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1.
Arq. bras. cardiol ; 116(5): 970-978, nov. 2021. tab, graf
Article in English, Portuguese | LILACS | ID: biblio-1248893

ABSTRACT

Resumo Fundamento: A vitamina D (VD) tem um importante papel na função cardíaca. No entanto, a vitamina exerce uma curva "dose-resposta" bifásica na fisiopatologia cardiovascular e pode causar efeitos deletérios, mesmo em doses não tóxicas. A VD exerce suas funções celulares ligando-se ao seu receptor. Ainda, a expressão da proteína de interação com a tiorredoxina (TXNIP) é positivamente regulada pela VD. A TXNIP modula diferentes visa de sinalização celular que podem ser importantes para a remodelação cardíaca. Objetivos: Avaliar se a suplementação com VD leva à remodelação cardíaca, e se a TXNIP e a tiorredoxina (Trx) estão associadas com esse processo. Métodos: Duzentos e cinquenta ratos Wistar machos foram alocados em três grupos: controle (C, n=21), sem suplementação com VD; VD3 (n = 22) e VD10 (n=21), suplementados com 3,000 e 10,000 UI de VD/ kg de ração, respectivamente, por dois meses. Os grupos foram comparados por análise de variância (ANOVA) com um fator e teste post hoc de Holm-Sidak (variáveis com distribuição normal), ou pelo teste de Kruskal-Wallis e análise post-hoc de Dunn. O nível de significância para todos os testes foi de 5%. Resultados: A expressão de TXNIP foi mais alta e a atividade do Trx foi mais baixa no grupo VD10. Os animais que receberam suplementação com VD apresentaram aumento de hidroperóxido lipídico e diminuição de superóxido dismutase e glutationa peroxidase. A proteína Bcl-2 foi mais baixa no grupo VD10. Observou-se uma diminuição na β-oxidação de ácidos graxos, no ciclo do ácido tricarboxílico, na cadeia transportadora de elétrons, e um aumento na via glicolítica. Conclusão: A suplementação com VD levou à remodelação cardíaca e esse processo pode ser modulado por TXNIP e Trx, e consequentemente por estresse oxidativo.


Abstract Background: Vitamin D (VD) has been shown to play an important role in cardiac function. However, this vitamin exerts a biphasic "dose response" curve in cardiovascular pathophysiology and may cause deleterious effects, even in non-toxic doses. VD exerts its cellular functions by binding to VD receptor. Additionally, it was identified that the thioredoxin-interacting protein (TXNIP) expression is positively regulated by VD. TXNIP modulate different cell signaling pathways that may be important for cardiac remodeling. Objective: To evaluate whether VD supplementation lead to cardiac remodeling and if TXNIP and thioredoxin (Trx) proteins are associated with the process. Methods: A total of 250 Male Wistar rats were allocated into three groups: control (C, n=21), with no VD supplementation; VD3 (n = 22) and VD10 (n=21), supplemented with 3,000 and 10,000 IU of VD/ kg of chow respectively, for two months. The groups were compared by one-way analysis of variance (ANOVA) and Holm-Sidak post hoc analysis, (variables with normal distribution), or by Kruskal-Wallis test and Dunn's test post hoc analysis. The significance level for all tests was 5%. Results: TXNIP protein expression was higher and Trx activity was lower in VD10. The animals supplemented with VD showed increased lipid hydroperoxide and decreased superoxide dismutase and glutathione peroxidase. The protein Bcl-2 was lower in VD10. There was a decrease in fatty acid β-oxidation, tricarboxylic acid cycle and electron transport chain with shift to increase in glycolytic pathway. Conclusion: VD supplementation led to cardiac remodeling and this process may be modulated by TXNIP and Trx proteins and consequently oxidative stress.


