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1.
J Mol Graph Model ; 109: 108030, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34509094

RESUMO

Cell division cycle 25B (CDC25B) was responsible for regulating the various stages of cell division in the cell cycle. R492L was one of the common types of CDC25B mutants. Researches showed that compared to CDC25BWT, CDC25BR492L mutant had a ∼100-fold reduction in the rate constant for forming phosphatase intermediate (k2). However, the molecular basis of how the CDC25BR492L mutant influenced the process of binding between CDC25B and CDK2/CyclinA was not yet known. Therefore, the optimizations of three-dimensional structure of the CDC25BWT-CDK2/CyclinA system and the CDC25BR492L-CDK2/CyclinA system were constructed by ZDOCK and RDOCK, and five methods were employed to verify the reasonability of the docking structure. Then the molecular dynamics simulations on the two systems were performed to explore the reason why CDC25BR492L mutant caused the weak interactions between CDC25BR492L and CDK2/CyclinA, respectively. The remote docking site (Arg488-Tyr497) and the second active site (Lys538-Arg544) of CDC25B were observed to have high fluctuations in the CDC25BR492L-CDK2/CyclinA system with post-analysis, where the high fluctuation of these two regions resulted in weak interactions between CD25B and CDK2. In addition, Asp38-Glu42 and Asp206-Asp210 of CDK2 showed the slightly descending fluctuation, and CDK2 revealed an enhanced the self-interaction, which made CDK2 keep a relatively stable state in the CDC25BR492L-CDK2/CyclinA system. Finally, Leu492 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25BR492L and CDK2 in the CDC25BR492L-CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately offered a helpful understanding of the weak interactions between CDC25BR492L and CDK2.

2.
Eur Radiol ; 31(9): 6522-6530, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33651201

RESUMO

OBJECTIVE: To summarize the occurrence of operative failures after microwave ablation (MWA) in patients with primary hyperparathyroidism (pHPT), analyze the possible reasons, and explore strategies for preventing and managing these situations. METHODS: This retrospective study reviewed 91 pHPT patients who underwent MWA from April 2015 to November 2019. A cure was defined as the reestablishment of normal calcium homeostasis lasting a minimum of 6 months. An operative failure was defined as a failure to normalize serum intact parathyroid hormone (iPTH) and/or calcium levels at 6 months or longer. Patients who encountered operative failures were compared with patients who were successfully cured. RESULTS: Eighty-eight pHPT patients, consisting of 29 men and 59 women, were finally enrolled. The median follow-up duration was 15.9 months (IQR, 6.1-31.5 months). Seventy-eight patients (78/88, 88.6%) were cured. Ten (10/88, 11.4%) patients experienced operative failure, including 9 persistent pHPT (10.2%) and 1 (1.1%) recurrent pHPT. Small parathyroid nodules (maximum diameter < 0.6 cm) and incomplete ablation were the two key factors leading to operative failure. Of the 9 patients with a maximum nodule diameter less than 0.6 cm, 77.8% (7/9) of them encountered operative failure. CONCLUSION: Operative failure occurred in 11.4% of the pHPT patients who underwent MWA. The possibility of operative failure was increased when the maximum diameter of parathyroid nodule was less than 0.6 cm. Complete ablation could help avoid operative failure. KEY POINTS: • Failed to ablate the target lesion and incomplete ablation were the key factors attributed to operative failures. • When the maximum diameter of the parathyroid nodules is less than 0.6 cm, the possibility of operative failure was higher.


Assuntos
Hiperparatireoidismo Primário , Ablação por Radiofrequência , Feminino , Humanos , Hiperparatireoidismo Primário/cirurgia , Masculino , Micro-Ondas , Hormônio Paratireóideo , Paratireoidectomia , Estudos Retrospectivos
3.
Mol Divers ; 25(3): 1873-1887, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33392964

RESUMO

The E69K mutation is one of the most frequent protein tyrosine phosphatase-2 (SHP2) mutations in leukemia, and it can cause the increase in the protein activity. Recent studies have shown that the E69K mutation was fairly sensitive to the allosteric inhibitor of SHP2 (SHP099). However, the molecular mechanism of the allosteric drug SHP099 inhibiting SHP2E69K remains unclear. Thus, the molecular dynamic simulations and the post-dynamics analyses (RMSF, PCA, DCCM, RIN and the binding free energies) for SHP2WT, SHP2WT-SHP099, SHP2E69K and SHP2E69K-SHP099 were carried out, respectively. Owing to the strong binding affinity of SHP099 to residues Thr219 and Arg220, the flexibility of linker region (residues Val209-Arg231) was reduced. Moreover, the presence of SHP099 kept the autoinhibition state of the SHP2 protein through enhancing the interactions between the linker region and Q loop in PTP domain, such as Thr219/Val490, Thr219/Asn491, Arg220/Ile488 and Leu254/Asn491. In addition, it was found that the residues (Thr219, Arg220, Leu254 and Asn491) might be the key residues responsible for the conformational changes of protein. Overall, this study may provide an important basis for understanding how the SHP099 effectively inhibited the SHP2E69K activity at the molecular level.

