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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(1): 125-129, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32027264

RESUMO

OBJECTIVE: To analyze relation of ASXL2 gene mutation with the clinical characteristics, prognosis and C-KIT gene mutation in acute myeloid leukemia (AML) patients with AML1-ETO fusion gene. METHODS: The clinical data of 63 primary AML patients with AML1-ETO fusion gene were collected and retrospectively analyzed. The mutation of ASXL2 gene was directly sequenced by PCR. The clinical characteristics, C-KIT mutation rate and prognosis were compared between the patients with ASXL2 gene mutation (group A) and non-mutation (group B). RESULTS: Among 63 patients, 8 (12.70%) cases of ASXL2 mutation gene was detected. Hemoglobin level in peripheral blood of patients in group A was significantly lower than that in group B (P<0.01). There was no significant difference in sex, ages proportion of bone marrow blasts, lymph node enlargement, peripheral blood leukocytes count and platelets between the two groups (P>0.05). The infiltration of central nervous system, liver and spleen was not found in both groups. The expression of CD33 in group A was significantly lower than that in group B (P<0.05), but the results of other immunophenotype analysis were not significantly different between the two groups (P>0.05). The remission rate and median survival time were not significantly different between two groups (P>0.05). The detection rate of C-KIT gene mutation were not significantly different between group A and group B (P>0.05). CONCLUSION: Among AML patients with AML1-ETO fusion gene, ASXL2 gene mutation accounts for a certain ratio, and the peripheral blood hemoglobin concentration and CD33 expression in these patients are often low. At the same time, ASXL2 gene mutation may not be closely related with C-KIT gene mutation.


Assuntos
Leucemia Mieloide Aguda , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Repressoras/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1/genética , Estudos Retrospectivos
3.
J Clin Pathol ; 73(2): 116-119, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31506288

RESUMO

Beyond targeted therapy for patients with BRAF-mutated melanomas and immunotherapy in patients lacking BRAF mutations, anti-MEK therapy has been proposed in patients with advanced melanomas harbouring BRAF fusions. BRAF fusions diagnosis in patients with advanced melanomas is the subject of the present study. Using BRAF fluorescent in situ hybridisation (FISH), we searched for BRAF fusions in 74 samples of 66 patients with advanced BRAF/NRAS/KIT wild-type melanomas. We identified 2/66 (3%) patients with BRAF fusions in a brain metastasis of one patient and in a lymph node metastasis and in a cutaneous metastasis for the second patient with 90%-95% of tumour nuclei containing isolated 3'-BRAF FISH signals. As a result, we conclude that BRAF FISH in patients with advanced BRAF/NRAS/KIT wild-type melanomas is a valuable and easy-to-perform test to diagnose BRAF fusions and to identify patients who could benefit of anti-MEK targeted therapy.


Assuntos
Biomarcadores Tumorais/genética , GTP Fosfo-Hidrolases/genética , Fusão Gênica , Hibridização in Situ Fluorescente , Melanoma/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/enzimologia , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Terapia de Alvo Molecular , Seleção de Pacientes , Medicina de Precisão , Valor Preditivo dos Testes , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/enzimologia
4.
Cell Physiol Biochem ; 53(6): 961-981, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31820856

RESUMO

BACKGROUND/AIMS: We assessed the effects of ticagrelor, aspirin and prasugrel, started 7days after myocardial ischemia-reperfusion injury on remodeling, inflammation and fibrosis in the rat. We examined whether ticagrelor can affect the number of progenitor cells in the border zone. Ticagrelor, started 24h after myocardial ischemia-reperfusion injury, attenuates the decrease in heart function and adverse remodeling, an effect which is blocked by aspirin. METHODS: Rats underwent 40min ischemia followed by reperfusion. Oral dosing with vehicle, ticagrelor (300mg/kg/d), aspirin (20mg/kg/d), their combination or prasugrel (15mg/kg/d) started 7days after infarction. Echocardiography was used to assess systolic function. Heart tissue were analyzed by rt-PCR, immunoblotting, ELISA and immunohistochemistry 2weeks after infarction. RESULTS: Both ticagrelor and aspirin attenuated the decrease in systolic function and remodeling, an effect that was blocked by their combination. Ticagrelor and aspirin attenuated the increase in ANP, BNP, collagen-I and collagen-III. Again, the effect was blocked by their combination. Ticagrelor increased c-Kit, Sca-1, Ki-67, CD34, attenuated the decrease in CD105 mRNA levels, and attenuated the increase in CD31, whereas aspirin increased Ki-67, suppressed the increase in CD31 and attenuated the decrease in CD105 mRNA levels. Prasugrel did not display any effects. CONCLUSION: Ticagrelor attenuated adverse remodeling and deterioration of left ventricular systolic function despite starting treatment after the myocardial ischemia-reperfusion injury is completed. Aspirin had similar effects; however, when combined with ticagrelor, the protective effects were significantly attenuated. Ticagrelor increased the levels of several markers of stem cells and regeneration, suggesting cardiac healing by recruiting regenerative cells into the infarct.


