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1.
Zhonghua Zhong Liu Za Zhi ; 42(5): 391-395, 2020 May 23.
Artigo em Chinês | MEDLINE | ID: mdl-32482028

RESUMO

Objective: To investigate the expression of IGF1R-Ras and RAGE-HMGB1 signaling pathways in colorectal cancer patients with type 2 diabetes mellitus and their significance. Methods: The resected cancer tissues were obtained from 59 patients with colorectal cancer (CRC), including 29 patients with type 2 diabetes mellitus (CRC/DM group) and 30 with CRC alone (CRC group). The expressions of IGF1R, Ras, RAGE and HMGB1 in cancer tissues were detected by immunohistochemistry. The differences between the two groups were compared and the relationship between the expression and clinicopathological characteristics was analyzed. Results: In CRC/DM group, the positive rates of IGF1R and Ras were both 65.5% (19/29), and 51.7% (15/29) patients had IGF1R+ Ras+ immunophenotype, which were significantly higher than those in CRC group [33.3% (10/30), 36.7% (11/30) and 20.0% (6/30); P=0.013, 0.027 and 0.011, respectively]. The expression of IGF1R and Ras in CRC / DM group was positively correlated (r=0.479, P=0.017). The positive rate of RAGE expression in CRC group and CRC/DM group was 70.0% (21/30) and 72.4% (21/29) respectively, and the positive rate of HMGB1 expression was 46.7% (14/30) and 58.6% (17/29) respectively, neither was observed with significant difference (P=0.358 and 0.838). However, the proportion of patients with RAGE+ HMGB1+ immunophenotype in CRC/DM group [55.2% (16/29)] was higher than that in CRC Group [26.7% (8/30)] which was statistically significant (P=0.026), and the expression of both proteins was positively correlated in CRC/DM group (r=0.578, P=0.003). The clinicopathological analysis showed that in both groups the expression of IGF1R, Ras, RAGE and HMGB1 had no correlation with the sex, age, differentiation degree, tumor length, T stage and lymph node metastasis (P>0.05). Conclusion: Both IGF1R-Ras and RAGE-HMGB1 pathways may be involved in the oncogenesis of colorectal cancer in patients with type 2 diabetes.


Assuntos
Neoplasias Colorretais/patologia , Diabetes Mellitus Tipo 2/complicações , Genes ras/genética , Proteína HMGB1/metabolismo , Receptor IGF Tipo 1/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/complicações , Neoplasias Colorretais/metabolismo , Proteína HMGB1/genética , Humanos , Prognóstico , Receptor IGF Tipo 1/genética
2.
Life Sci ; 255: 117816, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32454155

RESUMO

Non-small cell lung cancer (NSCLC) with RAS -mutant gene has been the most difficult obstacle to overcome. Over 25% of muted lung adenocarcinomas have RAS mutation. The prognosis of NSCLC patients with RAS-mutant genes is always poor because there is no effective drug to suppress RAS-mutant genes. NSCLC patients with RAS-mutant usually develop resistance to radiotherapy and chemotherapy, which in some cases leads to a 5-10% survival rate for non-small cell lung cancer (NSCLC). As little clinical symptom of NSCLC was presented at its early stages, thus it always brings in disappointing treatment outcome. Currently, NSCLC presents the highest morbidity and mortality all over the world. The combination of PI3K/AKT/mTOR pathway inhibitors with radiotherapy is a novel strategy to improve radiosensitivity and therapeutic outcome of NSCLC with a RAS-mutant gene. There have been many preclinical studies and clinical trials on the effect of PI3K/AKT/mTOR pathway inhibitors combined with radiotherapy in NSCLC with a RAS-mutant gene have been reported in the past years. This review provides current knowledge of the combination of PI3K/Akt/mTOR pathway inhibitors with radiotherapy, which prove to be a significant improvement for the treatment of NSCLC patients with RAS mutations and will benefit NSCLC patients with RAS mutations.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Genes ras/genética , Neoplasias Pulmonares/terapia , Animais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Terapia Combinada , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Fosfatidilinositol 3-Quinase/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo
3.
J Cancer Res Clin Oncol ; 146(6): 1427-1440, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32300865

