the frequency of birth weight below the tenth percentile was significantly higher in patients with HFMD and LRTIs (p = 0.002). CONCLUSIONS: The results of the study show that low birth weight is associated with a higher incidence of lower respiratory tract infections in young children with HFMD.
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Enfermedad de Boca, Mano y Pie/complicaciones , Recién Nacido de Bajo Peso , Infecciones del Sistema Respiratorio/complicaciones , Biomarcadores/sangre , Glucemia/análisis , Sedimentación Sanguínea , Proteína C-Reactiva/análisis , China/epidemiología , Femenino , Enfermedad de Boca, Mano y Pie/epidemiología , Humanos , Lactante , Recién Nacido , Recuento de Leucocitos , Masculino , Factores de RiesgoRESUMEN
OBJECTIVE: We present the prenatal diagnosis of a class II 1q21.1 microdeletion in monozygotic (MZ) twins with discordant phenotypes. CASE REPORT: A monochorionic diamniotic twin pair presented with discordant ultrasound anomalies; twin A had cardiovascular abnormalities, while twin B did not. No specific complications were noted in the twins during pregnancy. A single nucleotide polymorphism array revealed an identical class II 1q21.1 microdeletion inherited from a phenotypically normal mother and identified the twins as MZ. The deleted region encompassed both the proximal 1q21.1 thrombocytopenia absent radius syndrome region and the distal 1q21.1 recurrent microdeletion region. No other rare copy number variants (CNVs) were identified, and concordance was observed in the CNVs between the twins. CONCLUSION: Discordant cardiovascular abnormalities may occur in MZ twins carrying the same class II 1q21.1 microdeletion. Further studies involving discordant MZ twins are needed to determine the modifying factors of the phenotypic heterogeneity of the microdeletion.
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Anomalías Múltiples/diagnóstico , Anomalías Cardiovasculares/diagnóstico , Enfermedades en Gemelos/diagnóstico , Megalencefalia/diagnóstico , Diagnóstico Prenatal/métodos , Gemelos Monocigóticos/genética , Anomalías Múltiples/genética , Adulto , Anomalías Cardiovasculares/genética , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Variaciones en el Número de Copia de ADN , Enfermedades en Gemelos/genética , Femenino , Humanos , Megalencefalia/genética , Fenotipo , Embarazo , Embarazo Gemelar/genéticaRESUMEN
OBJECTIVE: To investigate the expression and clinical significance of PD-L1 and microRNA-138-5p in the peripheral blood mononuclear cells of patients with acute myeloid leukemia. METHODS: The SYBR Greenâ real-time PCR was used to detect the expression levels of PD-L1 mRNA and miR-138 in 20 cases of primary AML, 9 cases of relapsed/refractory AML and 8 cases of complete remission. The samples of peripheral blood of 20 healthy peoples were used as controls. RESULTS: The expression levels of PD-L1 in both the primary AML and the relapsed/refractory AML groups were significantly higher than those in the healthy control group (P<0.01), and the expression level of PD-L1 in the relapsed/refractory AML group was significantly higher than that in the primary AML group (P<0.01). The expression level of miR-138 in both the primary AML and the relapsed/refractory AML groups were significantly lower than that in the healthy control group (P<0.01). The 8 sampes out of 20 cases of primary AML patients achieved complete remission (CR) were collected and detected. The results showed that the expression level of miR-138 in the complete remission group was higher than that in the primary AML group (P<0.05), but the expression level of PD-L1 mRNA in the CR group was not significantly different from that in the primary AML group (P>0.05). and there was a negative correlation between PD-L1 mRNA and miR-138 in primary AML patients (P<0.05). CONCLUSION: The expression of PD-L1 increases and the expression of miR-138 down-regulates in PBMNCs of AML patients, furthermore, both correlate each other.