Assuntos
Apoptose/efeitos dos fármacos , Infarto do Miocárdio/patologia , Inibidores da Agregação de Plaquetas/farmacologia , Ticagrelor/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Animais , Aspirina/farmacologia , Aspirina/uso terapêutico , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Endoglina/genética , Endoglina/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/farmacologia , Cloridrato de Prasugrel/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Ratos , Ratos Sprague-Dawley , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Ticagrelor/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos
5.
Medicine (Baltimore) ; 98(44): e17769, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689840

RESUMO

RATIONALE: The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations. PATIENT CONCERNS AND DIAGNOSIS: We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I. INTERVENTIONS: She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy. OUTCOMES: Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression. LESSONS: Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Feminino , Humanos , Melanoma/genética , Melanoma/patologia , Mutação , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do Tratamento
6.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 696-701, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699203

RESUMO

Gastrointestinal stromal tumors(GISTs)are the most common mesenchymal tumors of the gastrointestinal tract and respond poorly to conventional radiochemotherapy.Complete excision is the only possible way to cure GISTs.Although targeted therapy is effective for GISTs,multiple and/or secondary mutations of KIT or PDGFRA gene have lead to increased drug resistance and disease relapse.A variety of tumor infiltrating immune cells and complex immune microenvironments have been found in GISTs.Many immune cells participate in the occurrence and development of GISTs and play key roles in targeted therapy.The feasibility and effectiveness of immunotherapy for GISTs have been well demonstrated in preclinical and clinical studies.


Assuntos
Tumores do Estroma Gastrointestinal/imunologia , Tumores do Estroma Gastrointestinal/terapia , Imunoterapia , Humanos , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Microambiente Tumoral
7.
An Bras Dermatol ; 94(4): 458-460, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31644622

RESUMO

Melanoma is widely known as the most lethal skin cancer. Specific tumor-related mortality can be significantly reduced if diagnosis and treatment are properly performed during initial phases of the disease. The current search for biomarkers in early-stage melanomas is a high-priority challenge for physicians and researchers. We aimed to assess the immunoexpression of BRAFV600E and KIT in a case series consisting of 44 early-stage melanomas. Formalin-fixed paraffin-embedded samples were systematically evaluated using a semi-quantitative method based on scores of percentage and intensity for immunostained tumor cells. We observed significant concordance between BRAFV600E and KIT immunoexpression in thin invasive melanomas. Our findings corroborate previous evidence showing abnormal expression of proteins associated with MAPK intracellular signaling pathway in early-stage melanomas.


Assuntos
Melanoma/patologia , Proteínas Proto-Oncogênicas B-raf/análise , Proteínas Proto-Oncogênicas c-kit/análise , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/análise , Mutação , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Estudos Retrospectivos , Adulto Jovem
8.
Int J Mol Sci ; 20(19)2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31590335

RESUMO

The stabilization of G-quadruplex DNA structures by small molecules with affinity to oncogene promoters has emerged as a promising anticancer strategy, due to a potential role in gene expression regulation. We explored the ability of BMH-21 (1) and its analogue BA-41 (2) to bind the G-quadruplex structure present in the c-KIT promoter by biophysical methods and molecular modeling. We provide evidence that both compounds interact with the c-KIT 21-mer sequence. The stable monomeric intramolecular parallel G-quadruplex obtained by the mutation of positions 12 and 21 allowed the precise determination of the binding mode by NMR and molecular dynamics studies. Both compounds form a complex characterized by one ligand molecule positioned over the tetrad at the 3'-end, stabilized by an extensive network of π-π interactions. The binding constants (Kb) obtained with fluorescence are similar for both complexes (around 106 M-1). Compound BA-41 (2) showed significant antiproliferative activity against a human lymphoma cell line, SU-DHL4, known to express substantial levels of c-KIT. However, the partial inhibition of c-KIT expression by Western blot analysis suggested that the interaction of compound 2 with the c-KIT promoter is not the primary event and that multiple effects provide a contribution as determinants of biological activity.