RESUMO

PURPOSE: RAS mutational status in colorectal cancer (CRC) represents a predictive biomarker of response to anti-EGFR therapy, but to date it cannot be considered an appropriate biomarker of response to anti-VEGF therapy. To elucidate the function of K-Ras in promoting angiogenesis, the effect of conditioned media from KRAS mutated and wild type colon cancer cell lines on HUVECs tubule formation ability and the correspondent production of pro-angiogenic factors have been evaluated by a specific ELISA assay. METHODS: Ras-activated signaling pathways were compared by western blot analysis and RTq-PCR. In addition, VEGF, IL-8, bFGF and HIF-1α expression was determined in K-RAS silenced cells. Furthermore, we conducted an observational study in a cohort of RAS mutated metastatic CRC patients, treated with first-line bevacizumab-based regimens, evaluating VEGF-A and IL-8 plasma levels at baseline, and during treatment. RESULTS: K-RAS promotes VEGF production by cancer cell lines. At the transcriptional level, this is reflected to a K-RAS dependent HIF-1α over-expression. Moreover, the HIF-1α, VEGF and FGF expression inhibition in KRAS knocked cells confirmed these results. Within the clinical part, no statistically significant correlation has been found between progression-free survival (PFS) and VEGF-A/IL-8 levels, but we cannot exclude that these biomarkers could be further investigated as predictive or prognostic biomarkers in this setting. CONCLUSION: Our study confirmed the direct involvement of K-Ras in promoting angiogenesis into colon cancer cell lines.


Assuntos
Indutores da Angiogênese/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias do Colo/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/patologia , Meios de Cultivo Condicionados , Inativação Gênica , Genes ras , Células Endoteliais da Veia Umbilical Humana , Humanos , Interleucina-8/metabolismo , Modelos Biológicos , Mutação , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Zhonghua Bing Li Xue Za Zhi ; 49(3): 256-261, 2020 Mar 08.
Artigo em Chinês | MEDLINE | ID: mdl-32187898

RESUMO

Objective: To investigate the frequency and clinical significance of RAS mutation in thyroid tumors with follicular differentiation. Methods: The samples and clinical data of 207 patients with thyroid follicular-differentiated tumors were collected at Shunyi Region Hospital of Beijing from January 2000 to December 2017, including 60 cases of follicular variant of papillary thyroid carcinoma (FVPTC), 42 cases of classical papillary thyroid carcinoma (CPTC), 26 cases of follicular thyroid carcinoma (FTC), 40 cases of follicular adenoma (FTA) and 39 cases of adenomatoid hyperplasia. BRAF V600E mutations were detected using immunohistochemical staining. FVPTC was divided into BRAF-like (BRAF V600E mutant) and RAS-like (without BRAF V600E mutant). Real-time fluorescence quantitative polymerase chain reaction was used to detect the RAS mutation in RAS-like FVPTC, CPTC, FTC, FTA and adenomatoid hyperplasia. The genetic differences in RAS mutation and their correlation with clinicopathological features were analyzed. Results: The average age of patients with benign and malignant tumors in thyroid with follicular differentiation was 53.2 years and 47.7 years, respectively. In these patients, 42 were male and165 were female. Most of the tumors had a maximum diameter of less than 4 cm, and rarely spread to the surrounding tissues of thyroid and were at early stage (stages Ⅰ and Ⅱ). The diameter of tumors in FTC was significantly larger than that in RAS-like FVPTC and CPTC groups (P<0.01). Peripheral thyroid invasion was rare in the RAS-like FVPTC, CPTC and FTC groups, but the clinical stage of FTC was more advanced than that of RAS-like FVPTC group (P<0.01) or CPTC group (P<0.01). The real-time fluorescence quantitative PCR showed that the RAS mutation rate in FTC was the highest (61.5%), significantly higher than that in others (P<0.01). The RAS mutation rate in CPTC was the lowest (4.8%), while those in RAS-like FVPTC, FTA and adenomatous hyperplasia were similar (about 15%). The Spearman rank correlation analysis showed that the RAS mutation was not correlated with age, sex or tumor size in benign lesions (FTA and adenomatous hyperplasia), nor was it associated with age, sex, tumor size, lymph node metastasis, spreading of tumors to thyroid and clinical stage in malignant tumors (RAS-like FVPTC, CPTC and FTC). Conclusions: RAS mutation can occur in both benign and malignant thyroid tumors with follicular differentiation, in which the incidence is the highest in FTC. Both morphologic and immunohistochemical changes should be taken into account. The molecular genetics of RAS-like FVPTC is similar to FTA and adenomatous hyperplasia. RAS gene mutation appears not to be a prognostic factor for thyroid diseases.


