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INTRODUCTION: The association between total immunoglobulin E (IgE) levels and urinary albumin excretion has not been fully established. Current study aimed to evaluate the association between total IgE levels and urinary albumin-to-creatinine ratio (UACR) among adult Americans. METHODS: Current cross-sectional study utilized data from the 2005 to 2006 National Health and Nutrition Examination Survey, including individuals aged 20 years and above. To assess the relationships between total IgE levels and UACR, both multivariable linear regression models and smooth curve fitting were employed. RESULTS: The study included a total of 3,400 participants (weighted mean age: 46.6 ± 0.8 years), with 1,625 females (weighted percentage: 47.8%). After adjusting for potential confounders, we observed a positive association between higher total IgE levels on a log2 scale and increased UACR (ß = 3.34; 95% CI: 1.40-5.28, p = 0.002). Furthermore, the association displayed a non-linear dose-response pattern. The interaction test revealed a significant distinction in the correlation between total IgE and UACR when stratified by hyperlipidemia (p for interaction <0.001). The results remained robust in sensitivity analyses. CONCLUSION: Our study revealed a significant and independent association between elevated total IgE levels and an increased UACR, which also exhibited a distinct non-linear pattern, highlighting the intricate nature of the connection between IgE levels and UACR.
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Albúminas , Inmunoglobulina E , Adulto , Femenino , Humanos , Estados Unidos , Persona de Mediana Edad , Estudios Transversales , Encuestas NutricionalesRESUMEN
BACKGROUND: Erythropoiesis-stimulating agents (ESAs) have played an important role in the treatment of renal anemia in children, but cannot improve hemoglobin to target level in some cases. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, can stimulate endogenous erythropoietin production and regulate iron metabolism even in patients with kidney failure. However, roxadustat has not yet been approved for use in children. CASE-DIAGNOSIS/TREATMENT: We report a case of refractory renal anemia in an 80-day-old boy, who was hyporesponsive to ESAs even in combination with iron supplementation and transfusion. Compassionate use of roxadustat successfully corrected the intractable anemia. Hyperkalemia is a manageable adverse event of concern during follow-up. CONCLUSION: The successful experience in this case may inform the clinical utility of roxadustat for refractory renal anemia in children, which should be further confirmed by well-designed prospective clinical trials.
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Anemia , Hematínicos , Insuficiencia Renal Crónica , Masculino , Niño , Humanos , Ensayos de Uso Compasivo , Estudios Prospectivos , Insuficiencia Renal Crónica/terapia , Anemia/etiología , Anemia/inducido químicamente , Hematínicos/efectos adversos , Enfermedad Crónica , Glicina/uso terapéutico , Glicina/farmacología , Isoquinolinas/efectos adversos , Hierro/uso terapéuticoRESUMEN
BACKGROUND: Galloway-Mowat syndrome (GAMOS) is a group of rare hereditary diseases by the combination of early onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies caused by WDR73, LAGE3, OSGEP, TP53RK, TPRKB, GON7, WDR4 or NUP133 mutations. CASE PRESENTATION: We present the clinical and genetic features of a two-year-old boy with early nephrotic syndrome, microcephaly, growth retardation hypotonia and hypothyroidism. Genetic testing showed the presence of a canonical-splice mutation in the LAGE3 gene (NM_006014: c.188 + 1C > T). A total of nine female members of the family carried the variant. Seven male members died prematurely, and three of them suffered from nephrotic syndrome, which is consistent with the x-linked gene map of the disease. The overall symptoms of the disease due to the LAGE3 mutation were mild compared to other pathogenic genes. CONCLUSION: As far as we know, this is the largest family case of GAMOS2 caused by LAGE3 mutation found so far. We also compared other subtypes of GAMOS. Due to the heterogeneity of the renal phenotype, regular proteinuria screening is recommended for all patients diagnosed with GAMOS.
