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1.
Dis Model Mech ; 16(8)2023 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-37486182

RESUMO

SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6×129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective in this study was to characterize the skeletal phenotype in these mice. Compared to wild-type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations and delayed skeletal development. Because poor survival prevents evaluation of mature knockout mice, we generated a conditional Slc7a7 deletion in mature osteoblasts or mesenchymal cells of the osteo-chondroprogenitor lineage, but no differences in bone architecture were observed. Overall, global Slc7a7 deficiency caused growth failure with low plasma IGF-1 concentrations and delayed skeletal development, but Slc7a7 deficiency in the osteoblastic lineage was not a major contributor to these phenotypes. Future studies utilizing additional tissue-specific Slc7a7 knockout models may help dissect cell-autonomous and non-cell-autonomous mechanisms underlying phenotypes in LPI.


Assuntos
Fator de Crescimento Insulin-Like I , Animais , Camundongos , Sistema y+L de Transporte de Aminoácidos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout
2.
Arch Dis Child Fetal Neonatal Ed ; 108(6): 631-637, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37130729

RESUMO

BACKGROUND: Prognostication of mortality and decision to offer extracorporeal membrane oxygenation (ECMO) treatment in infants with congenital diaphragmatic hernia (CDH) can inform clinical management. OBJECTIVE: To summarise the prognostic value of echocardiography in infants with CDH. METHODS: Electronic databases Ovid MEDLINE, Embase, Scopus, CINAHL, the Cochrane Library and conference proceedings up to July 2022 were searched. Studies evaluating the prognostic performance of echocardiographic parameters in newborn infants were included. Risk of bias and applicability were assessed using the Quality Assessment of Prognostic Studies tool. We used a random-effect model for meta-analysis to compute mean differences (MDs) for continuous outcomes and relative risk (RR) for binary outcomes with 95% CIs. Our primary outcome was mortality; secondary outcomes were need for ECMO, duration of ventilation, length of stay, and need for oxygen and/or inhaled nitric oxide. RESULTS: Twenty-six studies were included that were of acceptable methodological quality. Increased diameters of the right and left pulmonary arteries at birth (mm), MD 0.95 (95% CI 0.45 and 1.46) and MD 0.79 (95% CI 0.58 to 0.99), respectively) were associated with survival. Left ventricular (LV) dysfunction, RR 2.40, (95% CI 1.98 to 2.91), right ventricular (RV) dysfunction, RR 1.83 (95% CI 1.29 to 2.60) and severe pulmonary hypertension (PH), RR 1.69, (95% CI 1.53 to 1.86) were associated with mortality. Left and RV dysfunctions, RR 3.30 (95% CI 2.19 to 4.98) and RR 2.16 (95% CI 1.85 to 2.52), respectively, significantly predicted decision to offer ECMO treatment. Limitations are lack of consensus on what parameter is optimal and standardisation of echo assessments. CONCLUSIONS: LV and RV dysfunctions, PH and pulmonary artery diameter are useful prognostic factors among patients with CDH.


Assuntos
Hérnias Diafragmáticas Congênitas , Hipertensão Pulmonar , Recém-Nascido , Lactente , Humanos , Hérnias Diafragmáticas Congênitas/diagnóstico por imagem , Hérnias Diafragmáticas Congênitas/terapia , Hérnias Diafragmáticas Congênitas/complicações , Prognóstico , Ecocardiografia , Pulmão , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/complicações , Estudos Retrospectivos
3.
Genes (Basel) ; 13(5)2022 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-35627268

RESUMO

Acute myeloid leukemia (AML) is the most common type of leukemia in adults, accounting for 30% of all adult leukemia cases. While there have been recent improvements in the prognosis of the disease, the prognosis remains grim, and further understanding of AML and the development of new therapeutic agents is critical. This study aimed to investigate the potential interaction between colorectal cancer (CRC) cells and AML cells. Unexpectedly, we found that CRC cell-derived conditioned medium (CM) showed anticancer activities in AML cells by inducing apoptosis and differentiation. Mechanistic studies suggest that these phenotypes are closely associated with the suppression of PI3K/AKT/mTOR and MAPK survival signaling, the upregulation of myeloid differentiation-promoting transcription factors c/EBPα and PU.1, and the augmentation of executioner caspases-3/7. Importantly, bioinformatic analyses of our gene expression profiling data, including that derived from principal component analysis (PCA), volcano plots, boxplots, heat maps, kyoto encyclopedia of genes and genomes (KEGG) pathways, and receiver operating characteristic (ROC) curves, which evaluate gene expression profiling data, provided deeper insight into the mechanism in which CRC-CM broadly modulates apoptosis-, cell cycle arrest-, and differentiation-related gene expression, such as BMF, PLSCR3, CDKN1C, and ID2, among others, revealing the genes that exert anticancer effects in AML cells at the genomic level. Collectively, our data suggest that it may be worthwhile to isolate and identify the molecules with tumor-suppressive effects in the CM, which may help to improve the prognosis of patients with AML.


Assuntos
Neoplasias Colorretais , Leucemia Mieloide Aguda , Neoplasias Colorretais/genética , Meios de Cultivo Condicionados/farmacologia , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/genética
4.
Molecules ; 26(22)2021 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-34833935

RESUMO

Aralia continentalis has been used in Korea as a folk remedy for arthralgia, rheumatism, and inflammation. However, its anti-lymphoma effect remains uncharacterized. Here, we demonstrate that A. continentalis extract and its three diterpenes efficiently kill B-lymphoma cells. Our in vitro and in vivo results suggest that the cytotoxic activities of continentalic acid, a major diterpene from A. continentalis extract, are specific towards cancer cells while leaving normal murine cells and tissues unharmed. Mechanistically, continentalic acid represses the expression of pro-survival Bcl-2 family members, such as Mcl-1 and Bcl-xL. It dissociates the mitochondrial membrane potential, leading to the stimulation of effector caspase 3/7 activities and, ultimately, cell death. Intriguingly, this agent therapeutically synergizes with roflumilast, a pan-PDE4 inhibitor that has been successfully repurposed for the treatment of aggressive B-cell malignancies in recent clinical tests. Our findings unveiled that A. continentalis extract and three of the plant's diterpenes exhibit anti-cancer activities. We also demonstrate the synergistic inhibitory effect of continentalic acid on the survival of B-lymphoma cells when combined with roflumilast. Taken in conjunction, continentalic acid may hold significant potential for the treatment of B-cell lymphoma.


Assuntos
Antineoplásicos/farmacologia , Diterpenos/farmacologia , Linfoma de Células B/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Aralia/química , Linhagem Celular Tumoral , Humanos , Linfoma de Células B/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Extratos Vegetais/farmacologia , Raízes de Plantas/química , República da Coreia
5.
Urology ; 156: e150-e153, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33766714

RESUMO

Testicular tumors are rare in the prepubertal population and often are germ cell tumors. Myofibroma is a rare spindle cell neoplasm composed of myofibroblasts, which are intermediate cells between fibroblasts and smooth muscle cells. Only two prepubertal testicular myofibromas have been previously reported. While cryptorchidism is a risk factor for testicular germ cell tumors, the exact etiology of testicular myofibroma is unknown. We report a case of testicular myofibroma in a six-year-old male with a history of undescended testes, as well as a review of the literature. This case suggests a possible connection between undescended testes and testicular myofibroma.


Assuntos
Miofibroma , Neoplasias Testiculares , Criança , Criptorquidismo/complicações , Humanos , Masculino , Miofibroma/diagnóstico , Miofibroma/etiologia , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/etiologia
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