Assuntos
Quadruplex G , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , RNA Polimerase I/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-kit/metabolismo
9.
Zhonghua Wei Chang Wai Ke Za Zhi ; 22(9): 848-855, 2019 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-31550824

RESUMO

Objective: To explore the features of imatinib mesylate (IM) plasma concentration during adjuvant therapy and clinical factors associated with IM plasma concentration in patients with high risk gastrointestinal stromal tumors (GIST), and to determine whether IM plasma concentration <1100 µg/L influences the efficacy of adjuvant therapy. Methods: A retrospective case control study method was used. Case inclusion criteria: (1) complete resection of lesion and GIST confirmed by pathology; (2) high risk classified according to modified National Institutes of Health classification system (2008); (3) administration of IM 400 mg/d for at least 1 month; (4) not taking the medication likely affecting IM pharmacokinetic, such as rifampicin, dilantin, and carbamazepine, within 1 month before blood collection. Data of GIST patients who visited GIST Disease - Oriented Outpatient, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 to December 2018 were retrospectively analyzed. After taking IM for 22-26 hours, 5 ml of peripheral venous blood was collected into EDTA anticoagulant tube. IM plasma concentration was detected by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Patients were divided into <1100 µg/L group and ≥1100 µg/L group according to plasma concentration. Linear regression was used to analyze the relevance between clinical features and IM plasma concentration. Parameters with normal distribution were analyzed by Pearson correlation coefficient, and parameters with non-normal distribution were analyzed by Spearman correlation. Kaplan-Meier survival curves and COX regression model were used for survival analysis. Results: Among the 85 patients enrolled in the study, 49 patients (57.6%) were male and 36 (42.4%) were female, with mean age of (51.9±11.0) years. The body mass index was (22.5±2.9) kg/m(2) and body surface area was (1.6±0.2) m(2). Thirty patients received gene test, including 23 patients with c-Kit exon 11 mutation, 4 with c-Kit exon 9 mutation, 1 with c-Kit exon 11 and 17 mutation and 2 without c-Kit or PDGFRA gene mutation. The mean IM plasma concentration was (1391.4±631.3) µg/L, and there were 32 patients with plasma concentration <1100 µg/L and 53 patients with plasma concentration ≥1100 µg/L. There were no statistically significant differences between the two groups in gender, age, body mass index, body surface area, hematological examination (white blood cells, albumin, alanine aminotransferase, aspartate aminotransferase and serum creatinine), tumor location, tumor size, mitotic counts, duration of adjuvant therapy and methods of operation (all P>0.05). Positive correlation between IM plasma concentration and serum creatinine was observed in linear regression analysis (r=0.297, P=0.007), but there were no correlations between IM plasma concentration and age (r=0.044, P=0.686), body mass index (r=0.066, P=0.547), body surface area (r=-0.010, P=0.924), white blood cells (r=-0.080, P=0.478), albumin (r=-0.065, P=0.563), alanine aminotransferase (r=0.114, P=0.308), aspartate aminotransferase (r=0.170, P=0.127) and duration of adjuvant therapy (ρ=0.060, P=0.586). There was no statistically significant difference in IM plasma concentration between patients with different genders (t=0.336, P=0.738) and patients with different surgical methods (F=0.888, P=0.451). Up to March 1, 2019. the median follow-up time was 30 (range 4-49) months. Tumor recurrence was detected in two patients with plasma concentration <1100 µg/L and two with plasma concentration ≥1100 µg/L. One recurrent patient with plasma concentration <1100 µg/L was detected to harbor c-Kit exon 11 and exon 17 mutations, and the other did not receive gene detection. Two recurrent patients with plasma concentration ≥1100 µg/L were both detected to harbor c-Kit exon 9 mutation. The 3-year relapse-free survival rate was 96.4% in the cohort, 96.2% in patients with plasma concentration <1100 µg/L, and 96.6% in patients with plasma concentration ≥1100 µg/L. No significant difference in relapse-free survival was observed between the two groups (P=0.204). Univariate Cox analysis showed that IM plasma concentration <1100 µg/L was not a risk factor for patients with high risk GIST (HR=0.238, 95% CI: 0.022-2.637, P=0.242). Conclusions: IM plasma concentration of adjuvant therapy in patients with high risk GIST varies with individual. Patients with higher level of serum creatinine are more likely to have a higher plasma concentration. A blood drug concentration standard of less than 1100 µg/L for advanced GIST patients may not influence the prognosis of patients with high risk GIST.


Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Mesilato de Imatinib , Adulto , Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Estudos de Casos e Controles , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Mesilato de Imatinib/sangue , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Proteínas Proto-Oncogênicas c-kit/genética , Estudos Retrospectivos , Fatores de Risco , Espectrometria de Massas em Tandem
10.
Reprod Biol Endocrinol ; 17(1): 75, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506068

RESUMO

BACKGROUND: Although in vitro culture system has been optimized in the past few decades, the problem of few or no high quality embryos has been still not completely solved. Accordingly, fully understanding the regulatory mechanism of pre-implantation embryonic development would be beneficial to further optimize the in vitro embryo culture system. Recent studies have found the expression of c-kit in mouse embryo and its promotion effects on mouse embryonic development. However, it is unclear the expression, the role and the related molecular regulatory mechanism of c-kit in human pre-implantation embryo development. Therefore, the present study is to determine whether c-kit is expressed in human pre-implantation embryos, and to investigate the possible regulatory mechanism of c-kit signaling in the process of embryonic development. METHODS: The present study includes human immature oocytes and three pronucleus (3PN) embryos collected from 768 women (28-32 ages) undergoing IVF, and normal 2PN embryos collected from ICR mice. Samples were distributed randomly into three different experimental groups: SCF group: G-1™ (medium for culture of embryos from the pro-nucleate stage to day 3) or G-2™ (medium for culture of embryos from day3 to blastocyst stage) + HSA (Human serum album) solution + rhSCF; SCF + imanitib (c-kit inhibitor) group: G-1™ or G-2™ + HSA solution + rhSCF + imanitib; SCF + U0126 (MEK/ERK inhibitor) group: G-1™ or G-2™ + HSA solution + rhSCF + U0126; Control group: G-1™ or G-2™ + HSA solution + PBS; The rate of good quality embryos at day 3, blastulation at day 6 and good quality blastulation at day 6 were analysis. RT-PCR, western blot and immunofluorescence staining were applied to detect the target genes and proteins in samples collected from human or mice, respectively. RESULTS: c-kit was expressed ubiquitously in all human immature oocytes, 3PN embryos and 3PN blastocysts. In the experiment of human 3PN embryos, compared with other groups, SCF group showed obviously higher rate of good quality at day 3, better rate of blastocyst formation at day 6 and higher rate of good quality blastocyst formation at day 6. Furthermore, we observed a higher ETV5 expression in SCF group than that in other groups. Similar results were also found in animal experiment. Interestingly, we also found a higher phosphorylation level of MEK/ERK signal molecule in mice embryos from SCF group than those from other groups. Moreover, inhibition of MEK/ERK signaling would remarkably impeded the mice embryonic development, which might be due to the reduced ETV5 expression. CONCLUSIONS: The present study firstly revealed that c-kit signaling might promote the human pre-implantation embryonic development and blastocyst formation by up-regulating the expression of ETV5 via MEK/ERK pathway. Our findings provide a new idea for optimizing the in vitro embryo culture condition during ART program, which is beneficial to obtain high quality embryos for infertile patients.


Assuntos
Blastocisto/metabolismo , Transferência Embrionária/métodos , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica no Desenvolvimento , Proteínas Proto-Oncogênicas c-kit/genética , Transdução de Sinais/genética , Adulto , Animais , Proteínas de Ligação a DNA , Técnicas de Cultura Embrionária/métodos , Implantação do Embrião/genética , Feminino , Humanos , Camundongos Endogâmicos ICR , Gravidez , Proteínas Proto-Oncogênicas c-kit/metabolismo , Fatores de Transcrição
11.
Hematol Oncol ; 37(5): 628-633, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31523839