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Microcefalia , Síndrome Nefrótico , Femenino , Humanos , Masculino , Diagnóstico Tardío , Proteínas de Unión al GTP/genética , Microcefalia/diagnóstico , Microcefalia/genética , Mutación/genética , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/genética , PreescolarRESUMEN
BACKGROUND: Congenital anomalies of the kidney and urinary tracts (CAKUT) are the leading cause of kidney failure in children with phenotypic and genotypic heterogeneity. Our objective was to describe the genetic spectrum and identify the risk factors for kidney failure in children with CAKUT. METHODS: Clinical and genetic data were derived from a multicenter network (Chinese Children Genetic Kidney Disease Database, CCGKDD) and the Chigene database. A total of 925 children with CAKUT who underwent genetic testing from 2014 to 2020 across China were studied. Data for a total of 584 children wereobtained from the CCGKDD, including longitudinal data regarding kidney function. The risk factors for kidney failure were determined by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: A genetic diagnosis was established in 96 out of 925 (10.3%) children, including 72 (8%) with monogenic variants, 20 (2%) with copy number variants (CNVs), and 4 (0.4%)with major chromosomal anomalies. Patients with skeletal abnormalities were more likely to have large CNVs or abnormal karyotypes than monogenic variants. Eighty-two patients from the CCGKDD progressed to kidney failure at a median age of 13.0 (95% confidence interval, 12.4-13.6) years, and twenty-four were genetically diagnosed with variants of PAX2, TNXB, EYA1, HNF1B and GATA3 or the 48, XXYY karyotype. The multivariate analysis indicated that solitary kidney, posterior urethral valves, bilateral hypodysplasia, the presence of certain variants and premature birth were independent prognostic factors. CONCLUSIONS: The genetic spectrum of CAKUT varies among different subphenotypes. The identified factors indicate areas that require special attention.
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Based on the Chinese Children Genetic Kidney Disease Database (CCGKDD), we established a pediatric Gitelman syndrome (GS) cohort to explore the phenotype and genotype characteristics. Thirty-two patients with SLC12A3 gene variants were collected. Five cases (16%) were homozygous, 16 (50%) were compound heterozygous, 10 (31%) carried only a single variant, and the other one harbored two de novo variants beyond classification. p.(T60M) was found in eight patients. The average diagnosis age was 7.79 ± 3.54 years. A total of 31% of the patients were asymptomatic. Muscle weakness was the most common symptom, accounting for 50%. Earlier age of onset (4.06 ± 1.17 yr vs. 8.10 ± 3.46 yr vs. 8.61 ± 3.56 yr, p< 0.05) and lower urinary calcium-creatinine ratio (p = 0.024) were found in the homozygous group than those in the heterozygous and compound heterozygous group. Patients with p.(T60M) variant had an earlier age of onset (4.01 ± 2.83 yr vs. 6.92 ± 3.07 yr, p = 0.025) and lower urinary calcium-creatinine ratio (p = 0.056). Thus, more than 30% of GS children have no clinical symptoms. Homozygous variant and the p.(T60M) variant may be associated with earlier onset and lower urinary calcium excretion in Chinese pediatric GS.
