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1.
Anticancer Res ; 39(11): 6273-6282, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31704857

RESUMO

BACKGROUND/AIM: We have yet to understand why JAK2-positive myeloproliferative neoplasms (MPN) patients manifest different phenotypes despite harboring JAK2 mutations and what drives secondary transformations. PATIENTS AND METHODS: Using targeted sequencing, we analyzed mutational status of 17 polycythemia vera (PV), 16 essential thrombocythemia (ET), 8 primary myelofibrosis (PMF) patients who tested positive for JAK by polymerase chain reaction. RESULTS: The somatic mutations in JAK2 influence the clinical behavior of the disease. We found that ASXL1 or EZH2 mutation acquisition after JAK2 leads to PV, while ASXL1 mutation acquisition before JAK2 leads to ET or PMF. Mutations in TP53, ASXL1, and splicing genes are associated with the prognosis of MPN. PMF was more frequently associated with splicing mutations, while PV was more closely related to mutations in chromatin modifiers. The presence of these mutations influenced hemogram at MPN diagnosis. CONCLUSION: Each subtype of MPN harbors distinct patterns of somatic mutations and acquisition order, while mutations in TP53, ASXL1, and splicing genes may be associated with the prognosis of MPN.


Assuntos
Proteína Potenciadora do Homólogo 2 de Zeste/genética , Genes p53 , Janus Quinase 2/genética , Mutação , Policitemia Vera/genética , Mielofibrose Primária/genética , Proteínas Repressoras/genética , Trombocitemia Essencial/genética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Processamento de RNA
3.
Pathologe ; 40(6): 592-599, 2019 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-31511974

RESUMO

The Li-Fraumeni syndrome (LFS, online Mendelian inheritance in man, OMIM #151623) is considered to be one of the currently known most aggressive cancer predisposition syndromes. The heterogeneous spectrum of tumors is dominated by bone and soft tissue sarcomas, various brain tumors, premenopausal breast cancer and adrenocortical carcinoma (ACC). Even in childhood the cancer risk is very strongly increased and it is not uncommon for people with LFS to develop synchronous and metachronous tumors. Typical histopathological findings and molecular genetic signatures can help towards the diagnosis. Inheritance is autosomal dominant and the penetrance appears to be more variable than previously thought. The prevalence of LFS is approximately 1:5000 with a high interregional variance. The LFS is caused by germline mutations in the TP53 gene coding for the protein p53, an essential cellular transcription factor that initiates antitumor responses to cellular stress, such as DNA damage. In people with LFS, due to the loss of functional p53, the protective mechanism of the cells is weakened resulting in a significantly increased cancer risk. In order to improve the survival of people with LFS, structured tumor early recognition and surveillance strategies are recommended; however, national and international longitudinal observational studies are needed to evaluate the cost-effort-benefit balance. For this reason, the authors have established the LFS cancer predisposition registry in which all patients with LFS and other syndromes predisposing to cancer can be registered. Detailed information can be found at www.cancer-predisposition.org .


Assuntos
Predisposição Genética para Doença , Síndrome de Li-Fraumeni , Genes p53/genética , Humanos , Síndrome de Li-Fraumeni/genética , Síndrome de Li-Fraumeni/mortalidade , Síndrome de Li-Fraumeni/patologia
4.
Biomed Khim ; 65(4): 263-276, 2019 Jun.
Artigo em Russo | MEDLINE | ID: mdl-31436168

RESUMO

Protein p53 is one of the most studied proteins. This attention is primarily due to its key role in the cellular mechanisms associated with carcinogenesis. Protein p53 is a transcription factor involved in a wide variety of processes: cell cycle regulation and apoptosis, signaling inside the cell, DNA repair, coordination of metabolic processes, regulation of cell interactions, etc. This multifunctionality is apparently determined by the fact that p53 is a vivid example of how the same protein can be represented by numerous proteoforms bearing completely different functional loads. By alternative splicing, using different promoters and translation initiation sites, the TP53 gene gives rise to at least 12 isoforms, which can additionally undergo numerous (>200) post-translational modifications. Proteoforms generated due to numerous point mutations in the TP53 gene are adding more complexity to this picture. The proteoforms produced are involved in various processes, such as the regulation of p53 transcriptional activity in response to various factors. This review is devoted to the description of the currently known p53 proteoforms, as well as their possible functionality.


