ABSTRACT
Objective: To analyze the phenotype and genotype of two pedigrees with inherited fibrinogen (Fg) deficiency caused by two heterozygous mutations. We also preliminarily probed the molecular pathogenesis. Methods: The prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and plasma fibrinogen activity (Fg∶C) of all family members (nine people across three generations and three people across two generations) were measured by the clotting method. Fibrinogen antigen (Fg:Ag) was measured by immunoturbidimetry. Direct DNA sequencing was performed to analyze all exons, flanking sequences, and mutated sites of FGA, FGB, and FGG for all members. Thrombin-catalyzed fibrinogen polymerization was performed. ClustalX 2.1 software was used to analyze the conservatism of the mutated sites. MutationTaster, PolyPhen-2, PROVEAN, SIFT, and LRT online bioinformatics software were applied to predict pathogenicity. Swiss PDB Viewer 4.0.1 was used to analyze the changes in protein spatial structure and molecular forces before and after mutation. Results: The Fg∶C of two probands decreased (1.28 g/L and 0.98 g/L, respectively). The Fg∶Ag of proband 1 was in the normal range of 2.20 g/L, while it was decreased to 1.01 g/L in proband 2. Through genetic analysis, we identified a heterozygous missense mutation (c.293C>A; p.BβAla98Asp) in exon 2 of proband 1 and a heterozygous nonsense mutation (c.1418C>G; p.BβSer473*) in exon 8 of proband 2. The conservatism analysis revealed that Ala98 and Ser473 presented different conservative states among homologous species. Online bioinformatics software predicted that p.BβAla98Asp and p.BβSer473* were pathogenic. Protein models demonstrated that the p.BβAla98Asp mutation influenced hydrogen bonds between amino acids, and the p.BβSer473* mutation resulted in protein truncation. Conclusion: The dysfibrinogenemia of proband 1 and the hypofibrinogenemia of proband 2 appeared to be related to the p.BβAla98Asp heterozygous missense mutation and the p.BβSer473* heterozygous nonsense mutation, respectively. This is the first ever report of these mutations.
Subject(s)
Humans , Afibrinogenemia/genetics , Codon, Nonsense , Pedigree , Phenotype , Fibrinogen/genetics , GenotypeABSTRACT
Objective To investigate the relationship between albumin/globulin ratio (AGR) and postoperative survival among patients with esophageal squamous cell carcinoma(ESCC) undergoing radical oesophagectomy, to establish an effective prognostic nomogram for ESCC and to provide a reference for prognosis prediction of ESCC. Methods From February 2014 to September 2017, 390 ESCC patients who underwent surgery were retrospectively enrolled from the tumor hospital in Fujian Province. The receiver operating characteristic curves(ROC) were applied to establish optimal cutoff points. Chi-square test was used to estimate the relationship between the AGR and the clinical features. Cox proportional hazards model was used to estimate the HR and 95% CI for the associations between AGR and Prognosis of ESCC patients. A nomogram model was established to predict the outcome of ESCC patients. Results The ROC demonstrated the best cutoff value for AGR was 1.16. A total of 356 patients were recruited in the final analysis, who were divided into the high AGR group (≥1.16) and the low AGR group (<1.16) by the best cutoff value. Both 1-year and 3-year survival rates in the high AGR group were higher than those detected in the low AGR group(all P<0.05). Multivariate analysis showed that the T stage, N stage, and AGR were independent prognostic factors of overall survival(all P<0.05). The HR of T stage was 1.87 (T3-T4 vs T1-T2, 95% CI: 1.04-3.35); The HR of N stage was1.89 (N+ vs N0, 95% CI: 1.13-3.17); The HR of AGR was 0.57(the high AGR group vs the low AGR group, 95%CI: 0.36-0.90). The concordance index(C-index) of the nomogram to predict overall survival was 0.68 (95% CI: 0.62-0.73，P<0. 001)．Conclusions The AGR was an independent prognosis factor for operated ESCC patients. The prognosis of ESCC in the high AGR group was better than that in the low AGR group and the prognostic nomogram provides individualized risk estimate of survival in ESCC patients after surgery.
ABSTRACT
Objective To explore the effect of the combination of carnitine palmityl transferase 1( CPT1) inhibitor etomoxir and chemotherapy drug cisplatin on lung cancer cell line A549 proliferation and migration of lung cancer. Methods CCK8 was applied to investigate the effect of the combination of etomoxir and cisplatin on A549 survival. Transwell test was used to detect migration of lung cancer cell line A549 treated with the combination of etomoxir and cisplatin. Apoptosis of A549 was detected by annexin V/PI. A549 transplanted mice were used to test therapeu-tic effect of etomoxir combined with cisplatin. Results Tumor cells proliferation and migration were inhibited by the combination of etomoxir and cisplatin. Apoptosis of tumor cells was enhanced by the combination of etomoxir. After the treatment of the combination of etomoxir and cisplatin, tumor growth of mouse was inhibited. Conclusions The combination of etomoxir and cisplatin can decrease tumor cells survival and induce tumor cells apoptosis, and then inhibit tumor growth in mouse lung cancer model.