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Pueblo Asiatico/genética , Síndrome de Gitelman/genética , Adolescente , Edad de Inicio , Calcio/orina , Niño , Preescolar , Creatinina/orina , Enanismo/genética , Femenino , Estudios de Asociación Genética , Síndrome de Gitelman/etnología , Síndrome de Gitelman/orina , Humanos , Hipopotasemia/genética , Lactante , Masculino , Debilidad Muscular/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/genéticaRESUMEN
BACKGROUND: In mainland China, dialysis for children with end-stage renal disease (ESRD) was not introduced until the 1980s. To describe the development of pediatric dialysis in different regions of China, a national pediatric dialysis network, namely, International Pediatric Dialysis Network-China (IPDN-China) ( www.pedpd.org.cn ), was launched in 2012. METHODS: Original and updated information from the renal centers registered with the IPDN-China was collected between 2012 and 2016 from two sources, namely, the registry and the survey, and demographic features were analyzed. RESULTS: Due to promotion by the IPDN-China, the number of registered renal centers increased from 12 to 39 between 2012 and 2016, with a significant increase in the coverage of the Chinese administrative divisions (from 26.5 to 67.6%) (p < 0.01); and the coverage of the pediatric (0~14 years old) population increased to nearly 90% in 2016. The distribution of renal centers indicated that East China had the highest average number of registered centers per million population (pmp) 0~14-year-old age group. Seventeen relatively large dialysis centers were distributed across 14 divisions. Various modalities of renal replacement therapy (RRT) were available in most centers. The IPDN-China has promoted collaborations between dieticians, psychologists, and social workers on dialysis teams to provide better service to children with ESRD and their families. The proportion of centers with all three types of paramedic support (i.e., dieticians, psychologists, and social workers) as well as the proportion of centers with a partial paramedic team significantly increased between 2012 (25.0%) and 2016 (69.2%) (p < 0.05). In terms of the point prevalent cases of patients (aged < 18 years), data from the survey of 39 registered centers revealed that the number of children with ESRD who were on RRT was 578 (49% received a kidney transplant) at the end of 2016, which was more than that reported in previous surveys. Data from the registry showed that 349 dialysis patients had been enrolled as of the end of 2016. The median age at RRT start was 9.5 years, and the leading cause of ESRD was congenital abnormalities of the kidney and urinary tract (CAKUT). CONCLUSIONS: The IPDN-China has helped to promote the development of pediatric dialysis for ESRD in China by improving the organization of care for dialysis patients and increasing the availability and the quality of RRT for patients who need it. To improve knowledge about the epidemiology and outcomes of pediatric RRT around the country, a sustained effort needs to be made by the IPDN-China to increase the enrollment of dialysis patients and increase the number of registered centers in the future.
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Instituciones de Atención Ambulatoria/estadística & datos numéricos , Diálisis Renal/estadística & datos numéricos , Adolescente , Niño , Preescolar , China , Femenino , Accesibilidad a los Servicios de Salud/organización & administración , Humanos , Lactante , Recién Nacido , Masculino , Sistema de RegistrosRESUMEN
To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole-exome sequencing (WES) and trio-WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio-WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.
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Exoma/genética , Predisposición Genética a la Enfermedad , Enfermedades Renales Quísticas/genética , Insuficiencia Renal Crónica/genética , Niño , Preescolar , China/epidemiología , Estudios de Cohortes , Femenino , Pruebas Genéticas , Humanos , Riñón/metabolismo , Riñón/patología , Enfermedades Renales Quísticas/diagnóstico , Enfermedades Renales Quísticas/patología , Masculino , Fenotipo , Insuficiencia Renal Crónica/diagnóstico , Insuficiencia Renal Crónica/patología , Sistema Urinario/metabolismo , Sistema Urinario/patología , Secuenciación del ExomaRESUMEN
Background: Bacterial infections are very common among patients with hematological diseases. Scant data are available regarding differences in the epidemiology and biological features of bacterial infections in neutropenic and non-neutropenic patients. Methods: The aim of this survey was to compare the bacterial pathogens in neutropenic and non-neutropenic patients in the same ward during an 8-year period. Results: A total of 1139 bacterial strains were isolated from 1071 patients with hematological diseases. The percentage of Gram-negative bacteria was significantly higher in neutropenic patients than in non-neutropenic patients (70.4% vs. 55.0%, respectively, P < .01). In neutropenic patients, the most commonly-isolated bacterium was Pseudomonas aeruginosa, followed by Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Stenotrophomonas maltophilia. In respiratory exudates, Gram-negative bacteria were also more frequently isolated from neutropenic patients than from non-neutropenic patients (79.1% vs. 56.1%, respectively, P < .01). The proportion of non-fermentative Gram-negative bacilli was significantly higher in neutropenic patients than in non-neutropenic patients (52.9% vs. 30.5%, respectively, P < .01). In blood culture samples from neutropenic patients, the most frequently identified pathogens, apart from coagulase negative staphylococcus, were Gram-negative bacilli (58.2%). In addition, the proportion of Escherichia coli in neutropenic patients was significantly higher than that in non-neutropenic patients (P < .01). Escherichia coli and Klebsiella pneumoniae strains from neutropenic patients also produced extended-spectrum ß-lactamases at a higher rate of than those strains from non-neutropenic patients (Escherichia coli, 57.6% vs. 30.3%, respectively, P < .01; Klebsiella pneumonia, 31.9% vs. 13.0%, respectively, P < .01). Conclusions: This study showed that there are significant differences in the epidemiology and biological features of bacteria isolated from neutropenic and non-neutropenic patients.