Subject(s)
Animals , Male , Rats , Thioredoxins/metabolism , Ventricular Remodeling , Vitamin D , Rats, Wistar , Oxidative Stress , Cell Cycle Proteins , Dietary Supplements
2.
Braz. dent. j ; 32(4): 74-82, July-Aug. 2021. tab, graf
Article in English | LILACS, BBO | ID: biblio-1345513

ABSTRACT

Abstract The Inhibitor of Growth (ING) gene family is a group of tumor suppressor genes that play important roles in cell cycle control, senescence, DNA repair, cell proliferation, and apoptosis. However, inactivation and downregulation of these proteins have been related in some neoplasms. The present study aimed to evaluate the immunohistochemical profiles of ING3 and ING4 proteins in a series of benign epithelial odontogenic lesions. Methods: The sample comprised of 20 odontogenic keratocysts (OKC), 20 ameloblastomas (AM), and 15 adenomatoid odontogenic tumors (AOT) specimens. Nuclear and cytoplasmic immunolabeling of ING3 and ING4 were semi-quantitatively evaluated in epithelial cells of the odontogenic lesions, according to the percentage of immunolabelled cells in each case. Descriptive and statistics analysis were computed, and the p-value was set at 0.05. Results: No statistically significant differences were found in cytoplasmic and nuclear ING3 immunolabeling among the studied lesions. In contrast, AOTs presented higher cytoplasmic and nuclear ING4 labeling compared to AMs (cytoplasmic p-value = 0.01; nuclear p-value < 0.001) and OKCs (nuclear p-value = 0.007). Conclusion: ING3 and ING4 protein downregulation may play an important role in the initiation and progression of more aggressive odontogenic lesions, such as AMs and OKCs.


Resumo Objetivos: A família dos Genes Inibidores de Crescimento (ING) é um grupo de genes supressores tumorais que desempenham papéis importantes no controle do ciclo celular, na senescência, no reparo do DNA, na proliferação celular e na apoptose. No entanto, a inativação e a regulação negativa dessas proteínas têm sido relacionadas em algumas neoplasias. O objetivo do presente estudo foi avaliar o perfil imuno-histoquímico das proteínas ING3 e ING4 em uma série de lesões odontogênicas epiteliais benignas. Métodos: A amostra foi composta por espécimes de 20 ceratocistos odontogênicos (CO), 20 ameloblastomas (AM) e 15 tumores odontogênicos adenomatoides (TOA). A imunoexpressão nuclear e citoplasmática de ING3 e ING4 foram avaliadas semi-quantitativamente nas células epiteliais das lesões odontogênicas, de acordo com a porcentagem de células imunomarcadas em cada caso. As análises descritivas e estatísticas foram computadas, e o valor de p estabelecido foi de 0,05. Resultados: Não foram encontradas diferenças estatisticamente significativas na imunoexpressão citoplasmática e nuclear de ING3 entre as lesões estudadas. Em contrapartida, os TOAs apresentaram maior marcação citoplasmática e nuclear de ING4 em comparação aos AMs (valor de p citoplasmático=0,01; valor de p nuclear <0,001) e COs (valor nuclear de p=0,007). Conclusão: A regulação negativa das proteínas ING3 e ING4 pode desempenhar um papel importante na iniciação e na progressão de lesões odontogênicas mais agressivas, como AMs e COs.


Subject(s)
Humans , Ameloblastoma , Odontogenic Cysts , Odontogenic Tumors , Homeodomain Proteins , Cell Cycle Proteins , Tumor Suppressor Proteins , Cell Proliferation
3.
Article in Chinese | WPRIM | ID: wpr-879534

ABSTRACT

OBJECTIVE@#To explore the genetic basis for 7 patients with Alström syndrome.@*METHODS@#DNA was extracted from peripheral blood samples of the patients and their parents. Whole exome sequencing was carried out for the patients. Suspected variant was verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#Genetic testing revealed 12 variants of the ALMS1 gene among the 7 patients, including 7 nonsense and 5 frameshift variants, which included c.5418delC (p.Tyr1807Thrfs*23), c.10549C>T (p.Gln3517*), c.9145dupC (p.Thr3049Asnfs*12), c.10819C>T (p.Arg3607*), c.5701_5704delGAGA (p.Glu1901Argfs*18), c.9154_9155delCT (p.Cys3053Serfs*9), c.9460delG (p.Val3154*), c.9379C>T (p.Gln3127*), c.12115C>T (p.Gln4039*), c.1468dupA (p.Thr490Asnfs*15), c.10825C>T (p.Arg3609*) and c.3902C>A (p.Ser1301*). Among these, c.9154_ 9155delCT, c.9460delG, c.9379C>T, and c.1468dupA were unreported previously. Based on the standards and guidelines of American College of Medical Genetics and Genomics, the c.9379C>T and c.12115C>T variants of the ALMS1 gene were predicted to be likely pathogenic (PVS1+PM2), whilst the other 10 variants were predicted to be pathogenic (PVS1+ PM2+ PP3+PP4).@*CONCLUSION@#ALMS1 variants probably underlay the Alström syndrome in the 7 patients, and genetic testing can provide a basis for the clinical diagnosis of this syndrome. The discovery of four novel variants has expanded the mutational spectrum of Alström syndrome.