RESUMO

The association of systemic mastocytosis with another hematologic neoplasia of myeloid or lymphoid origin is recognized as an advanced subvariant of mastocytosis. Here, we report the association of indolent or smoldering systemic mastocytosis with three cases of myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis, a recently recognized disease characterized by SF3B1 mutations. The hierarchical pattern of KIT, SF3B1, JAK2, and additional mutations was studied in whole and fractionated subpopulations of peripheral blood cells and whole bone marrow. In two cases, we could demonstrate a multilineage D816V KIT mutation, involving all myeloid lineages in one patient and also the lymphoid series in the other. Two patients displaying both SF3B1 and V617F JAK2 mutations had a very poor prognosis. Another patient bearing SF3B1, but not V617F JAK2 mutation, had a favorable response to erythropoietin treatment and long survival.


Assuntos
Eritroblastos/patologia , Mastocitose Sistêmica/complicações , Mastocitose Sistêmica/diagnóstico , Síndromes Mielodisplásicas/complicações , Transtornos Mieloproliferativos/complicações , Trombocitose/complicações , Idoso , Biomarcadores , Medula Óssea/patologia , Humanos , Imuno-Histoquímica , Masculino , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/terapia , Mutação , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Células Mieloides/metabolismo , Células Mieloides/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Linhagem , Proteínas Proto-Oncogênicas c-kit/genética , Trombocitose/diagnóstico
12.
Biochemistry (Mosc) ; 84(8): 941-953, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31522676

RESUMO

Transforming growth factor beta (TGF-ß) acts as a tumor-suppressing cytokine in healthy tissues and non-malignant tumors. Yet, in malignancy, TGF-ß can exert the opposite effects that can promote proliferation of cancer cells. C-Kit plays a prominent role in stem cell activation and liver regeneration after injury. However, little is known about the cross-talk between TGF-ß and C-Kit and its role in the progression of hepatocellular carcinoma (HCC). Here, we studied the effect of increasing doses of TGF-ß1 on CD44+CD90+ liver stem cells (LSCs) and C-Kit gene expression in malignant and adjacent non-malignant liver tissues excised from 32 HCC patients. The percentage of LSCs in malignant tumors was two times higher compared to their counterparts from the non-malignant tissues. When treated with increasing doses of TGF-ß1, proliferation of both malignant and non-malignant LSCs was progressively suppressed, but low TGF-ß1 dose failed to suppress the growth of malignant LSCs. Moreover, C-Kit exons 9 and 11 were expressed in malignant LSCs, but not in their non-malignant counterparts. Analysis of C-Kit detected mutations in exon 9 (but not in exon 11) in some malignant liver cells resulting in the changes in the amino acid sequence and dysregulation of protein structure and function. Interestingly, in malignant liver cells, mutations in exon 9 were associated with high-viremia hepatitis C virus (HCV), and expression of this exon was not suppressed by the TGF-ß1 treatment at all doses. To our knowledge, this is the first report that mutations in the C-Kit gene in HCC patients are associated with high- viremia HCV. Our study emphasizes the need for investigation of the TGF-ß1 level and C-Kit mutations in patients with chronic HCV for HCC prevention and better therapy management.


Assuntos
Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Hepacivirus , Hepatite C Crônica/genética , Hepatite C Crônica/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Fator de Crescimento Transformador beta1/farmacologia , Idoso , Carcinoma Hepatocelular/etiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Farmacorresistência Viral Múltipla , Éxons/genética , Feminino , Expressão Gênica , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Receptores de Hialuronatos/metabolismo , Fígado/patologia , Neoplasias Hepáticas/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Células-Tronco Neoplásicas/metabolismo , Antígenos Thy-1/metabolismo , Viremia
13.
Pol J Pathol ; 70(2): 63-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31556556

RESUMO

The aim of this research was to investigate the clinical role and prognostic value of CD117 expression assessed immunohistochemically in lung carcinoma through a comprehensive meta-analysis in which 27 publications were acquired and 2645 patients were ultimately analysed. Statistical analysis and corresponding plots were performed using STATA version 12.0. Publication bias was assessed by Begg's funnel plots and Egger's test. Pooled HR and its 95% CI (HR = 1.53, 95% CI: 1.13-2.07, p = 0.007) for overall survival of patients indicated a poor prognostic value for CD117 expression in lung carcinoma, which was accompanied by heterogeneity and publication bias. In the subgroup analysis, there was strong evidence that could support an association between CD117 expression and poor prognosis in NSCLC patients (HR = 2.03, 95% CI: 1.41-2.90, p < 0.001; heterogeneity: I2 = 41.9%, c2 = 15.49, p = 0.078). Multivariate analysis also revealed consistent results in high-quality studies with reported HRs (HR = 2.16, 95% CI: 1.67-2.79, p < 0.001), and Asian patients (HR = 2.12, 95% CI: 1.45-3.10, p < 0.001). The correlations between CD117 expression and age, clinical stage, TNM stage, lymph node metastasis, or histology were not statistically significant. In conclusion, CD117 expression might be a potential marker for predicting poor prognosis, faster tumour growth, and early lymph node metastasis in NSCLC.