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Bacterias Gramnegativas/aislamiento & purificación , Infecciones por Bacterias Gramnegativas/epidemiología , Infecciones por Bacterias Gramnegativas/microbiología , Enfermedades Hematológicas/complicaciones , Neutropenia/microbiología , Bacteriemia/microbiología , China/epidemiología , Enfermedades Hematológicas/microbiología , Hematología , Unidades Hospitalarias , Humanos , Faringe/microbiología , Estudios Retrospectivos , Esputo/microbiologíaRESUMEN
Disease recurrence is the most important obstacle to achieve long-term survival for patients with advanced acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to reduce the relapse risk and improve the survival, the strategy of early tapering of immunosuppressive agents was prospectively evaluated. Thirty-one patients with advanced AML received early tapering of immunosuppressive drugs, while 32 patients with AML in complete remission (CR) were given the routine tapering of immunosuppressive agents after HLA-matched donor transplantation. All advanced AML patients achieved CR after allo-HSCT. At 24 months after transplantation, relapse incidences were 22% in advanced group and 16% in CR group (P = 0.553); disease-free survival (DFS) and overall survival (OS) were 57.7 and 57.8% in advanced group, while in CR group were 66.6% (P = 0.388) and 66.2% (P = 0.423); immunosuppressive agent-free DFS (IDFS) were similar between two groups (P = 0.407). Acute graft-versus-host disease (aGvHD) incidences were similar between two groups (P = 0.311). Chronic GvHD (cGvHD) incidence was much higher in advanced group than in CR group (70.4 vs 38.7%, P = 0.02), but severe cGvHD had no difference. In multivariate analysis, cGvHD was an independent prognostic factor for lower risk of relapse and better DFS and OS; early tapering of immunosuppressive agents was an independent prognostic factor for cGvHD. The study suggested that advanced AML patients could be directly treated with allo-HSCT and its survival could be improved through the strategy of early tapering of immunosuppressive agents without significant adverse effects ( Clinicaltrials.org NCT03150134).
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Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/administración & dosificación , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Prueba de Histocompatibilidad , Humanos , Incidencia , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Donantes de Tejidos , Trasplante Homólogo/efectos adversos , Adulto JovenRESUMEN
In this study, we investigated whether miR-125a participated in the resistance of the leukemia cell lines to the chemotherapeutic agent daunorubicin. Higher expression of miR-125a is correlated with lower treatment response and shorter overall survival in acute leukemia patients. Overexpression of miR-125a induced drug resistance in HL-60, K562, and THP-1cell lines through reducing apoptosis. We also showed that miR-125a mediated daunorubicin resistance in leukemia cell lines through the decrease of GRK2 and Puma which were proved to be direct targets of miR-125a. This study may provide novel therapeutic targets for therapy and improve predictions of therapeutic responses in leukemia to daunorubicin.
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Apoptosis/efectos de los fármacos , Daunorrubicina/farmacología , Leucemia/tratamiento farmacológico , MicroARNs/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Reguladoras de la Apoptosis/fisiología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Quinasa 2 del Receptor Acoplado a Proteína-G/fisiología , Humanos , Leucemia/patología , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/fisiologíaRESUMEN
Targeting leukemia initiating cells is considered to be an effective way to cure leukemia, for which it is critical to identify novel therapeutic targets. Herein, we demonstrate that CD244, which was initially reported as a key regulator for natural killer cells, is highly expressed on both mouse and human leukemia initiating cells. Upon CD244 knockdown, human leukemia cell lines and primary leukemia cells have markedly impaired proliferation abilities both in vitro and in vivo Interestingly, the repopulation ability of both mouse and human hematopoietic stem cells is not impaired upon CD244 knockdown. Using an MLL-AF9-induced murine acute myeloid leukemia model, we show that leukemogenesis is dramatically delayed upon CD244 deletion, together with remarkably reduced Mac1+/c-Kit+ leukemia cells (enriched for leukemia initiating cells). Mechanistically, we reveal that CD244 is associated with c-Kit and p27 except for SHP-2 as previously reported. CD244 co-operates with c-Kit to activate SHP-2 signaling to dephosphorylate p27 and maintain its stability to promote leukemia development. Collectively, we provide intriguing evidence that the surface immune molecule CD244 plays an important role in the maintenance of stemness of leukemia initiating cells, but not in hematopoietic stem cells. CD244 may represent a novel therapeutic target for the treatment of acute myeloid leukemia.