Assuntos
Processamento Alternativo , Genes p53 , Proteína Supressora de Tumor p53/química , Humanos , Mutação Puntual , Isoformas de Proteínas/química , Processamento de Proteína Pós-Traducional , Relação Estrutura-Atividade
6.
Arkh Patol ; 81(3): 12-18, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31317926

RESUMO

OBJECTIVE: To identify the expression of the molecular markers p53 and p16INK4A in head and neck squamous cell carcinoma (HNSCC) and to assess their impact on its clinical and morphological characteristics and overall survival (OS) rates in patients with HNSCC. MATERIAL AND METHODS: Histological blocks were immunohistochemically studied using anti-p16 and p53 monoclonal antibodies in Krasnodar Clinical Oncology Dispensary One in 2011 to 2016. Overexpression of p16INK4A was established in the presence of 3 and 4 staining points (nuclear and/or cytoplasmic staining in 40% or more tumor cells). That of p53 was determined in the presence of nuclear staining (3+) in more than 50% of tumor cells. RESULTS: Overexpression of p16 was found in 15 (27%) patients (9 (60%) men and 6 (40%) women). The p16-positive tumor status was associated with the female sex (p=0.023), which was characteristic of tonsil cancer (p<0.001) and represented by the nonkeratinizing type (p=0.008). Overexpression of p16 was associated with more frequent regional lymph node metastases (p=0.029). Overexpression of p53 was related to G2 tumor (p=0.021) and expression of p53 was less than 50% associated with tongue body cancer (p=0.004). Kaplan-Meier analysis showed that the 3-year OS in p16-positive HNSCC patients was significantly higher than that in p16-negative ones (p=0.048). Significantly higher OS rates were observed in p16-positive HNSCC patients than in p16INK4A-negative ones for Stage III-IV (p=0.021). OS rates in HNSCC patients with co-expression of p16INK4A (3 and 4 points) and p53 (3+) were significantly higher than in the absence of a combination of these molecular markers (p=0.049). At the same time, OS in HNSCC patients with co-expression of p16INK4A (3 and 4 points), p53 (3+) was significantly higher than in the absence of a set of these molecular markers for stage III-IV (p=0.01). OS in patients with Stages I-II HNNSCC and co-expression of p16INK4A (3 and 4 points) and p53 (3+) did not significantly differ from that in the absence of a set of these molecular markers (p=0.960). CONCLUSION: Overexpression of p16INK4A (3 and 4 points) can be used as a prognostic marker to divide patients into subgroups with different clinical and morphological characteristics. The data on the correlation of p53 overexpression as a marker of mutations in the TP53 gene are contradictory and the study has not revealed the worst overall survival rates. A set of markers for the expression of p16 (≥40%) and p53 (≥50%) has been proposed for use as a favorable prognostic sign.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Inibidor p16 de Quinase Dependente de Ciclina , Genes p53 , Neoplasias de Cabeça e Pescoço , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Células Epiteliais , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Prognóstico , Proteína Supressora de Tumor p53/metabolismo
7.
Gastroenterology ; 157(3): 838-850.e6, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31163177