Assuntos
Carcinoma Papilar, Variante Folicular , Neoplasias da Glândula Tireoide , Feminino , Genes ras , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas B-raf
5.
Zhonghua Yi Xue Za Zhi ; 100(4): 301-306, 2020 Feb 04.
Artigo em Chinês | MEDLINE | ID: mdl-32075360

RESUMO

Objective: To investigate the clinicopathological characteristics, MSI and K-ras mutation of double primary malignancies (DPM) associated with colorectal cancer (CRC). Methods: From January 2015 to December 2016, the clinicopathological data of CRC patients treated by surgery in the Affiliated Drum Tower Hospital of Nanjing University Medical School were collected, and the clinical data was analyzed. Multiplex real-time fluorescence quantitative PCR and amplification refractory mutation was performed to identify MSI and K-ras gene mutations. Results: Of all patients with CRC, 5.2% (55/1 066) were DPM. There was no significant difference in the male and female ratio, age, colorectal cancer site, T stage, N stage composition ratio between DPM patients with CRC and patients with single CRC (P>0.05). There were significant difference of TNM stage between the two group (P<0.05). The most frequent location of CRC was the colon in both DPM patients with CRC and patients with single CRC[35.5% (359/1 011) and 41.8% (23/55), respectively]. Of 55 DPM patients with CRC, 48 were metachronous DPM patients, 7 were synchronous DPM patients and 41 were colorectal cancer first. In extracolonic organ, digestive system (23/55) was the most commonly occurring system and stomach (11/55) was the most common lesion. DPM patients with CRC had higher incidence of MSI-H than patients with single CRC (P<0.05). There was no significant difference of K-ras gene mutation between DPM patients with CRC and patients with single CRC (P>0.05). MSI-H and K-ras mutation were present in only 2 patients of DPM patients with CRC. Conclusions: The rectum is the most common lesion site in CRC patients. The stomach is the most common extracolonic organ of DPM patients with CRC. DPM patients with CRC has high risk of MSI-H, but no significant difference in the incidence of K-ras mutation.


Assuntos
Neoplasias Colorretais , Genes ras , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Instabilidade de Microssatélites , Mutação , Estadiamento de Neoplasias
6.
Bull Cancer ; 107(4): 499-505, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32063345

RESUMO

Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.


Assuntos
Tumores do Estroma Gastrointestinal/genética , Condroma/genética , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/terapia , Genes ras , Humanos , Leiomiossarcoma/genética , Neoplasias Pulmonares/genética , Mutação , Neurofibromatose 1/genética , Paraganglioma Extrassuprarrenal/genética , Doenças Raras , Receptores Proteína Tirosina Quinases/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Neoplasias Gástricas/genética , Succinato Desidrogenase/deficiência
8.
Value Health ; 23(1): 114-126, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31952666

RESUMO

BACKGROUND: Monoclonal antibodies against epidermal growth factor receptor (EGFR) have proved beneficial for the treatment of metastatic colorectal cancer (mCRC), particularly when combined with predictive biomarkers of response. International guidelines recommend anti-EGFR therapy only for RAS (NRAS,KRAS) wild-type tumors because tumors with RAS mutations are unlikely to benefit. OBJECTIVES: We aimed to review the cost-effectiveness of RAS testing in mCRC patients before anti-EGFR therapy and to assess how well economic evaluations adhere to guidelines. METHODS: A systematic review of full economic evaluations comparing RAS testing with no testing was performed for articles published in English between 2000 and 2018. Study quality was assessed using the Quality of Health Economic Studies scale, and the British Medical Journal and the Philips checklists. RESULTS: Six economic evaluations (2 cost-effectiveness analyses, 2 cost-utility analyses, and 2 combined cost-effectiveness and cost-utility analyses) were included. All studies were of good quality and adopted the perspective of the healthcare system/payer; accordingly, only direct medical costs were considered. Four studies presented testing strategies with a favorable incremental cost-effectiveness ratio under the National Institute for Clinical Excellence (£20 000-£30 000/QALY) and the US ($50 000-$100 000/QALY) thresholds. CONCLUSIONS: Testing mCRC patients for RAS status and administering EGFR inhibitors only to patients with RAS wild-type tumors is a more cost-effective strategy than treating all patients without testing. The treatment of mCRC is becoming more personalized, which is essential to avoid inappropriate therapy and unnecessarily high healthcare costs. Future economic assessments should take into account other parameters that reflect the real world (eg, NRAS mutation analysis, toxicity of biological agents, genetic test sensitivity and specificity).