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Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Leucemia/metabolismo , Células Madre Neoplásicas/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Transducción de Señal , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/metabolismo , Animales , Biomarcadores , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Modelos Animales de Enfermedad , Humanos , Inmunofenotipificación , Leucemia/genética , Ratones , Ratones Noqueados , Modelos Biológicos , Fenotipo , Unión Proteica , Estabilidad Proteica , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genéticaRESUMEN
OBJECTIVE: To investigate the association of drug resistance of Mycoplasma pneumoniae (MP) with DNA load and genotypes in children with MP pneumonia. METHODS: A total of 230 children who were hospitalized and diagnosed with MP pneumonia between January 2012 and December 2016 were enrolled. Throat swabs were collected from the 230 children, and a rapid drug sensitivity assay was used to determine the sensitivity of clinical isolates of MP to nine commonly used antibacterial agents. Quantitative real-time PCR was used to measure MP-DNA load in throat swabs. PCR sequencing was used to determine the genotype of 2063 locus of the MP 23S rRNA V domain. RESULTS: Of the 230 children, 86 (37.4%) had genotype A in 2063 locus, 134 (58.3%) had genotype G, 8 (3.5%) had genotype C, and 2 (0.9%) had genotype T. Mutant strains (genotype G+C+T) had a significantly higher MP-DNA load than wild-type strains (genotype A) (P<0.05). The strains resistant to erythromycin, azithromycin, clarithromycin, and clindamycin had a significantly higher MP-DNA load than non-resistant strains (P<0.05). MP had a high drug resistance rate to macrolide antibiotics. More than 60% of the cases with resistance to macrolides were found to have A2063G mutations. MP was rarely resistant to quinolones (less than 2%). CONCLUSIONS: Mutations in 2063 locus of the MP 23S rRNA V domain may result in the resistance of MP to macrolides and the change in DNA load and can be used as a basis for selecting drugs for MP.
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ADN Bacteriano/análisis , Farmacorresistencia Bacteriana , Mycoplasma pneumoniae/efectos de los fármacos , Neumonía por Mycoplasma/microbiología , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Masculino , Mycoplasma pneumoniae/genética , Neumonía por Mycoplasma/tratamiento farmacológicoRESUMEN
Deregulation of microRNA (miRNA) expression can lead to cancer initiation and progression. However, limited information exists on the function of miRNAs in cancer maintenance. We examined these issues in the case of myeloproliferative diseases and neoplasms (MPN), a collection of hematopoietic neoplasms regarded as preleukemic, thereby representing early neoplastic states. We report here that microRNA-125a (miR-125a)-induced MPN display a complex manner of oncogene dependence. Following a gain-of-function genomics screen, we overexpressed candidate miR-125a in vivo, which led to phenotypes consistent with an atypical MPN characterized by leukocytosis, monocytosis, splenomegaly, and progressive anemia. The diseased MPN state could be recapitulated in a doxycycline-inducible mouse model. Upon doxycycline withdrawal, the primary MPN phenotypes rapidly resolved after the discontinuation of miR-125a overexpression. However, reinduction of miR-125a led to complex phenotypes, with some animals rapidly developing lethal anemia with extensive damages in the spleen. Forced expression of miR-125a resulted in elevated cellular tyrosine phosphorylation and hypersensitivity toward hematopoietic cytokines. Furthermore, we demonstrate that miR-125a targets multiple protein phosphatases. Our data demonstrate that miR-125a-induced MPN is addicted to its sustained overexpression, and highlight the complex nature of oncogenic miRNA dependence in an early neoplastic state.