4.
PLoS One ; 10(6): e0129474, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26058041

RESUMO

Cancer is a serious disease responsible for many deaths every year in both developed and developing countries. One reason is that the mechanisms underlying most types of cancer are still mysterious, creating a great block for the design of effective treatments. In this study, we attempted to clarify the mechanism underlying esophageal cancer by searching for novel genes and chemicals. To this end, we constructed a hybrid network containing both proteins and chemicals, and generalized an existing computational method previously used to identify disease genes to identify new candidate genes and chemicals simultaneously. Based on jackknife test, our generalized method outperforms or at least performs at the same level as those obtained by a widely used method--the Random Walk with Restart (RWR). The analysis results of the final obtained genes and chemicals demonstrated that they highly shared gene ontology (GO) terms and KEGG pathways with direct and indirect associations with esophageal cancer. In addition, we also discussed the likelihood of selected candidate genes and chemicals being novel genes and chemicals related to esophageal cancer.


Assuntos
Neoplasias Esofágicas/genética , Proteínas/genética , Algoritmos , Biologia Computacional/métodos , Bases de Dados Genéticas , Ontologia Genética , Humanos
5.
Biomed Res Int ; 2015: 964795, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25874234

RESUMO

Thyroid cancer is a typical endocrine malignancy. In the past three decades, the continued growth of its incidence has made it urgent to design effective treatments to treat this disease. To this end, it is necessary to uncover the mechanism underlying this disease. Identification of thyroid cancer-related genes and chemicals is helpful to understand the mechanism of thyroid cancer. In this study, we generalized some previous methods to discover both disease genes and chemicals. The method was based on shortest path algorithm and applied to discover novel thyroid cancer-related genes and chemicals. The analysis of the final obtained genes and chemicals suggests that some of them are crucial to the formation and development of thyroid cancer. It is indicated that the proposed method is effective for the discovery of novel disease genes and chemicals.


Assuntos
Bases de Dados Genéticas , Ligantes , Neoplasias da Glândula Tireoide/genética , Algoritmos , Descoberta de Drogas , Humanos , Mapas de Interação de Proteínas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia
6.
Biomed Res Int ; 2014: 891945, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25050377

RESUMO

Glioma, as the most common and lethal intracranial tumor, is a serious disease that causes many deaths every year. Good comprehension of the mechanism underlying this disease is very helpful to design effective treatments. However, up to now, the knowledge of this disease is still limited. It is an important step to understand the mechanism underlying this disease by uncovering its related genes. In this study, a graphic method was proposed to identify novel glioma related genes based on known glioma related genes. A weighted graph was constructed according to the protein-protein interaction information retrieved from STRING and the well-known shortest path algorithm was employed to discover novel genes. The following analysis suggests that some of them are related to the biological process of glioma, proving that our method was effective in identifying novel glioma related genes. We hope that the proposed method would be applied to study other diseases and provide useful information to medical workers, thereby designing effective treatments of different diseases.


Assuntos
Algoritmos , Neoplasias Encefálicas/genética , Genes Neoplásicos , Estudos de Associação Genética/métodos , Glioma/genética , Ontologia Genética , Humanos , Transdução de Sinais/genética
7.
Biomed Res Int ; 2014: 371397, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24729971

RESUMO

Gastric cancer, as one of the leading causes of cancer related deaths worldwide, causes about 800,000 deaths per year. Up to now, the mechanism underlying this disease is still not totally uncovered. Identification of related genes of this disease is an important step which can help to understand the mechanism underlying this disease, thereby designing effective treatments. In this study, some novel gastric cancer related genes were discovered based on the knowledge of known gastric cancer related ones. These genes were searched by applying the shortest path algorithm in protein-protein interaction network. The analysis results suggest that some of them are indeed involved in the biological process of gastric cancer, which indicates that they are the actual gastric cancer related genes with high probability. It is hopeful that the findings in this study may help promote the study of this disease and the methods can provide new insights to study various diseases.


Assuntos
Algoritmos , Bases de Dados de Proteínas , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Mapeamento de Interação de Proteínas/métodos , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Simulação por Computador , Mineração de Dados/métodos , Humanos
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