Assuntos
Neoplasias Colorretais/economia , Neoplasias Colorretais/genética , Análise Mutacional de DNA/economia , Genes ras , Custos de Cuidados de Saúde , Mutação , Testes Farmacogenômicos/economia , Variantes Farmacogenômicos , Medicina de Precisão/economia , Antineoplásicos Imunológicos/economia , Antineoplásicos Imunológicos/uso terapêutico , Tomada de Decisão Clínica , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Análise Custo-Benefício , Custos de Medicamentos , Receptores ErbB/antagonistas & inibidores , Predisposição Genética para Doença , Humanos , Metástase Neoplásica , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Anos de Vida Ajustados por Qualidade de Vida
9.
Appl Biochem Biotechnol ; 190(2): 703-711, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31475312

RESUMO

Colorectal cancer (CRC) ranks among the most prevalent cancer types in both men and women. Screening of RAS (Kirsten rat sarcoma viral oncogene homolog (KRAS), neuro-blastoma RAS viral oncogene homolog (NRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF)) somatic mutations is necessary prior to considering anti-epidermal growth factor receptor (EGFR) therapies in CRC patients. Next-generation sequencing studies have confirmed that RAS gene panels could be used while developing treatment strategies for patients with CRC. The present study explored genetic mutations in KRAS, NRAS, and BRAF in CRC patients in the Telangana state of India. Patients with confirmed CRC (n = 100) who visited the Apollo hospitals were evaluated. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissues, and pyrosequencing analysis was performed. Patient DNA samples were screened for 54 different KRAS, NRAS, and BRAF mutations, which revealed 34 somatic mutations. Exon 11 of BRAF possessed 4 mutations with highest individuals documented with G469A mutation. Pyrosequencing, a reliable method for analyzing somatic mutations present in RAS, could aid in taking treatment decisions for patients with CRC.


Assuntos
Neoplasias Colorretais/genética , Genes ras , Mutação , Estudos de Casos e Controles , Cidades , Predisposição Genética para Doença , Humanos , Índia
10.
Gene ; 727: 144262, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31759987

RESUMO

Neuroblastoma is an extracranial solid tumor that mainly occurs in childhood. Mutations of NRAS gene have been described in several cancers. However, whether NRAS gene polymorphisms can predict the risk of neuroblastoma have not been investigated. We hypothesized that variations of NRAS gene contribute to neuroblastoma predisposition. Therefore, we conducted a multi-center case-control study using 263 cases and 715 controls to examine the association of NRAS gene rs2273267 A>T polymorphism and neuroblastoma risk. We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the strength of the associations. Relative to those with AA genotype, subjects with AT/TT genotype had reduced neuroblastoma risk (adjusted OR = 0.72, 95% CI = 0.54-0.96, P = 0.024). Stratified analysis revealed that rs2273267 AT/TT carriers were less likely to develop neuroblastoma for patients with tumor originating from the adrenal gland (adjusted OR = 0.67, 95% CI = 0.45-0.99, P = 0.047) and clinical stages III + IV (adjusted OR = 0.57, 95% CI = 0.36-0.90, P = 0.015). Our findings underline the likely importance of NRAS gene rs2273267 A>T in the risk of neuroblastoma. Further independent case-control studies with functional analysis are needed to verify the role of NRAS gene rs2273267 A>T polymorphism in the risk of neuroblastoma.