Subject(s)
Alstrom Syndrome/genetics , Cell Cycle Proteins/genetics , Humans , Mutation , Pedigree , Whole Exome Sequencing
4.
Article in Chinese | WPRIM | ID: wpr-879525

ABSTRACT

OBJECTIVE@#To carry out genetic testing for an abortus suspected with Cornelia de Lange syndrome (CdLS).@*METHODS@#History of gestation and the family was taken. Combined with prenatal ultrasonography and the phenotype of the abortus, a diagnosis was made for the proband. Fetal tissue and peripheral blood samples of its parents were collected for the extraction of genomic DNA. Whole exome sequencing was carried out to detect mutations related to the phenotype. Suspected mutations were verified in the parents through Sanger sequencing.@*RESULTS@#Prenatal ultrasound found that the forearms and hands of the fetus were anomalous, in addition with poorly formed vermis cerebellum, slight micrognathia, and increased echo of bilateral renal parenchyma. Examination of the abortus has noted upper limb and facial malformations. Whole exome sequencing revealed that the fetus carried a heterozygous c.2118delG (p.Lys706fs) frameshift mutation of the NIPBL gene. The same mutation was not found in either parent.@*CONCLUSION@#The heterozygous c.2118delG (p.Lys706fs) frameshift mutation of the NIPBL gene probably underlies the CdLS in the fetus. Above finding has provided a basis for the genetic counseling for the family.


Subject(s)
Cell Cycle Proteins/genetics , DNA Mutational Analysis , De Lange Syndrome/pathology , Female , Fetus , Humans , Male , Mutation , Phenotype , Pregnancy , Whole Exome Sequencing
5.
Journal of Experimental Hematology ; (6): 1522-1527, 2021.
Article in Chinese | WPRIM | ID: wpr-922289

ABSTRACT

OBJECTIVE@#To investigate the expression of cell division cycle protein 37 (Cdc37) in multiple myeloma (MM) and its effect on MM cell proliferation.@*METHODS@#The expression of Cdc37 mRNA in CD138@*RESULTS@#Cdc37 was highly expressed in newly diagnosed CD138@*CONCLUSION@#Cdc37 is highly expressed in newly diagnosed MM patients. Inhibition of Cdc37 results in decreased proliferation activity and G


Subject(s)
Animals , Apoptosis , Cell Cycle Proteins , Cell Proliferation , Chaperonins , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Multiple Myeloma
6.
Journal of Experimental Hematology ; (6): 1485-1492, 2021.
Article in Chinese | WPRIM | ID: wpr-922283

ABSTRACT

OBJECTIVE@#To explore the regulatory effect of TRIP13 on the proliferation and apoptosis of B-cell lymphoma cells and its possible molecular mechanism by knocking down/overexpressing TRIP13 on the cell lines Granta-519 and JVM-2.@*METHODS@#Lentiviral transfection technology was used to construct Granta-519 and JVM-2 cells with knocked down or overexpressed TRIP13 and their control cells. The efficiency of transfection was determined by fluorescence microscopy. The efficiency of knockdown and overexpression was evaluated by real-time quantitative PCR and Western blot. The proliferation was detected by CCK-8 assay. The apoptosis was detected by the Annexin V-APC single staining. The cell cycle was detected by the PI staining. The expression levels of P53, MDM4, and BCL-2 were evaluated by Western blot.@*RESULTS@#After TRIP13 was knocked down, the proliferation ability of Granta-519 and JVM-2 cells was significantly reduced, and the apoptosis rate significantly increased. After TRIP13 was overexpressed, the proliferation ability of Granta-519 and JVM-2 cells was significantly enhanced, and the apoptosis was significantly reduced. After TRIP13 was knocked down, Granta-519 cells had obvious G@*CONCLUSION@#TRIP13 promotes the proliferation of B-cell lymphoma cells, inhibits their apoptosis, and affects their proliferation and apoptosis by participating in the regulation of the cell cycle. TRIP13 promotes the expression of BCL-2 proteins and inhibits the expression of MDM4 protein in B-cell lymphoma cells.