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Neoplasias de la Médula Ósea/genética , MicroARNs/genética , Trastornos Mieloproliferativos/genética , Oncogenes/genética , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Neoplasias de la Médula Ósea/metabolismo , Neoplasias de la Médula Ósea/patología , Trasplante de Médula Ósea , Línea Celular , Ensayo de Unidades Formadoras de Colonias , Doxiciclina/farmacología , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Interleucina-3/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Ratones , Ratones Endogámicos C57BL , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
AIM: Hypoxia, a characteristic of almost all types of solid tumors, has been associated with poor outcome in a number of human malignancies. The aim of this study was to investigate the molecular mechanisms involved in hypoxia-induced activation of the human survivin gene promoter in cervical HeLa cells. MATERIAL AND METHODS: Immunohistochemical staining was used to detect the expression of HIF-1α and survivin in cervical cancer samples and normal cervical samples. Under normoxic and hypoxic conditions, the expression of hypoxia inducible factor (HIF)-1α and survivin in cervical cancer HeLa cells was detected by quantitative reverse transcription polymerase chain reaction and Western blotting. Luciferase reporter assays was used to investigate the molecular mechanisms in hypoxia-induced survivin activation. We also studied the effect of HIF-1α overexpression on the expression of survivin in cervical cancer HeLa cells. RESULTS: Significant HIF-1α and survivin overexpression is associated with cervical cancer, and HIF-1α protein expression is strongly correlated with survivin protein expression. In cervical cancer cell line (HeLa), hypoxia upregulated both HIF-1α and survivin expression. Moreover, luciferase reporter assays using survivin core promoter demonstrated that survivin transcription was activated under hypoxia conditions and was associated with HIF-1α overexpression. The transcriptional activation of reporter genes in response to hypoxia is independent of potential HIF-1α-responsive element, located between -86 and -82 regions. HIF-1α overexpression significantly activated survivin expression. CONCLUSION: Our results demonstrate that survivin expression is upregulated following the induction of HIF-1α by hypoxia resulting from tumor formation, possibly leading to tumor progression. These findings have potential implication in developing novel cancer therapy targeting HIF-1.
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Carcinoma/metabolismo , Cuello del Útero/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas de Neoplasias/metabolismo , Regulación hacia Arriba , Neoplasias del Cuello Uterino/metabolismo , Anciano , Carcinoma/patología , Hipoxia de la Célula , Línea Celular Tumoral , Cuello del Útero/patología , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis/biosíntesis , Proteínas Inhibidoras de la Apoptosis/genética , Persona de Mediana Edad , Mutación , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Regiones Promotoras Genéticas , Survivin , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Acute tubular necrosis (ATN) is the most common reason for acute kidney injury (AKI), and there is still an absence of effective therapies. OBJECTIVE: To assess the value of bone marrow cell mobilization by stem cell factor (SCF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy in rats with gentamicin-induced ATN. METHODS: ATN was induced in male Sprague-Dawley (SD) rats with five daily high-dose intraperitoneal injections of gentamicin. Subcutaneous injections of SCF and GM-CSF were administered simultaneously and these cytokines were observed on days 2, 5, 10, 17, 24, and 31. Peripheral blood and renal tissue CD34+ cell count, mortality rate, blood urea nitrogen (BUN), serum creatinine (SCr), creatinine clearance rate (CCr), and histopathologic lesion scores were determined. Twelve hours after bone marrow ablation (BMA) by lethal X-ray radiation, specific pathogen-free (SPF) ATN rats were given five daily injections of SCF and GM-CSF. BUN, SCr, and