Assuntos
GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Neuroblastoma/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Feminino , GTP Fosfo-Hidrolases/metabolismo , Frequência do Gene/genética , Genes ras/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Lactente , Masculino , Proteínas de Membrana/metabolismo , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
11.
Growth Factors ; 37(5-6): 209-225, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31878812

RESUMO

The discovery of epidermal growth factor (EGF) and its receptor (EGFR) revealed the connection between EGF-like ligands, signaling from the EGFR family members and cancer. Over the next fifty years, analysis of EGFR expression and mutation led to the use of monoclonal antibodies to target EGFR in the treatment of metastatic colorectal cancer (mCRC) and this treatment has improved outcomes for patients. The use of the RAS oncogene mutational status has helped to refine patient selection for EGFR antibody therapy, but an effective molecular predictor of likely responders is lacking. This review analyzes the potential utility of measuring the expression, levels and activation of EGF-like ligands and associated processes as prognostic or predictive markers for the identification of patient risk and more effective mCRC therapies.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Família de Proteínas EGF/metabolismo , Mutação , Metástase Neoplásica/tratamento farmacológico , Anticorpos Monoclonais/metabolismo , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/metabolismo , Receptores ErbB/metabolismo , Genes ras , Humanos , Ligantes , Seleção de Pacientes , Medicina de Precisão , Risco , Transdução de Sinais , Resultado do Tratamento
13.
Anal Chim Acta ; 1092: 49-56, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31708032

RESUMO

The studied challenge is the specific detection of low-abundant genomic variants that differ by a single nucleotide from the wild type. The combination of blocked recombinase polymerase amplification (RPA) and selective capture by probes immobilised on magnetic-core particles integrated into a flow system is presented. The sensing principle was demonstrated as the effective concentration-detection of the specific generated products was achieved. The analytical performance of resulting assay was successfully compared to PCR-based methods or array formats, providing faster effective detection of the selective products. As proof of concept, the single-nucleotide substitutions of the KRAS gene at codon 12 were studied in chip with parallel microchambers and permanent magnets. The blocked RPA products (generated at 37 °C) from tumour biopsies (extracted DNA 4 ng) provided a specific fluorescent bead-line that depends on the present mutation. The results agree with those reported by next-generation sequencing and provide new opportunities for in vitro diagnostic and personalised medicine.


Assuntos
Alelos , Biomarcadores Tumorais/análise , DNA/análise , Proteínas Proto-Oncogênicas p21(ras)/genética , Biomarcadores Tumorais/genética , DNA/genética , Sondas de DNA/química , Sondas de DNA/genética , Corantes Fluorescentes/química , Genes ras , Humanos , Dispositivos Lab-On-A-Chip , Limite de Detecção , Fenômenos Magnéticos , Microscopia de Fluorescência , Mutação , Técnicas de Amplificação de Ácido Nucleico/instrumentação , Técnicas de Amplificação de Ácido Nucleico/métodos , Hibridização de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Estudo de Prova de Conceito
14.
PLoS One ; 14(10): e0224600, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31671149

RESUMO

Mitogen-activated protein kinase (MAPK) kinase (MEK) is an integral component of the RAS pathway and a therapeutic target in RAS-driven cancers. Although tumor responses to MEK inhibition are rarely durable, MEK inhibitors have shown substantial activity and durable tumor regressions when combined with systemic immunotherapies in preclinical models of RAS-driven tumors. MEK inhibitors have been shown to potentiate anti-tumor T cell immunity, but little is known about the effects of MEK inhibition on other immune subsets, including B cells. We show here that treatment with a MEK inhibitor reduces B regulatory cells (Bregs) in vitro, and reduces the number of Bregs in tumor draining lymph nodes in a colorectal cancer model in vivo. MEK inhibition does not impede anti-tumor humoral immunity, and B cells contribute meaningfully to anti-tumor immunity in the context of MEK inhibitor therapy. Treatment with a MEK inhibitor is associated with improved T cell infiltration and an enhanced response to anti-PD1 immunotherapy. Together these data indicate that MEK inhibition may reduce Bregs while sparing anti-tumor B cell function, resulting in enhanced anti-tumor immunity.


Assuntos
Linfócitos B Reguladores/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Animais , Azetidinas/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Genes ras/efeitos dos fármacos , Humanos , Imunoterapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Mikrochim Acta ; 186(12): 843, 2019 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-31768709