Subject(s)
ATPases Associated with Diverse Cellular Activities/metabolism , Apoptosis , Cell Cycle Proteins , Cell Proliferation , Humans , Lymphoma, B-Cell , Proto-Oncogene Proteins
7.
Journal of Experimental Hematology ; (6): 1424-1428, 2021.
Article in Chinese | WPRIM | ID: wpr-922275

ABSTRACT

OBJECTIVE@#To investigate the relationship between hypoxia inducible factor 1 (HIF1α) and Wilms' tumor 1associating protein (WTAP) expression level in t(8;21) acute myeloid leukemia cells.@*METHODS@#The t(8;21) acute myeloid leukemia cell lines, including SKNO-1 and Kasumi-1 were treated by Echinomycin for 24 h, RT-qPCR and Western blot were used to detect the expression levels of WTAP mRNA and the protein. The CoCl @*RESULTS@#The expression level of WTAP mRNA and the protein in the echinomycin treated group was significantly lower than those in the control group (P<0.01). The expression level of WTAP protein in the CoCl@*CONCLUSION@#The inhibition of HIF1-α could down-regulates the expression of WTAP, while the up-regulation of HIF1α could up-regulates the expression of WTAP, which shows that there is a positive correlation of HIF1α and WTAP expression. This result suggesting that HIF1α may be involves in the expression regulation of WTAP gene.


Subject(s)
Cell Cycle Proteins , Humans , Hypoxia-Inducible Factor 1, alpha Subunit , Leukemia, Myeloid, Acute/genetics , Nuclear Proteins , RNA Splicing Factors , RNA, Messenger
8.
Article in Chinese | WPRIM | ID: wpr-922013

ABSTRACT

OBJECTIVE@#To explore the genetic etiology of a neonate with suggestive features of Cornelia de Lange Syndrome (CdLS).@*METHODS@#Chromosome karyotyping, copy number variation sequencing (CNV-seq) and whole exome sequencing (WES) were carried out for the child. Meanwhile, peripheral venous blood samples were taken from his parents for verifying the suspected pathogenic variants detected in the child.@*RESULTS@#The child has exhibited developmental delay, microcephaly, ptosis, micrognathia, and low ear setting, and was suspected as CdLS. No abnormality was found by karyotyping and CNV-seq analysis. WES has detected 5 heterogeneous variants and 1 hemizygous variant on the X chromosome. Combining the genetic pattern and result of family verification, a hemizygous C.3500T>C (p.ile1167thr) of the SMC1A gene was predicted to underlay the clinical manifestations of the patient. This variant was not recorded in the dbSNP and gnomAD database. PolyPhen2, Provean, SIFT all predicted the variant to be harmful, and PhastCons conservative prediction is was a conservative mutation. ACMG variant classification standard evidence supports are PM2, PP2, and PP3.@*CONCLUSION@#The novel c.3500T>C (p.Ile1167Thr) missense mutation of the SMC1A gene probably underlay the genetic etiology of CdLS in this child. Above results has enriched the mutation spectrum of CdLS type II, and facilitated clinical counseling for this family.


Subject(s)
Cell Cycle Proteins/genetics , Child , DNA Copy Number Variations , De Lange Syndrome/genetics , Humans , Infant, Newborn , Mutation , Phenotype , Whole Exome Sequencing
9.
Article in Chinese | WPRIM | ID: wpr-888696

ABSTRACT

OBJECTIVE@#To explore the role of small nuclear noncoding RNA 7SK in embryonic stem cell (ESCs) proliferation and the value of 7SK as a target for early diagnosis and treatment for primordial dwarfism (PD).@*METHODS@#ESC line R1 was transfected with the CRISPR/Cas9 system, and sequencing of the PCR product and glycerol gradient analysis were performed to identify novel 7SK deletion mutations. A lentivirus system was used to knock down cyclin-dependent kinase 9 (CDK9) in clones with 7SK deletion mutations, and the effect of CDK9 knockdown on the protein level of cell division cycle 6 (CDC6) was analyzed with Western blotting.@*RESULTS@#We identified a novel deletion mutation of 7SK at 128-179 nt in the ESCs, which resulted in deficiency of cell proliferation. 7SK truncation at 128-179 nt significantly reduced the protein expressions of La-related protein 7 (LARP7) and CDC6.@*CONCLUSIONS@#7SK truncation at 128-179 nt can significantly impair proliferation of ESCs by downregulating CDC6. 7SK is a key regulator of proliferation and mediates the growth of ESCs through a mechanism dependent on CDK9 activity, suggesting the value of 7SK truncation at 128-179 nt as a potential target for early diagnosis and treatment of PD.