Assuntos
Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas c-kit/genética , Biomarcadores Tumorais/genética , Progressão da Doença , Humanos , Neoplasias Pulmonares/diagnóstico , Metástase Linfática , Prognóstico
14.
J Ovarian Res ; 12(1): 89, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31547830

RESUMO

BACKGROUND: Gonadoblastoma (GB) is a rare mixed germ cell-sex cord-stromal tumour, first described in humans, commonly found in dysgenetic gonads of intersex patients that have a Y chromosome. However, this entity in not recognized in the WHO classification of tumours of genital system of domestic animals. Herein, we describe a case of ovarian gonadoblastoma with proliferation of dysgerminoma and sex cord-stromal tumour components, in a phenotypically and cytogenetically normal bitch. CASE PRESENTATION: A 17-year-old cross-breed bitch had a firm, grey-white multinodular mass in the left ovary. The tumour was submitted to histopathological examination and Y chromosome detected through karyotype analysis and PCR studies. Microscopically, the ovary was almost replaced by an irregular neoplasm composed of three distinct, intermixed elements: dysgerminoma, mixed germ cell-sex cord-stromal tumour resembling human GB and a proliferative sex cord-stromal tumour component. The germ cells of gonadoblastoma and dysgerminoma components were immunoreactive for c-KIT. Sex cord-stromal cells of gonadoblastoma were immunoreactive for α-inhibin. The sex cord-stromal tumour was immunoreactive for AE1/AE3, occasionally for α-inhibin and negative for epithelial membrane antigen (EMA). The karyotype was 78, XX and PCR analysis confirmed the absence of the Y chromosome. CONCLUSION: Based on these findings, a diagnosis of gonadoblastoma with proliferation of dysgerminoma and sex cord-stromal tumour was made. This is the first case of ovarian gonadoblastoma in a female dog.


Assuntos
Disgerminoma/diagnóstico , Gonadoblastoma/diagnóstico , Neoplasias Ovarianas/diagnóstico , Tumores do Estroma Gonadal e dos Cordões Sexuais/diagnóstico , Adulto , Animais , Proliferação de Células/genética , Doenças do Cão/diagnóstico , Doenças do Cão/patologia , Cães , Disgerminoma/complicações , Disgerminoma/patologia , Disgerminoma/veterinária , Feminino , Gonadoblastoma/complicações , Gonadoblastoma/patologia , Gonadoblastoma/veterinária , Humanos , Cariótipo , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/veterinária , Ovário/patologia , Fenótipo , Proteínas Proto-Oncogênicas c-kit/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/complicações , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/veterinária , Células Estromais/patologia , Cromossomo Y/genética
15.
BMC Cancer ; 19(1): 913, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31514735

RESUMO

BACKGROUND: Gastrointestinal stromal tumor (GIST) is the most common primary mesenchymal neoplasm of the gastrointestinal tract. Mutations of KIT and platelet-derived growth factor receptor alpha have been well characterized in GISTs. Patients with KIT mutations are generally sensitive to treatment with tyrosine kinase inhibitors. However, some patients with GIST, while initially sensitive to TKIs, gain resistance in later stages of treatment. Heterologous rhabdomyomsarcomatous dedifferentiation of advanced GISTs after long-term imatinib mesylate (IM) therapy has been reported. In these cases, the underlying molecular mechanism of tumor progression and transformation is unclear. CASE PRESENTATION: We report one such patient with rhabdomyosarcomatous dedifferentiation of a GIST without metastatic disease after brief 3-month therapy with IM. The tumor was composed of two distinct phenotypes, a CD117 negative region with rhabdomyosarcomatous differentiation directly adjacent to a CD117 positive classic GIST region. Molecular analysis identified the activating KIT exon 11 mutation in both regions, indicating a common origin for both phenotypes. Additionally, the dedifferentiated component contained two synonymous variants in platelet-derived growth factor receptor alpha and KIT. The increased number of synonymous variants in the rhabdomyosarcomatous region may reflect increased genetic instability of this tumor that may have resulted in the loss of CD117 expression in the dedifferentiated component. CONCLUSION: This study adds to the growing consensus that rhabdomyosarcomatous GIST progresses from a common GIST primary tumor. The role of IM in this progression is uncertain; however short duration of IM treatment in this study supports the hypothesis that rhabdomyosarcomatous GIST progression is not a consequence of IM therapy. Furthermore, we provide additional information supporting the observation that CD117 negative rhabdomyosarcomatous transformation maintains the activating KIT variant without KIT expression.