RESUMO

BACKGROUND & AIMS: Little is known about mechanisms of perineural invasion (PNI) by pancreatic ductal adenocarcinomas (PDAs) or other tumors. Annexin A2 (ANXA2) regulates secretion of SEMA3D, an axon guidance molecule, which binds and activates the receptor PLXND1 to promote PDA invasion and metastasis. We investigated whether axon guidance molecules promote PNI and metastasis by PDA cells in mice. METHODS: We performed studies in a dorsal root ganglion (DRG) invasion system, wild-type C57BL/6 mice (controls), mice with peripheral sensory neuron-specific disruption of PlxnD1 (PLAC mice), LSL-KRASG12D/+;LSL-TP53R172H/+;PDX-1-CRE+/+ (KPC) mice, and KPC mice crossed with ANXA2-knockout mice (KPCA mice). PDA cells were isolated from KPC mice and DRG cells were isolated from control mice. Levels of SEMA3D or ANXA2 were knocked down in PDA cells with small hairpin and interfering RNAs and cells were analyzed by immunoblots in migration assays, with DRGs and with or without antibodies against PLXND1. PDA cells were injected into the pancreas of control and PLAC mice, growth of tumors was assessed, and tumor samples were analyzed by histology. DRG cells were incubated with SEMA3D and analyzed by live imaging. We measured levels of SEMA3D and PLXND1 in PDA specimens from patients with PNI and calculated distances between tumor cells and nerves. RESULTS: DRG cells increase the migration of PDC cells in invasion assays; knockdown of SEMA3D in PDA cells or antibody blockade of PLXND1 on DRG cells reduced this invasive activity. In mice, orthotopic tumors grown from PDA cells with knockdown of SEMA3D, and in PLAC mice, orthotopic tumors grown from PDA cells, had reduced innervation and formed fewer metastases than orthotopic tumors grown from PDA cells in control mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. CONCLUSIONS: DRG cells increase the migratory and invasive activities of pancreatic cancer cells, via secretion of SEMA3D by pancreatic cells and activation of PLXND1 on DRGs. Knockdown of SEMA3D and loss of neural PLXND1 reduces innervation of orthotopic PDAs and metastasis in mice. Increased levels of SEMA3D and PLXND1 in human PDA specimens associated with PNI. Strategies to disrupt the axon guidance pathway mediated by SEMA3D and PLXND1 might be developed to slow progression of PDA.


Assuntos
Anexina A2/metabolismo , Orientação de Axônios , Carcinoma Ductal Pancreático/metabolismo , Movimento Celular , Gânglios Espinais/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neoplasias Pancreáticas/metabolismo , Semaforinas/metabolismo , Animais , Anexina A2/deficiência , Anexina A2/genética , Orientação de Axônios/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/secundário , Comunicação Celular , Gânglios Espinais/patologia , Regulação Neoplásica da Expressão Gênica , Genes p53 , Genes ras , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Humanos , Glicoproteínas de Membrana/deficiência , Glicoproteínas de Membrana/genética , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Invasividade Neoplásica , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Crescimento Neuronal , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fenótipo , Semaforinas/genética , Transdução de Sinais , Transativadores/genética , Células Tumorais Cultivadas
8.
Artigo em Chinês | MEDLINE | ID: mdl-31189235

RESUMO

Objective: To investigate alteration of proteins profile in malignant transformation bronchial epithelial cells(16HBE-T) induced by hexavalent chromium[(Cr(VI))] and analyze the expression level of SET protein, then to provide some new insights for the carcinogenesis mechanism of Cr(VI). Methods: Total protein was extracted from 16HBE cells and was alkylated and desalinated before digested into peptides. The products were labeled with Tandem Mass Tag (TMT) and identified using LC-ESI-MS/MS. Results: A total of 3 517 proteins were found, expression differences greater than 1.5 or less 0.67 times were to found have 185 and 201 proteins, respectively. Gene enrichment analysis revealed that differential proteins were mainly involved in autophagy, DNA damage repair, RNA processing and other biological processes. Western blot results showed the expression level of SET was significantly increased while downregulated in histone H3K18/27 acetylation and p53 protein. Conclusion: Proteins involved in multiple biological processes altered in 16HBE-T cells and regulation mode of SET inhibiting histone H3K18/27 acetylation regulating transcriptional activity of p53 may paly an important role in Cr(VI)-association carcinogenesis.