Subject(s)
Cell Cycle Proteins , Cell Proliferation , Embryonic Stem Cells/metabolism , HeLa Cells , Humans , Nuclear Proteins , Positive Transcriptional Elongation Factor B/metabolism , RNA, Long Noncoding/genetics , RNA-Binding Proteins , Ribonucleoproteins , Transcription Factors
10.
Journal of Experimental Hematology ; (6): 1365-1368, 2021.
Article in Chinese | WPRIM | ID: wpr-888568

ABSTRACT

Bromodomain-containing protein 4 (BRD4) is one of the most important members in the bromodomain and extra terminal domain(BET) family, it plays an important role in cellular physiology in human body, such as cell cycles, cell proliferation, and immune response. Recent studies have shown that BRD4 is associated with occurrence and development of acute myeloblastic leukemia, multiple myeloma and lymphoma. The mechanisms of BRD4 in hematologic malignancies including the regulation of c-Myc expression, and participation of the composition of super-enhancer, etc. At present, many kinds of inhibitors have been developed to target inhibit BRD4 for therapy in hematologic malignancies, and some of BRD4 inhibitors have entered phase Ⅱ clinical trials, which suggested that BRD4 inhibitors are expected to become new therapeutic agents for hematologic malignancies. In this review, the research advance of BRD4 and BRD4 inhibitors in hematologic malignancies was summarized briefly.


Subject(s)
Cell Cycle Proteins , Cell Proliferation , Hematologic Neoplasms/drug therapy , Humans , Nuclear Proteins , Protein Domains , Transcription Factors
11.
Journal of Experimental Hematology ; (6): 1129-1135, 2021.
Article in Chinese | WPRIM | ID: wpr-888528

ABSTRACT

OBJECTIVE@#To investigate the effect of CDK1 interference regulation of PLK1, Aurora B and TRF1 on the proliferation of leukemia cells.@*METHODS@#The human myelogenous leukemia cell line HL-60 was selected as the research object, and the effect of TRF1 expression and its changes on cell proliferation and cycle was investigated by regulating intracellular CDK1 expression. The objects were divided into 5 groups, including control group, shRNA-NC group, CDK1-shRNA group, pcDNA group and pcDNA-CDK1 group. RT-PCR was used to detect the CDK1 expression of cells in each group; colony formation was used to detect the proliferation of the cells. Western blot was used to detect the expression of CDK1, PLK1, Aurora B, TRF1, and cyclin p53, p27, cyclinA.@*RESULTS@#The phosphorylation level of PLK1, Aurora B and the expression of TRF1 in the CDK1-shRNA group were significantly down-regulated as compared with those in the control group (P<0.05). Compared with the control group, the cells in CDK1-shRNA group showed lower clone formation rate, the increasing of cycle-associated proteins p53 and p27 and the decreasing of cyclinA expression (P<0.05). It was shown that interfered CDK1 expression could inhibit the proliferation of HL-60 cells and prolong the time that they enter mitosis, thereby extending the cell cycle. Compared with the control group, the overexpressed CDK1 in the pcDNA-CDK1 group made the phosphorylation level of PLK1, Aurora B, and TRF1 expression increase significantly (P<0.05), also the colony formation rate (P<0.05). The cycle-related proteins p53 and p27 was down-regulated, while cyclinA expression was up-regulate significantly (P<0.05). The results indicted that overexpressed CDK1 could stimulate adverse reactions, thereby promoting the proliferation of HL-60 cells and shortening the cell cycle.@*CONCLUSION@#Knocking out CDK1 can inhibit the phosphorylation of PLK1 and Aurora B and negatively regulate TRF1, thereby inhibiting the proliferation of leukemia cells.


Subject(s)
CDC2 Protein Kinase , Cell Cycle Proteins/genetics , Cell Proliferation , Humans , Leukemia , Mitosis , Phosphorylation , Proto-Oncogene Proteins/genetics
12.
Article in Chinese | WPRIM | ID: wpr-887881

ABSTRACT

FAM60A,a cell cycle protein,is a subunit of the SIN3 transcription regulator family member A/histone deacetylase(SIN3-HDAC)complex and plays an important role in cell cycle regulation,cell morphology change,cell proliferation,differentiation and migration,early embryogenesis and so on.Studies in recent years have shown that FAM60A plays a role in the occurrence and development of tumors including human osteosarcoma,esophageal cancer,gastric cancer,lung cancer and liver cancer,providing a new research direction for tumor diagnosis and treatment.Based on the research results in recent years at home and abroad,this paper discussed the effects of FAM60A on cellular functions.