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Antígeno B7-H1/genética , Leucemia Mieloide Aguda , MicroARNs/genética , Humanos , Leucemia Mieloide Aguda/genética , Leucocitos Mononucleares , Inducción de RemisiónRESUMEN
The human solute carrier family 10 member 1 (SLC10A1) gene encodes sodium taurocholate cotransporting polypeptide (NTCP), the principal transporter of conjugated bile salts from the plasma into hepatocytes. Although the function of NTCP has been studied extensively and a number of SLC10A1 variations have been identified in humans, information regarding NTCP deficiency is limited. To date, only one patient with NTCP deficiency has been described; however, in the present study a pediatric patient who experienced intractable and striking hypercholanemia is presented. Analysis of the SLC10A1 gene in the patient revealed a homozygous p.Ser267Phe (c.800C>T) variation, which proved to be a single-nucleotide polymorphism (SNP) in the allele frequency of 4.7% of healthy controls. This variation involved a conserved amino acid residue on the orthologous alignment that was predicted to be 'disease-causing' by functional analysis using a number of bioinformatic tools. Next generation sequencing was performed; however, no other genetic causes were identified that would affect the bile acid homeostasis in the patient. Moreover, an adult, with the same genotype as the pediatric patient, was identified for the first time as experiencing mild hypercholanemia. The molecular and clinical findings in the present study suggest, for the first time, that there is an association between p.Ser267Phe SNP and hypercholanemia, and this information may be used to clinically identify NTCP deficiency worldwide.
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Citrin deficiency (CD) is a Mendelian disease due to biallelic mutations of SLC25A13 gene. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is the major pediatric CD phenotype, and its definite diagnosis relies on SLC25A13 genetic analysis. China is a vast country with a huge population, but the SLC25A13 genotypic features of CD patients in our country remains far from being well clarified. Via sophisticated molecular analysis, this study diagnosed 154 new CD patients in mainland China and identified 9 novel deleterious SLC25A13 mutations, i.e. c.103A > G, [c.329 - 154_c.468 + 2352del2646; c.468 + 2392_c.468 + 2393ins23], c.493C > T, c.755 - 1G > C, c.845_c.848 + 1delG, c.933_c.933 + 1insGCAG, c.1381G > T, c.1452 + 1G > A and c.1706_1707delTA. Among the 274 CD patients diagnosed by our group thus far, 41 SLC25A13 mutations/variations were detected. The 7 mutations c.775C > T, c.851_854del4, c.1078C > T, IVS11 + 1G > A, c.1364G > T, c.1399C > T and IVS16ins3kb demonstrated significantly different geographic distribution. Among the total 53 identified genotypes, only c.851_854del4/c.851_854del4 and c.851_854del4/c.1399C > T presented different geographic distribution. The northern population had a higher level of SLC25A13 allelic heterogeneity than those in the south. These findings enriched the SLC25A13 mutation spectrum and brought new insights into the geographic distribution of the variations and genotypes, providing reliable evidences for NICCD definite diagnosis and for the determination of relevant molecular targets in different Chinese areas.
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Pueblo Asiatico/genética , Citrulinemia/epidemiología , Citrulinemia/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Mutación , China/epidemiología , Femenino , Humanos , Recién Nacido , Masculino , Epidemiología Molecular/métodos , Patología Molecular/métodosRESUMEN
BACKGROUND: Recent studies show that preterm birth is associated with hypertension in later life. The renin-angiotensin system (RAS) during pregnancy influences fetal growth and development. In the current study, we investigated the impact of fetal as well as maternal angiotensin (1-7) [Ang (1-7)] and angiotensin II (Ang II) plasma concentrations on the risk of preterm birth. METHODS: Three hundred and nine pregnant women were prospectively included into the study. The pregnant women were divided into two groups, for example, preterm birth of lower than 37 gestational weeks (nâ=â17) and full-term birth of 37 gestational weeks or more (nâ=â292). Maternal and neonatal plasma Ang (1-7) and Ang II concentrations were analyzed at birth from maternal venous blood and umbilical cord blood, respectively. Risk factors for premature birth were determined by multiple logistic regression analysis. RESULTS: Fetal and maternal plasma Ang (1-7) concentrations in the preterm group were lower than those of the term group fetal Ang (1-7) preterm birth: 486.15â±â337.34â ng/l and fetal Ang (1-7) term birth: 833.84â±â698.12â ng/l and maternal Ang (1-7) preterm birth: 399.86â±â218.93â ng/l; maternal Ang (1-7) term birth: 710.34â±â598.22â ng/l. Multiple logistic regression analysis considering confounding factors revealed that preeclampsia (Pâ<â0.001), premature rupture of membranes (Pâ=â0.001), lower concentration of maternal Ang (1-7) (Pâ=â0.013) and fetal plasma Ang (1-7) (Pâ=â0.032) were independently associated with preterm birth. We could furthermore demonstrate that the maternal Ang (1-7)/Ang II ratio is independently associated with gestational hypertension or preeclampsia, factors causing preterm birth. CONCLUSIONS: Lower concentrations of maternal and fetal Ang (1-7) are independently associated with preterm birth - a risk factor of hypertension in later life.