Assuntos
Transformação Celular Neoplásica , Cromo , Proteômica , Brônquios , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Cromo/toxicidade , Reparo do DNA , Genes p53/efeitos dos fármacos , Chaperonas de Histonas/metabolismo , Espectrometria de Massas em Tandem , Fatores de Transcrição/metabolismo
9.
Am J Vet Res ; 80(7): 680-688, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31246118

RESUMO

OBJECTIVE: To examine effects of a common mutation (2-base insertion in exon 5) of the TP53 gene on biological function of p53 protein in canine histiocytic sarcoma cells. SAMPLE: Canine histiocytic tumor cell lines DH82 with deletion of TP53 and CHS-3 with the wild-type TP53 and canine wild-type and mutant TP53 fragments. PROCEDURES: Wild-type or mutant TP53 with a polyprotein peptide tag at the N-terminus was transduced into DH82 and CHS-3 cells. Expression of p53 protein, changes in function as a transcription factor, and susceptibility to doxorubicin and nimustine were compared. RESULTS: Transduced p53 protein was detected in wild-type TP53-transduced DH82 and CHS-3 cells, whereas expression was not detected in mutant TP53-transduced cells. There were significant increases in expression of target genes of p53 protein, including p21 and MDM2, in wild-type TP53-transduced cells, compared with results for native and mock-transfected cells, but not in mutant TP53-transduced cells. There was no significant difference in drug susceptibilities among native and derivative cells of CHS-3. However, cell viabilities of wild-type TP53-transduced DH82 cells incubated with doxorubicin were significantly lower than viabilities of native, mock-transfected, and AT insertion mutation-TP53-transduced DH82 cells; susceptibility to nimustine did not differ significantly among cells. CONCLUSIONS AND CLINICAL RELEVANCE: Expression of p53 protein and its function as a transcription factor were lost after addition of a 2-base insertion in the TP53 gene in canine histiocytic tumor cells. Additional studies are needed to investigate the clinical relevance of this mutation in histiocytic sarcomas of dogs.


Assuntos
Cães , Mutagênese Insercional/fisiologia , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Doenças do Cão/fisiopatologia , Genes p53/genética , Sarcoma Histiocítico/fisiopatologia , Sarcoma Histiocítico/veterinária , Mutação , Proteína Supressora de Tumor p53/metabolismo
11.
Zhonghua Xue Ye Xue Za Zhi ; 40(5): 378-383, 2019 May 14.
Artigo em Chinês | MEDLINE | ID: mdl-31207701

RESUMO

Objective: To analyze the survival and first-line immune-chemotherapy (CIT) of chronic lymphocytic leukemia (CLL) with abnormal TP53 gene in the era of traditional CIT. Methods: The clinical data of 118 CLL patients diagnosed from January 2003 to August 2017 were collected. Survival was analyzed according to indicators including sex, age, Binet risk stratification, B symptoms, ß(2)-microglobulin (ß(2)-MG) , immunoglobulin heavy chain variable region gene (IGHV) mutation status, chromosome karyotype and TP53 gene deletion/mutation. The efficacy of first-line CIT of 101 CLL patients was further analyzed. Results: Among 118 patients, median progression-free survival (PFS) was 12 (95%CI 10.148-13.852) months and median overall survival (OS) was 53 (95%CI 41.822-64.178) months, only 30.5% patients survived over 5 years. Low ß(2)-MG<3.5 mg/L indicated longer PFS (P=0.027) , female and Binet A patients had longer OS (P=0.011 and 0.013, respectively) . Of 118 patients, 17 (14.4%) didn't receive any therapy until follow-up time or the dead time. Among the 101 patients who received ≥1 CIT, median time to first treatment (TTFT) was 1 (0-62) months, patients in Binet A had longer TTFT (P<0.001) compared to the patients in Binet B/C. According to statistical needs, we divided those first-line CIT into four groups: there were 30 cases (29.7%) in mild chemotherapy group (mainly treated with nitrogen mustard phenylbutyrate or rituximab alone) , 32 cases (31.7%) in the fludarabine-containing group, 23 cases (22.8%) in high-dose methyprednisolone (HDMP) containing group and 16 cases (15.8%) in the other chemotherapy group. The first regimen contained HDMP can bring longer PFS (P<0.001) , however the OS between four groups had no statistical differences. Conclusion: CLL patients with abnormal TP53 gene had poor response to immunotherapy, rapid clinical progressing, first-line immunotherapy containing HDMP can prolong PFS and will create an opportunity for patients to participate in clinical trials of novel drugs.