Subject(s)
Cell Cycle Proteins , Cell Differentiation , Cell Proliferation , DNA-Binding Proteins , Humans , Sin3 Histone Deacetylase and Corepressor Complex
13.
Article in Chinese | WPRIM | ID: wpr-880129

ABSTRACT

OBJECTIVE@#To investigate the expression of WTAP gene in acute myeloid leukemia (AML) and its clinical significance.@*METHODS@#74 acute myeloid leukemia patients with non-M3 type and 19 normal donors were selected, and real-time quantitative polymerase chain reaction was used to detect the mRNA expression level of WTAP gene in their bone marrow cells. The relationship between the mRNA expression level of WTAP gene and the clinical characteristics was analyzed.@*RESULTS@#The relative mRNA expression of WTAP gene in the non-M3 AML group was significantly higher than that in the healthy control group, and the difference showed statistically significant (P0.05) according to the classification of FAB. The mRNA expression level of WTAP gene in FLT3-ITD mutated AML patients was higher than that in FLT3-ITD unmutated group (P=0.016), and the mRNA expression level of WTAP gene in AML patients with CEBPα mutation was lower than that in CEBPα unmutated group (P=0.016). The expression level of WTAP mRNA was positively correlated with WT1 expression (r=0.6866, P0.05). The expression level of WTAP mRNA showed no obvious effect on the complete remission of patients after first treatment. The different expression level of WTAP gene at initial diagnosis showed also no effect on the overall survival time of patients.@*CONCLUSION@#The expression level of WTAP gene is increasing in new diagnosed non-M3 acute myeloid leukemia. There is a positive correlation between the expression level of WTAP gene and the expression level of WT1 fusion gene. WTAP mRNA always shows higher expression in patients with FLT3-ITD mutation than that in patients without FLT3-ITD mutation, and shows lower expression in patients with CEBPα mutation than that in unmutated group.


Subject(s)
Cell Cycle Proteins , Humans , Karyotype , Leukemia, Myeloid, Acute/genetics , Mutation , Prognosis , RNA Splicing Factors , Remission Induction , fms-Like Tyrosine Kinase 3/genetics
14.
Braz. j. med. biol. res ; 54(7): e10612, 2021. tab, graf
Article in English | LILACS | ID: biblio-1249314

ABSTRACT

Genomic studies have provided insights into molecular subgroups and oncogenic drivers of pediatric brain tumors (PBT) that may lead to novel therapeutic strategies. Participants of the cohort Pediatric Brain Tumor Atlas: CBTTC (CBTTC cohort), were randomly divided into training and validation cohorts. In the training cohort, Kaplan-Meier analysis and univariate Cox regression model were applied to preliminary screening of prognostic genes. The LASSO Cox regression model was implemented to build a multi-gene signature, which was then validated in the validation and CBTTC cohorts through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. Also, gene set enrichment analysis (GSEA) and immune infiltrating analyses were conducted to understand function annotation and the role of the signature in the tumor microenvironment. An eight-gene signature was built, which was examined by Kaplan-Meier analysis, revealing that a significant overall survival difference was seen, either in the training or validation cohorts. The eight-gene signature was further proven to be independent of other clinic-pathologic parameters via the Cox regression analyses. Moreover, ROC analysis demonstrated that this signature owned a better predictive power of PBT prognosis. Furthermore, GSEA and immune infiltrating analyses showed that the signature had close interactions with immune-related pathways and was closely related to CD8 T cells and monocytes in the tumor environment. Identifying the eight-gene signature (CBX7, JADE2, IGF2BP3, OR2W6P, PRAME, TICRR, KIF4A, and PIMREG) could accurately identify patients' prognosis and the signature had close interactions with the immunodominant tumor environment, which may provide insight into personalized prognosis prediction and new therapies for PBT patients.