Assuntos
Transformação Celular Neoplásica , Tumores do Estroma Gastrointestinal/diagnóstico , Rabdomiossarcoma/patologia , Idoso , Transformação Celular Neoplásica/genética , Análise Citogenética , Tumores do Estroma Gastrointestinal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Rabdomiossarcoma/diagnóstico por imagem , Rabdomiossarcoma/genética , Tomografia Computadorizada por Raios X
16.
J Exp Clin Cancer Res ; 38(1): 334, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370857

RESUMO

BACKGROUND: Runt-related transcription factor 1 (RUNX1) plays the roles of an oncogene and an anti-oncogene in epithelial tumours, and abnormally elevated RUNX1 has been suggested to contribute to the carcinogenesis of colorectal cancer (CRC). However, the mechanism remains unclear. METHODS: The expression of RUNX1 in CRC and normal tissues was detected by real-time quantitative PCR and Western blotting. The effect of RUNX1 on CRC migration and invasion was conducted by functional experiments in vitro and in vivo. Chromatin Immunoprecipitation assay verified the direct regulation of RUNX1 on the promoter of the KIT, which leads to the activation of Wnt/ß-catenin signaling. RESULTS: RUNX1 expression is upregulated in CRC tissues. Upregulated RUNX1 promotes cell metastasis and epithelial to mesenchymal transition (EMT) of CRC both in vitro and in vivo. Furthermore, RUNX1 can activate Wnt/ß-catenin signalling in CRC cells by directly interacting with ß-catenin and targeting the promoter and enhancer regions of KIT to promote KIT transcription. These observations demonstrate that RUNX1 upregulation is a common event in CRC specimens and is closely correlated with cancer metastasis and that RUNX1 promotes EMT of CRC cells by activating Wnt/ß-catenin signalling. Moreover, RUNX1 is regulated by Wnt/ß-catenin. CONCLUSION: Our findings first demonstrate that RUNX1 promotes CRC metastasis by activating the Wnt/ß-catenin signalling pathway and EMT.


Assuntos
Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Transição Epitelial-Mesenquimal , Via de Sinalização Wnt , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/genética , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Metástase Neoplásica , Regiões Promotoras Genéticas , Ligação Proteica , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , beta Catenina/metabolismo
17.
Drug Des Devel Ther ; 13: 2371-2379, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31409971

RESUMO

Background: Cervical cancer is the second most common malignant cancer in women worldwide. Evidence indicated that miR-664 was significantly downregulated in cervical cancer. However, the mechanisms by which miR-664 regulates the tumorigenesis of cervical cancer remain unclear. Thus, this study aimed to investigate the role of miR-664 in cervical cancer. Methods: Quantitative reverse transcription polymerase chain reaction was used to detect the level of miR-664 in tumor tissues and cell line. The dual luciferase reporter system assay and Western blotting were used to explore the interaction of miR-664 and c-Kit in cervical cancer. Results: The expression of miR-664 in patients with cervical cancer was dramatically decreased compared with that in adjacent tissues. MiR-664 mimics significantly inhibited proliferation in SiHa cells via inducing apoptosis. In addition, miR-664 mimics induced apoptosis in SiHa cells via increasing the expressions of Bax and active caspase 3 and decreasing the level of Bcl-2. Moreover, dual-luciferase assay showed that c-Kit was the directly binding target of miR-664 in SiHa cells; overexpression of miR-664 downregulated the expression of c-Kit. Meanwhile, upregulation of miR-664 significantly decreased the levels of c-Myc and Cyclin D in cells. Furthermore, miR-664 markedly inhibited tumor growth of cervical cancer in xenograft. Conclusion: Our data indicated that miR-664 exerted antitumor effects on SiHa cells by directly targeting c-Kit in vitro and in vivo. Therefore, miR-664 might be a potential therapeutic target for the treatment of patients with cervical cancer.