Assuntos
Leucemia Linfocítica Crônica de Células B , Proteína Supressora de Tumor p53/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Feminino , Genes p53 , Humanos , Imunoterapia , Leucemia Linfocítica Crônica de Células B/genética , Análise de Sobrevida
13.
Medicine (Baltimore) ; 98(18): e15449, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31045815

RESUMO

TP53 gene is mutated in approximately 80% of triple-negative breast cancer (TNBC). However, the prognostic significance of immunohistochemical (IHC)-detected p53 protein expression remains controversial in TNBC. In this study, we retrospectively analyzed the association between IHC-detected p53 expression and the prognosis in a cohort of 278 patients with stage I-III triple-negative breast invasive ductal carcinoma (IDC), who received surgery at the department of breast surgery in the Fourth Hospital of Hebei Medical University from 2010-01 to 2012-12. We found a positive expression ratio of IHC-detected p53 in triple-negative breast IDC of 58.6% (163/278). Furthermore, levels of expression were significantly associated with vessel tumor emboli and higher histologic grade (P = .038, P = .043, respectively), with the highest expression level observed in G3 breast cancer (64.7%). Additionally, Kaplan-Meier analysis showed that p53 expression indicated worse overall survival (OS) in the whole cohort (79.6% vs 89.6%, Log-rank test P = .025) as well as in stratified prognostic stage II patients (90.8% vs 100%, Log-rank test P = .027). The mortality risk of p53 expression patients was 2.22 times higher than that of p53 negative patients (HR: 2.222; 95%CI: 1.147-4.308). In addition, p53 expression was also associated with poor disease-free survival (DFS) (76.7% vs 86.8%, P = .020). Cox proportional hazard ratio model showed p53 expression was an independent risk factor for OS (P = .018) and DFS (P = .018) after controlling for tumor size, lymph node status, and vessel tumor emboli. Altogether, our data showed that IHC-detected p53 expression is a promising prognostic candidate for poor survival in triple-negative breast IDC patients. However, more studies are needed to determine if p53 may be applied to clinical practice as a biomarker and/or novel therapeutic target for TNBC.


Assuntos
Carcinoma Ductal/mortalidade , Carcinoma Ductal/patologia , Genes p53/fisiologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genética
14.
MBio ; 10(3)2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088931

RESUMO

The abnormal proliferation of cancer cells is driven by deregulated oncogenes or tumor suppressors, among which the cancer-vulnerable genes are attractive therapeutic targets. Targeting mislocalization of oncogenes and tumor suppressors resulting from aberrant nuclear export is effective for inhibiting growth transformation of cancer cells. We performed a clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) screening in a unique model of matched primary and oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV)-transformed cells and identified genes that were growth promoting and growth suppressive for both types of cells, among which exportin XPO1 was demonstrated to be critical for the survival of transformed cells. Using XPO1 inhibitor KPT-8602 and by small interfering RNA (siRNA) knockdown, we confirmed the essential role of XPO1 in cell proliferation and growth transformation of KSHV-transformed cells and in cell lines of other cancers, including gastric cancer and liver cancer. XPO1 inhibition induced cell cycle arrest through p53 activation, but the mechanisms of p53 activation differed among the different types of cancer cells. p53 activation depended on the formation of promyelocytic leukemia (PML) nuclear bodies in gastric cancer and liver cancer cells. Mechanistically, XPO1 inhibition induced relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. Taken the data together, we have identified novel growth-promoting and growth-suppressive genes of primary and cancer cells and have demonstrated that XPO1 is a vulnerable target of cancer cells. XPO1 inhibition induces cell arrest through a novel PML- and p62-dependent mechanism of p53 activation in some types of cancer cells.IMPORTANCE Using a model of oncogenic virus KSHV-driven cellular transformation of primary cells, we have performed a genome-wide CRISPR-Cas9 screening to identify vulnerable genes of cancer cells. This screening is unique in that this virus-induced oncogenesis model does not depend on any cellular genetic alterations and has matched primary and KSHV-transformed cells, which are not available for similar screenings in other types of cancer. We have identified genes that are both growth promoting and growth suppressive in primary and transformed cells, some of which could represent novel proto-oncogenes and tumor suppressors. In particular, we have demonstrated that the exportin XPO1 is a critical factor for the survival of transformed cells. Using a XPO1 inhibitor (KPT-8602) and siRNA-mediated knockdown, we have confirmed the essential role of XPO1 in cell proliferation and in growth transformation of KSHV-transformed cells, as well as of gastric and liver cancer cells. XPO1 inhibition induces cell cycle arrest by activating p53, but the mechanisms of p53 activation differed among different types of cancer cells. p53 activation is dependent on the formation of PML nuclear bodies in gastric and liver cancer cells. Mechanistically, XPO1 inhibition induces relocalization of autophagy adaptor protein p62 (SQSTM1), recruiting p53 for activation in PML nuclear bodies. These results illustrate that XPO1 is a vulnerable target of cancer cells and reveal a novel mechanism for blocking cancer cell proliferation by XPO1 inhibition as well as a novel PML- and p62-mediated mechanism of p53 activation in some types of cancer cells.