Subject(s)
Humans , Child , Brain Neoplasms/genetics , Gene Expression Profiling , Prognosis , Gene Expression Regulation, Neoplastic , Cell Cycle Proteins , Kaplan-Meier Estimate , Tumor Microenvironment , Polycomb Repressive Complex 1
15.
Acta Physiologica Sinica ; (6): 426-432, 2020.
Article in Chinese | WPRIM | ID: wpr-827045

ABSTRACT

The purpose of the present study was to investigate the effects of forkhead box O4 (FOXO4) on the senescence of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The hUC-MSCs were induced to senescence by natural passage, and FOXO4 expression was inhibited by lentiviral shRNA transfection. The hallmark of cell senescence was analyzed by β-galactosidase staining, and the cell viability was assayed by CCK-8 method. Flow cytometry was used to investigate the apoptosis of hUC-MSCs. The expression levels of Bcl-2, Bax, FOXO4, interleukin 6 (IL-6) and cleaved Caspase-3 were detected by qPCR and Western blot. Immunofluorescence staining was used to detect FOXO4 expression. The amount of IL-6 secreted by hUC-MSCs was detected by ELISA. The results showed that, compared with the passage 1, senescent hUC-MSCs showed up-regulated expression levels of Bax and FOXO4, down-regulated expression levels of Bcl-2 and cleaved Caspase-3, and increased IL-6 mRNA expression and secretion. FOXO4 inhibition in senescent hUC-MSCs promoted cell apoptosis, reduced cell viability, and inhibited the mRNA expression and secretion of IL-6. These results suggest that FOXO4 maintains viability and function of senescent hUC-MSCs by repressing their apoptosis response, thus accelerating senescence of the whole cell colony.


Subject(s)
Apoptosis , Cell Cycle Proteins , Cell Survival , Cellular Senescence , Forkhead Transcription Factors , Humans , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells , Transcription Factors , Umbilical Cord
16.
Article in Chinese | WPRIM | ID: wpr-826558

ABSTRACT

OBJECTIVE@#To detect pathogenic variant in a neonate suspected for Cornelia de Lange syndrome (CdLS).@*METHODS@#Potential mutations of CdLS-related genes (NIPBL, SMC1A, SMC3, RAD21 and HDAC8) were detected by high-throughput target region capture and next-generation sequencing. Suspected variants was verified by Sanger sequencing.@*RESULTS@#The child was found to harbor a heterozygous splice site variant, c.6109-1G>A, of the NIPBL gene. Sanger sequencing suggested that neither parent has carried the same variant, suggesting that it was de novo. The variant was unreported by HGMD and ExAC database, and was predicted to alter an acceptor splicing site. No pathogenic variants of SMC1A, SMC3, RAD21 and HDAC8 genes were detected.@*CONCLUSION@#The heterozygous c.6109-1G>A splicing variant of the NIPBL gene may underlie the disease in this child. Above finding has expanded the variant spectrum of the NIPBL gene.


Subject(s)
Cell Cycle Proteins , Genetics , De Lange Syndrome , Genetics , Genetic Testing , Genetic Variation , High-Throughput Nucleotide Sequencing , Humans , Infant, Newborn , Mutation , Phenotype
17.
Article in Chinese | WPRIM | ID: wpr-826539

ABSTRACT

OBJECTIVE@#To detect pathogenic variant in a juvenile with severe type Cornelia de Lange syndrome (CdLS).@*METHODS@#A 12-year-old female presented with comprehensive developmental retardation and deformity of lower limbs. Genomic DNA was extracted from peripheral blood sample of the patient. Whole exome sequencing was performed to identify pathogenic variants. Putative variant was verified by Sanger sequencing. The impact of variants was predicted and validated by bioinformatic analysis.@*RESULTS@#A de novo missense variant, c.1507A>G (p. Lys503Glu), was found in the NIPBL gene of the proband. The variant was unreported previously and predicted to be pathogenic by PolyPhen-2, MutationTaster and SIFT. Using HomoloGene system, the 503 loci in the NIPBL protein are highly conserved. The change of amino acid (Glu), locating in 503 locus, was found to cause the Neuromodulin_N superfamily domain destroyed, resulting in severe damage to the function of NIPBL protein.@*CONCLUSION@#The de novo missense variant c.1507A>G (p. Lys503Glu) of the NIPBL gene probably underlies the disease in this patient.