histopathologic lesion scores were evaluated on days 2, 5, and 10. RESULTS: Peripheral blood CD34+ cell count increased significantly in ATN rats between 2 and 10 days after SCF and GM-CSF injection. Mortality was reduced from 34.7% in the ATN group to 18.6% in the ATN+CSF. In addition, cytokines administration significantly decreased SCr and BUN. Moreover, cytokines rapidly ameliorated tubular injury. There was no significant effect on ATN rats after BMA. CONCLUSIONS: This study demonstrated that SCF and GM-CSF effectively mobilized bone marrow cells in ATN rats, and cytokines administration partially prevented gentamicin-induced ATN. These results suggest that bone marrow stem cell (BMSC) mobilization may be an effective therapy for ATN.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Células Madre Hematopoyéticas/efectos de los fármacos , Necrosis Tubular Aguda/prevención & control , Túbulos Renales/fisiología , Recuperación de la Función , Factor de Células Madre/farmacología , Animales , Creatinina/metabolismo , Modelos Animales de Enfermedad , Quimioterapia Combinada , Necrosis Tubular Aguda/metabolismo , Necrosis Tubular Aguda/patología , Masculino , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
Mesenchymal stem cells (MSCs) have already demonstrated definitive evidence of their clinical benefits in acute graft-versus-host disease (aGvHD) and other inflammatory diseases. However, the comprehensive mechanism of MSCs' immunomodulation properties has not been elucidated. To reveal their potential immunosuppressive molecules, we used RNA sequencing to analyze gene expression in different tissue-derived MSCs, including human bone marrow, umbilical cord, amniotic membrane, and placenta, and found that chitinase-3-like protein 1 (Chi3l1) was highly expressed in human umbilical cord mesenchymal stem cells (hUC-MSCs). We found that hUC-MSCs treated with interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) exhibited increased expression of Chi3l1 and concurrently repressed T-helper 17 cell (Th17) differentiation through inhibition of signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, Chi3l1 knockdown hUC-MSCs exhibited impaired therapeutic efficacy in aGvHD mice with an increased inflammatory response by promoting Th17 cell differentiation, including an increase in IL-17A in the spleen, intestine, and serum. Collectively, these results reveal a new immunosuppressive molecule, Chi3l1, in hUC-MSCs in the treatment of aGvHD that regulates Th17 differentiation and inhibits STAT3 activation. These novel insights into the mechanisms of hUC-MSC immunoregulation may lead to the consistent production of hUC-MSCs with strong immunosuppressive functions and thus improved clinical utility.
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Little is known regarding whether the cell of origin differs among different leukemia types. To address this fundamental issue, we determined the cell of origin in five distinct types of acute leukemia induced by N-Myc overexpression in mice. CD150+CD48-CD41-CD34-c-Kit+Sca-1+Lin- (KSL) (HSC1) cells, CD150-CD48-CD41-CD34-KSL (HSC2) cells, CD150+CD41+CD34-KSL (HPC1) cells, CD150+CD41+CD34+KSL (HPC2) cells, and CD150-CD41-CD34+KSL (HPC3) cells were purified from the bone marrow of adult C57BL/6 mice, transduced with the N-Myc retrovirus vector, and transplanted into lethally irradiated mice. B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), acute undifferentiated leukemia (AUL), and mixed phenotype acute leukemia (MPAL) developed from five populations. RNA sequencing data supported the phenotypical diagnoses of leukemia, except that AUL appeared transcriptionally close to T-ALL. Whole-genome sequencing revealed that retroviral integration sites were irrelevant to the leukemia types and that T-ALL and AML of MPAL shared the same integration site and many gene mutations, suggesting their common origin. Additionally, leukemic stem cells were identified in the KSL cell population, suggesting that the phenotypes of leukemic stem cells are irrelevant to leukemia types. This study provides experimental evidence for the similar and multiple cells of origin in acute leukemia.