RESUMO

Voltammetric detection of the K-ras gene fragment was accomplished through the combined application of (a) a switchable DNA nanostructure, (b) the use of hairpin probe and exonuclease III (Exo III)-assisted signal amplification, (c) a split G-quadruplex, and (d) by exploiting the redox activity of DNAzyme. Three assistant oligonucleotides were designed to construct a DNA tweezer on a gold electrode. It is in "open state" in the absence of K-ras DNA. Then, a hairpin probe was introduced, whose stem-loop structure can be opened through hybridization with the K-ras DNA. Exo III is added which hydrolyzes the complementary region of the hairpin sequence to release a single-stranded rest fragment. The ssDNA hybridizes with the DNA tweezer on the electrode which thereby is switched to the "closed state". This leads to the formation of G-quadruplex due to the shortened distance of the split G-quadruplex-forming sequences in the tweezer. The voltammetric signal of the G-quadruplex-hemin complex, with a peak near -0.3 V vs. Ag/AgCl, is used as the signal output. Under the optimal conditions, the current response in differential pulse voltammetry (DPV) increases linearly with the concentration of K-ras DNA in the range of 0.01-1000 pM, and the detection limit is 2.4 fM. The assay can clearly discriminate K-ras DNA from a single-base mutation. The method has excellent selectivity and was applied to the determination of K-ras DNA in (spiked) serum samples. Graphical abstractSchematic representation of a method for the determination of the K-ras gene fragment through a combination of switchable DNA tweezer, split G-quadruplex, and exonuclease III (ExoIII)-assisted target recycling signal amplification.


Assuntos
Técnicas Biossensoriais/métodos , DNA/sangue , Técnicas Eletroquímicas/métodos , Genes ras , Nanoestruturas/química , Oligodesoxirribonucleotídeos/química , Sequência de Bases , DNA/genética , Técnicas Eletroquímicas/instrumentação , Eletrodos , Quadruplex G , Ouro/química , Hemina/química , Humanos , Sequências Repetidas Invertidas , Limite de Detecção , Mutação , Hibridização de Ácido Nucleico , Oligodesoxirribonucleotídeos/genética
16.
J Evid Based Med ; 12(4): 300-312, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31596544

RESUMO

OBJECTIVES: To investigate the efficacy and safety of adding anti-epidermal growth factor receptor [EGFR] MoAbs to various chemotherapy regimens in patients with RAS wild-type metastasized colorectal cancer (RAS WT metastatic colorectal cancer [mCRC]) and to identify the optimal combination regimens. METHODS: We searched MEDLINE, EMBASE, and CENTRAL from the inception date to 20th May 2019. Randomized clinical trials investigating chemotherapy with or without anti-EGFR MoAbs in treatment of patients with RAS WT mCRC were included. RESULTS: Eighteen studies involving 8848 participants were eligible. Comparing with oxaliplatin-based chemotherapy, adding anti-EGFR MoAbs benefited only in progression-free survival (PFS) (hazard ratio [HR] = 0.80, 95% confidence interval [CI]: 0.67 to 0.94), but not in overall survival (OS) (HR = 0.89, 95% CI: 0.78 to 1.02). Further sensitivity analysis indicated that adding anti-EGFR MoAbs to FOLFOLX regimen as a first-line treatment showed benefits in both PFS and OS (PFS: HR = 0.74, 95% CI: 0.64 to 0.84; OS: HR = 0.83, 95% CI: 0.73 to 0.95, respectively). Comparing with irinotecan-based chemotherapy or best supportive care, adding anti-EGFR MoAbs revealed an improvement in both PFS (HR = 0.77, 95% CI: 0.69 to 0.86; HR = 0.46, 95% CI: 0.40 to 0.54, respectively) and OS (HR = 0.89, 95% CI: 0.80 to 0.98; HR = 0.65, 95% CI: 0.54 to 0.78, respectively). CONCLUSION: Anti-EGFR MoAbs as a monotherapy or in combination with either irinotecan-based chemotherapy or FOLFOX in patients with RAS wild-type mCRC have better response and survival outcome, whereas OS does not benefit from adding anti-EGFR MoAbs to another oxaliplatin-based regimen. Anti-EGFR MoAbs have increased the risk of adverse effects than chemotherapy alone. More high-quality randomized controlled trials for RAS wild type are necessary.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Panitumumabe/uso terapêutico , Neoplasias Colorretais/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Genes ras , Humanos , Irinotecano/uso terapêutico , Oxaliplatina/uso terapêutico
18.
Anticancer Res ; 39(10): 5645-5652, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570462