Subject(s)
Cell Cycle Proteins , Genetics , Child , De Lange Syndrome , Genetics , Developmental Disabilities , Genetics , Female , Humans , Mutation, Missense , Phenotype
18.
Article in Chinese | WPRIM | ID: wpr-826537

ABSTRACT

OBJECTIVE@#To explore the clinical features and genetic variant in a child featuring megalencephalic leukoencephalopathy with subcortical cyst (MLC) type 2B.@*METHODS@#Clinical and imaging data of the child was collected. Potential variant of hepatocyte adhesion molecule (HEPACAM) gene was detected by Sanger sequencing. The growth and development of her mother and uncle was also reviewed.@*RESULTS@#The patient, a 1-year-and-7-month female, presented with convulsion, mental retardation and abnormally increased head circumference. Cranial MRI revealed extensive long T1 long T2 signals in the white matter of bilateral cerebral hemisphere, right anterior sac cyst, cerebral gyrus widening, and shallow sulcus. Sanger sequencing identified a c.437C>T missense variant in exon 3 of the HEPACAM gene. The same variant was detected in her mother but not father. Her mother and maternal uncle both had a history of increased head circumference when they were young. In their adulthood, the head circumference was in the normal range but still greater than the average.@*CONCLUSION@#The heterozygous variant of the HEPACAM gene probably underlies the MLC2B in this child. The variant has derived from her asymptomatic mother, which suggested incomplete penetrance of the MLC2B.


Subject(s)
Adult , Cell Cycle Proteins , Genetics , Cerebrum , Diagnostic Imaging , Cysts , Diagnostic Imaging , Genetics , Female , Genetic Variation , Hereditary Central Nervous System Demyelinating Diseases , Diagnostic Imaging , Genetics , Humans , Infant
19.
Article in Chinese | WPRIM | ID: wpr-826366

ABSTRACT

To analyze the expression of splicing factors in gastric cancer using bioinformatics methods and investigate the effect of aberrantly expressed serine/arginine-rich splicing factor(SRSF10)on the phenotype of gastric cancer cells. The RNA-seq data of gastric cancer and paracancerous tissues were downloaded from The Cancer Genome Atlas(TCGA)cancer database,and bioinformatics analysis was performed to obtain the splicing factors differentially expressed in gastric cancer.The splicing factor SRSF10 was selected to investigate its effect on the development of gastric cancer.RNA interference technology was used to construct SRSF10 knockdown gastric cancer cells.MTS,Transwell,and cell scratches were used to study the effect of SRSF10 knockdown on gastric cancer cell phenotype. A total of 48 splicing factors were identified in gastric cancer by a series of bioinformatics techniques,of which 35 were up-regulated and 13 were down-regulated.The splicing factor SRSF10,which was up-regulated,was selected for further study.It was found that the gastric cancer cells after SRSF10 knockdown proliferated more slowly and had lower migration ability than normal gastric cancer cells. Multiple splicing factors are found in gastric cancer and may play an important role in the development of gastric cancer.The splicing factor SRSF10 may contribute to the pathogenesis of gastric cancer.


Subject(s)
Alternative Splicing , Cell Cycle Proteins , Computational Biology , Gene Expression Regulation, Neoplastic , Humans , RNA Splicing Factors , Repressor Proteins , Serine-Arginine Splicing Factors , Stomach Neoplasms
20.
Chinese Journal of Biotechnology ; (12): 2298-2312, 2020.
Article in Chinese | WPRIM | ID: wpr-878487

ABSTRACT

Polo-like kinase 1 (Plk1) is widely regarded as one of the most promising targets for cancer therapy due to its essential role in cell division and tumor cell survival. At present, most Plk1 inhibitors have been developed based on kinase domain, some of which are in clinical trial. However, inhibitors targeting kinase domain face off-target effect and drug resistance owing to the conserved nature and the frequent mutations in the ATP-binding pocket. In addition to a highly conserved kinase domain, Plk1 also contains a unique Polo-Box domain (PBD), which is essential for Plk1's subcellular localization and mitotic functions. Inhibitors targeting Plk1 PBD show stronger selectivity and less drug resistance for cancer therapy. Therefore, Plk1 PBD is an attractive target for the development of anti-cancer agents. In this review, we will summarize the up-to date drug discovery for targeting Plk1 PBD, including the molecular structure and cellular functions of Plk1 PBD. Small-molecule inhibitors targeting Plk1 PBD not only provide an opportunity to specifically inhibit Plk1 activity for cancer treatment, but also unveil novel biological basis regarding the molecular recognition of Plk1 and its substrates.


Subject(s)
Cell Cycle Proteins/genetics , Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Protein-Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics
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