Assuntos
Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Herpesvirus Humano 8/patogenicidade , Carioferinas/genética , Receptores Citoplasmáticos e Nucleares/genética , Sistemas CRISPR-Cas , Pontos de Checagem do Ciclo Celular , Detecção Precoce de Câncer , Genes p53 , Humanos , Carioferinas/antagonistas & inibidores , Leucemia Promielocítica Aguda , Neoplasias Hepáticas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Proteína Sequestossoma-1/genética , Neoplasias Gástricas , Células Tumorais Cultivadas
15.
Leukemia ; 33(8): 2022-2033, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30992504

RESUMO

Monitoring tumour burden and therapeutic response through analyses of circulating cell-free tumour DNA (ctDNA) and extracellular RNA (exRNA) in multiple myeloma (MM) patients were performed in a Phase Ib trial of 24 relapsed/refractory patients receiving oral azacitidine in combination with lenalidomide and dexamethasone. Mutational characterisation of paired BM and PL samples at study entry identified that patients with a higher number of mutations or a higher mutational fractional abundance in PL had significantly shorter overall survival (OS) (p = 0.005 and p = 0.018, respectively). A decrease in ctDNA levels at day 5 of cycle 1 of treatment (C1D5) correlated with superior progression-free survival (PFS) (p = 0.017). Evaluation of exRNA transcripts of candidate biomarkers indicated that high CRBN levels coupled with low levels of SPARC at baseline were associated with shorter OS (p = 0.000003). IKZF1 fold-change <0.05 at C1D5 was associated with shorter PFS (p = 0.0051) and OS (p = 0.0001). Furthermore, patients with high baseline CRBN coupled with low fold-change at C1D5 were at the highest risk of progression (p = 0.0001). In conclusion, this exploratory analysis has provided the first demonstration in MM of ctDNA for predicting disease outcome and of the utility of exRNA as a biomarker of therapeutic response.


Assuntos
DNA Tumoral Circulante/análise , Mieloma Múltiplo/tratamento farmacológico , RNA/análise , Efeitos Psicossociais da Doença , Genes p53 , Humanos , Fator de Transcrição Ikaros/análise , Mieloma Múltiplo/sangue , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Mutação , Peptídeo Hidrolases/análise , Prognóstico
17.
Zhonghua Xue Ye Xue Za Zhi ; 40(3): 215-221, 2019 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-30929389