RESUMO

BACKGROUND/AIM: The aim of our study was to assess the predictive role of primary tumour sidedness (PTS) in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS and treated with targeted agents. PATIENTS AND METHODS: The cohort included 178 patients treated with first-line chemotherapy plus cetuximab, panitumumab or bevacizumab. RESULTS: We observed longer progression-free survival (PFS) and overall survival (OS) in patients with left-sided (L-CRC) compared to right-sided tumours (R-CRC) treated with anti-EGFR mAbs (p=0.0033 and p=0.0037), while there was no difference in patients treated with bevacizumab (p=0.076 and p=0.56). Finally, we observed longer PFS and OS in patients with L-CRC treated with anti-EGFR mAbs and those with R-CRC treated with bevacizumab compared to the reverse combination (p=0.0002 and p=0.011). CONCLUSION: PTS is a predictive factor for anti-EGFR mAbs, not for bevacizumab. Superior survival was observed when anti-EGFR mAbs were used for L-CRC and bevacizumab for R-CRC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Bevacizumab/administração & dosagem , Cetuximab/administração & dosagem , Neoplasias Colorretais/genética , Intervalo Livre de Doença , Receptores ErbB/genética , Feminino , Genes ras/genética , Humanos , Masculino , Panitumumabe/administração & dosagem
19.
Radiol Oncol ; 53(3): 265-274, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31553708

RESUMO

Background Colorectal cancer is a successful model of genetic biomarker development in oncology. Currently, several predictive or prognostic genetic alterations have been identified and are used in clinical practice. The RAS gene family, which includes KRAS and NRAS act as predictors for anti-epithelial growth factor receptor treatment (anti-EGFR), and it has been suggested that NRAS mutations also play a role in prognosis: patients harboring NRAS alterations have a significantly shorter survival compared to those with wild type tumours. BRAF V600E mutations are rare and occur mostly in tumors located in the ascending colon in elderly female patients. BRAF is instrumental in establishing prognosis: survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognostic factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative predictive factor for anti-EGFR therapies. Two new biomarkers have recently been added to the metastatic colorectal cancer panel: HER2 and microsatellite instability. While HER2 is still being investigated in different prospective studies in order to validate its prognostic role, microsatellite instability already guides clinical decisions in substituted with advanced colorectal cancer. Conclusions There are current evidences that support using above mentioned genetic biomarkers to better identify the right medicine that is supposed to be used in the right patient. This approach contributes to a more individualized patient-oriented treatment in daily clinical practice.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes erbB-2 , Genes ras , Instabilidade de Microssatélites , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Receptores ErbB/antagonistas & inibidores , Feminino , Marcadores Genéticos , Humanos , Ipilimumab/uso terapêutico , Masculino , Panitumumabe/uso terapêutico , Prognóstico , Fatores Sexuais , Trastuzumab/uso terapêutico
20.
Clin Chim Acta ; 498: 47-51, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31430440

RESUMO

Pancreatic cancer is one of the deadliest cancers having an exceptionally high mortality rate. Despite a relatively low incidence (10th among cancers), it is the fourth leading cause of cancer-related deaths in most developed countries. Improving early diagnosis of pancreatic cancer and strengthening the standardised comprehensive treatment remain the main focus of pancreatic cancer research. Tumor markers are usually tumor-associated proteins of clinical relevance in these patients. Although tumor markers carbohydrate antigen (CA 19-9) and carcino-embryonic antigen (CEA) are commonly used, neither demonstrate high diagnostic accuracy. Recently, hematopoietic growth factors (HGFs) and various enzymes have been reported as potential biomarkers for pancreatic cancer. These include macrophage-colony stimulating factor (M-CSF) and granulocyte-colony stimulating factor (G-CSF), interleukin-3 (IL-3), macrophage inhibitory cytokine (MIC-1) and various enzymes (alcohol dehydrogenase, aldehyde dehydrogenase, lysosomal exoglycosidases). With the development of molecular technology, detecting K-ras mutation in serum via polymerase chain reaction (PCR) is becoming more common and efficient. Because K-ras mutation rates are high in many cancers, some regard it as a potential tumor marker. Others have shown the value of serum miRNAs in detection of pancreatic cancer. Unfortunately, there are currently no effective methods of sufficient diagnostic accuracy to detect early-stage surgically resectable pancreatic cancer. In this article we highlight these biomarkers and summarise recent developments in the diagnosis and treatment of pancreatic cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias Pancreáticas/diagnóstico , Patologia Molecular/métodos , Animais , Genes ras/genética , Humanos , Mutação , Neoplasias Pancreáticas/terapia , Patologia Molecular/tendências , Reação em Cadeia da Polimerase
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