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Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Animales , Antígenos CD34 , Humanos , Leucemia Mieloide Aguda/genética , Ratones , Ratones Endogámicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
Myelodysplastic syndromes (MDS) are generally considered as a group of clonal diseases derived from hematopoietic stem cells, but a number of studies have suggested that they are derived from myeloid progenitor cells. We aimed to identify the cell of origin in MDS by single-cell analyses. Targeted single-cell RNA sequencing, covering six frequently mutated genes (U2AF1, SF3B1, TET2, ASXL1, TP53, and DNMT3A) in MDS, was developed and performed on individual cells isolated from the CD34+ and six lineage populations in the bone marrow of healthy donors (HDs) and patients with MDS. The detected mutations were used as clonal markers to define clones. By dissecting the distribution of clones in six lineages, the clonal origin was determined. We identified three mutations both in HDs and patients with MDS, termed clonal hematopoiesis (CH) mutations. We also identified fifteen mutations only detected in patients with MDS, termed MDS mutations. Clonal analysis showed that CH clones marked by CH mutations and MDS clones marked by MDS mutations were derived from hematopoietic stem cells as well as various hematopoietic progenitor cells. Most patients with MDS showed the chimeric state with CH clones and MDS clones. Clone size analysis suggested that CH mutations may not contribute to clonal expansion of MDS. In conclusion, MDS comprise multiple clones derived from hematopoietic stem and progenitor cells.
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OBJECTIVE: This study aimed to evaluate the effects of a structured team nursing model on the efficacy and quality of cardiopulmonary resuscitation (CPR) in acute myocardial infarction patients undergoing percutaneous coronary intervention (PCI). METHODS: With the random number table, 130 myocardial infarction patients undergoing PCI were divided into two groups, including the control group (n=65) receiving routine emergency resuscitation and nursing care, and the study group (n=65) receiving a structured team care model. The efficacy of CPR, cardiac function, exercise tolerance, ability of daily living activities, quality of life, complication rate and nursing satisfaction were compared between the two groups. RESULTS: The door-to-balloon time, length of stay at the emergency department, duration of balloon dilation, bedtime and hospital stay in the study group were shorter than those in the control group (P<0.05). The study group showed lower LVEDD and LVESD and higher LVEF than the control group after nursing (P<0.05). The extend of physical limitation, angina stability, level of disease awareness, number of angina attacks, and treatment satisfaction scores in the 6-MWT, MBI, and SAQ scales in the study group after nursing were higher than those in the control group (P<0.05). The complication rate in the study group (7.69%) was lower than that in the control group (20.00%) (P<0.05). The study group had higher satisfaction with operational skills, teamwork, clinical practice, rescue awareness, orderliness, and timeliness than the control group (P<0.05). CONCLUSION: Structured team nursing model is helpful to improve the timeliness and quality of CRP, shorten the treatment time, improve patients' cardiac function and exercise tolerance, improve self-care ability and quality of life, reduce the occurrence of complications, and enhance the patient-nurse relationship.
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OBJECTIVE: This study explored the feasibility of congenital heart disease (CHD) screening by combining a percutaneous oxygen saturation (POX) test with cardiac auscultation method in neonates. METHODS: POX tests and cardiac auscultation were used concurrently to screen 8305 neonates born in Jinjiang City Hospital between January 2016 and December 2018 for CHD. The positive screening results (positive POX or positive cardiac auscultation) were confirmed with echocardiography, while any false negative results were identified through follow-up and parent feedback. Sensitivity, specificity, positive/negative predictive values, Youden's index, and the area under the receiver operator characteristic curve (AUC) of the single use and combined use of the two methods (a POX test and auscultation) were calculated, and the results were compared. RESULTS: Among 8305 neonates, 22 cases were positive for POX alone, of which 6 cases were diagnosed by echocardiography; 83 cases were positive for cardiac auscultation alone, of which 47 cases were diagnosed by echocardiography; and 8 cases were positive for both methods, all of which were confirmed by echocardiography. Four more cases were confirmed during follow-up. Sensitivity, specificity, and the positive and negative predictive values of combined screening were 93.85%, 99.37%, 53.98% and 99.95%, respectively, while Youden's index was 0.93, and the AUC was 0.966. Sixty-five cases of CHD were diagnosed, the total incidence being 7.82%, and a ventricular septal defect was found to be the most common type. CONCLUSION: The combination of POX test and cardiac auscultation as a screening method for neonatal CHD can reduce missed diagnoses and increase the detection rate of CHD in newborn infants.