RESUMO

Objective: To explore the clinical implications and prognostic value of TP53 gene mutation and deletion in patients with myelodysplastic syndromes (MDS) . Methods: 112-gene targeted sequencing and interphase fluorescence in situ hybridization (FISH) were used to detect TP53 mutation and deletion in 584 patients with newly diagnosed primary MDS who were admitted from October 2009 to December 2017. The association of TP53 mutation and deletion with several clinical features and their prognostic significance were analyzed. Results: Alterations in TP53 were found in 42 (7.2%) cases. Of these, 31 (5.3%) cases showed TP53 mutation only, 8 (1.4%) cases in TP53 deletion only, 3 (0.5%) cases harboring both mutation and deletion. A total of 37 mutations were detected in 34 patients, most of them (94.6%) were located in the DNA binding domain (exon5-8) , the remaining 2 were located in exon 10 and splice site respectively. Patients with TP53 alterations harbored significantly more mutations than whom without alterations (z=-2.418, P=0.016) . The median age of patients with TP53 alterations was higher than their counterparts[60 (21-78) years old vs 52 (14-83) years old, z=-2.188, P=0.029]. TP53 alterations correlated with complex karyotype and International prognostic scoring system intermediate-2/high significantly (P<0.001) . Median overall survival of patients with TP53 alterations was shorter than the others[13 (95%CI 7.57-18.43) months vs not reached, χ(2)=12.342, P<0.001], while the significance was lost during complex karyotype adjusted analysis in multivariable model. Conclusion: TP53 mutation was more common than deletion in MDS patients. The majority of mutations were located in the DNA binding domain. TP53 alterations were strongly associated with complex karyotype and always coexisted with other gene mutations. TP53 alteration was no longer an independent prognostic factor when complex karyotype were occurred in MDS.


Assuntos
Genes p53 , Síndromes Mielodisplásicas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/genética , Prognóstico , Proteína Supressora de Tumor p53 , Adulto Jovem
18.
Analyst ; 144(8): 2649-2655, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30843550

RESUMO

In this work, we propose an ultrasensitive fluorescence strategy for DNA detection. This method utilizes a molecular beacon (MB), a hairpin probe (HP), and an enzyme to trigger dual-cycling reactions (cycles I and II). In cycle I, the target is repeatedly used to amplify the fluorescence emission through hybridizations with the MB and cleavage reactions achieved by the enzyme. In cycle II, hybridization reactions between the HP and a segment of the MB continuously regenerate the target to trigger more cycle I reactions, leading to an enhanced fluorescent signal. The detection limit of the method is determined to be as low as 50 fM within 45 min, which is 2 to 3 orders of magnitude lower than that of the conventional fluorescence strategies. The method also shows a high selectivity over mismatched and random DNA sequences. The signal amplification mechanism of the strategy offers insights into constructing efficient and ultrasensitive biosensors for various applications.


Assuntos
DNA/sangue , Genes p53 , Espectrometria de Fluorescência/métodos , Animais , Técnicas Biossensoriais/métodos , Bovinos , DNA/química , DNA/genética , Desoxirribonuclease I/química , Fluorescência , Corantes Fluorescentes/química , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico/métodos , Hibridização de Ácido Nucleico
19.
Res Vet Sci ; 124: 57-60, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30852355

RESUMO

Canine histiocytic sarcoma (HS) is an aggressive tumor type originating from dendritic cells or macrophages. We previously reported high incidence of the two-base (AT) insertion mutation (insAT) in the tumor protein p53 (TP53) gene in dogs with HS, and the aim of this study was to investigate the clinical significance of insAT in canine HS. The present study established a sensitive digital PCR-based assay for detecting insAT and examined its associations with clinical variables and survival time. The mutation was detected in 26 of 64 dogs (41%), and the mean mutant allele frequency was 1.9% (range, 0.014-35%), indicating that not all tumor cells harbor insAT. The incidence of insAT was significantly higher in dogs with metastatic lesions than in those without metastatic lesions. However, the existence of insAT was not associated with survival time or response to chemotherapy with lomustine or nimustine. This study suggested that HS cells might acquire insAT in the TP53 gene during development of metastasis, but insAT was not a prognostic factor in canine HS. Further studies are needed to investigate the contribution of insAT to the development of metastatic lesions of canine HS.


Assuntos
Doenças do Cão/genética , Sarcoma Histiocítico/veterinária , Mutagênese Insercional/genética , Proteína Supressora de Tumor p53/genética , Animais , Doenças do Cão/etiologia , Cães , Feminino , Genes p53 , Sarcoma Histiocítico/etiologia , Sarcoma Histiocítico/genética , Masculino , Proteína Supressora de Tumor p53/metabolismo
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