Assuntos
MicroRNAs/farmacologia , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismo
18.
BMC Cancer ; 19(1): 805, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412814

RESUMO

BACKGROUND: Clinical features of Asian melanoma patients are distinct from those of Western patients. This study was designed to determine the molecular and clinical characteristics of Asian melanoma patients treated with anti-PD-1 antibody. METHODS: Patients with recurrent or metastatic melanoma who began anti-PD-1 antibody therapy between January 2015 and April 2018 were retrospectively reviewed. Patients who underwent next-generation sequencing were also analyzed. RESULTS: A total of 152 patients were included. The median age was 61 years, and 53% of patients were female. A total of 56 patients (37%) received immunotherapy as second-line or greater chemotherapy. Primary sites were acral (38%), mucosal (31%), cutaneous (24%), uveal (2%), and unknown (5%). The overall response rate was 17% (95% CI, 11-22%), and disease control rate was 60% (95% CI, 52-68%). The median progression-free survival (PFS) was 4.2 months (95% CI, 1.8-6.6 months), and median overall survival (OS) was 32.9 months (95% CI, 20.0-45.7 months). However, BRAFV600 and KIT mutational statuses were not associated with response or survival. High neutrophil-lymphocyte ratio (NLR) was associated with poor PFS (median PFS 6.9 vs. 2.4 months, p = 0.015) and OS (median OS NR vs. 10.4 months, p < 0.001). In multivariate analysis, high NLR independently predicted poor survival. CONCLUSION: This study includes the largest set of integrated genomic data analyzing Asian patients with melanoma treated with immunotherapy. BRAF V600 and KIT mutational statuses were not associated with response or survival, and high NLR was a strong predictor of poor response to and survival with anti-PD-1 therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Melanoma/terapia , Receptor de Morte Celular Programada 1/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Humanos , Imunoterapia , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Melanoma/patologia , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Neutrófilos/metabolismo , Neutrófilos/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
19.
Pediatr Blood Cancer ; 66(11): e27951, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31368255
20.
Fish Shellfish Immunol ; 93: 801-814, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31419534

RESUMO

The signaling mediated by small non-proteinogenic molecules, which probably have the capacity to serve as a bridge amongst complex systems is one of the most exiting challenges for the study. In the current report, stem cells differentiation of the immune system in Nile tilapia treated with sub-basal doses of GABA evaluated as c-kit+ and Sca-1+ cells disappearance on pronephros, thymus, spleen and peripheral blood mononuclear cells by flow cytometry was assessed. Explanation of biological response was performed by molecular docking approach and multiparametric analysis. Stem cell differentiation depends on a delicate balance of negative and positive interactions of this neurotransmitter with receptors and transcription factors involved in this process. This in turn depends on the type of interaction with hematopoietic niche to differentiate into primordial, early or late hematopoiesis as well as from the dose delivery. In fish treated with the low doses of GABA (0.1% over basal value) primordial hematopoiesis is regulated by interaction of glutamate (Glu) with the Ly-6 antigen. Early hematopoiesis was influenced by the bond of GABA near or adjacent to turns of FLTR3-Ig-IV domain. During late hematopoiesis, negative regulation by structural modifications on PU.1/IRF-4 complex, IL-7Rα and GM-CSFR mainly prevails. Results of molecular docking were in agreement with the percentages of the main blood cells lineages estimated in pronephros by flow cytometry. Current study provides the first evidences about the role of inhibitory and excitatory neurotransmitters such as GABA and Glu, respectively with the most transcriptional factors and receptors involved on hematopoiesis in adult Nile tilapia.


Assuntos
Ciclídeos/fisiologia , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Células-Tronco Hematopoéticas/fisiologia , Animais , Antígenos Ly/genética , Antígenos Ly/imunologia , Diferenciação Celular/fisiologia , Ciclídeos/imunologia , Células-Tronco Hematopoéticas/imunologia , Sistema Imunitário/fisiologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/imunologia , Ácido gama-Aminobutírico/farmacologia
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