RESUMO
Heart failure (HF) is a significant public health problem worldwide. It has long been noted that premenopausal women, compared to postmenopausal women and men, have lower rates for developing this disease, as well as subsequent morbidity and mortality. This difference has been attributed to estrogen playing a cardioprotective role in these women, though exactly how it does so remains unclear. In this review, we examine the presence of estrogen receptors within the cardiovascular system, as well as the role they play behind the cardioprotective effect attributed to estrogen. Furthermore, we highlight the underlying mechanisms behind their alleviation of HF, as well as possible treatment approaches, such as hormone replacement therapy and exercise regimens, to manipulate these mechanisms in treating and preventing HF.
Assuntos
Sistema Cardiovascular , Insuficiência Cardíaca , Feminino , Humanos , Masculino , Estrogênios/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Terapia de Reposição Hormonal , Receptores de EstrogênioRESUMO
BACKGROUND: This study aimed to analyze associations between genetic variants and plasma concentrations along with clinical outcomes in dabigatran in patients with non-valvular atrial fibrillation (NVAF). METHODS: We conducted a prospective study and enrolled NVAF patients treated with dabigatran in the real world. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration. All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up. RESULTS: Eighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. There was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran (P = 0.013). Our results showed that the CES1 SNP rs8192935 significantly influenced dabigatran trough concentrations in the Chinese population, and carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 SNP c.2482-2236G > A (rs4148738) was associated with major bleeding events in the addictive model (P = 0.046, OR = 3.29) and dominant model (P = 0.040, OR = 8.17). Additionally, the ABCB1 SNP c.3435 C > T (rs1045642) was associated with the incidence of major bleeding events in the addictive model (P = 0.043, OR = 3.34) and dominant model (P = 0.046, OR = 7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events. CONCLUSION: Our results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events for the first time in a Chinese population.
Assuntos
Fibrilação Atrial , Dabigatrana , Humanos , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/genética , Antitrombinas , Estudos Prospectivos , Hemorragia/epidemiologia , Polimorfismo de Nucleotídeo Único , Anticoagulantes/uso terapêutico , Hidrolases de Éster Carboxílico/genética , Hidrolases de Éster Carboxílico/metabolismo , Hidrolases de Éster Carboxílico/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/uso terapêuticoRESUMO
Lung cancer is the first leading cause of cancer deaths. Chemotherapy toxicity is one of factors that limited the efficacy of platinum-based chemotherapy in lung cancer patients. Transporters and DNA repair genes play critical roles in occurrence of platinum-based chemotherapy toxicity. To investigate the relationships between transporter and DNA repair gene polymorphisms and platinum-based chemotherapy toxicity in lung cancer patients, we selected 60 polymorphisms in 14 transporters and DNA repair genes. The polymorphisms were genotyped in 317 lung cancer patients by Sequenom MassARRAY. Logistic regression was performed to estimate the association of toxicity outcome with the polymorphisms by PLINK. Our results showed that polymorphisms of SLC2A1 (rs3738514, rs4658, rs841844) were significantly related to overall toxicity. XRCC5 (rs1051685, rs6941) and AQP2 (10875989, rs3759125) polymorphisms were associated with hematologic toxicity. AQP2 polymorphisms (rs461872, rs7305534) were correlated with gastrointestinal toxicity. In conclusion, genotypes of these genes may be used to predict the platinum-based chemotherapy toxicity in lung cancer patients.
Assuntos
Aquaporina 2/genética , Transportador de Glucose Tipo 1/genética , Autoantígeno Ku/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Antineoplásicos/efeitos adversos , Reparo do DNA/genética , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Proteínas de Membrana Transportadoras/genética , Pessoa de Meia-IdadeRESUMO
PURPOSE: To investigate the influence of ABCB1 polymorphisms on prognostic outcomes in Chinese patients with de novo intermediate-risk acute myeloid leukemia (AML) and to examine the gene expression level in relation to the genetic variation. METHODS: In total, 263 Chinese intermediate-risk AML patients treated with anthracycline and cytarabine were enrolled. G2677T, C1236T, and C3435T of the ABCB1 gene were analyzed by the allele-specific matrix-assisted laser desorption. Expression of ABCB1 messenger RNA (mRNA) was tested in 101 patients of known genotype and haplotype for ABCB1 polymorphisms. Basic clinical characteristics of these patients were collected from medical records. RESULTS: Survival analysis showed that patients with AML (TTT haplotype) had a longer overall survival (OS) (p < 0.001, 29.2 months, 95 % confidence interval [CI], 26.9-31.5 months) and relapse-free survival (RFS) (p = 0.005, 21.8 months, 95 % CI, 19.5-24.0 months) compared with those without TTT haplotype (21.9 months, 95 % CI, 19.6-24.2 months; 16.5 months, 95 % CI, 14.6-18.5 months). After adjusting for age; gender; leukocyte count; hemoglobin level; platelet levels; French, American, and British classification; lactate dehydrogenase levels; Eastern Cooperative Oncology Group performance status; nucleophosmin gene; and fms-related tyrosine kinase 3 gene, the multivariate survival analysis showed that the TTT haplotype appeared to be a predicting factor for OS (p = 0.001, hazard ratio = 1.854, 95 % CI, 1.301-2.641) and RFS (p = 0.009, hazard ratio = 1.755, 95 % CI, 1.153-2.671). Moreover, a significant association between the TTT haplotype and relapse in AML patients was observed in this study (p = 0.002, odds ratio = 0.410, 95 % CI, 0.235-0.715). Gene expression level was significantly lower in patients with the TTT haplotype than in the patients with the other haplotypes (p = 0.004). CONCLUSIONS: The findings suggested the TTT haplotype was possibly related to the OS, RFS, and relapse in Chinese patients with AML.
Assuntos
Antraciclinas/uso terapêutico , Povo Asiático/genética , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adolescente , Adulto , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Feminino , Genótipo , Haplótipos , Humanos , Leucemia Mieloide Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Recidiva , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
AIM: Eukaryotic translation initiation factor 3 subunit A (eIF3a) plays critical roles in regulating the initiation of protein translation, and eIF3a is highly expressed in lung cancer. In this study, we investigated the association of the positively selected SNPs of eIF3a with the response to and toxicity of platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). METHODS: SNP data for eIF3a locus were downloaded from HapMap database. For each SNP, haplotype, LD profile and population differentiation were analyzed. The long-range haplotype (LRH) test was employed to identify positively selected SNPs of eIF3a. A total of 325 NSCLC patients were enrolled and genotyped for these SNPs. RESULTS: Five positively selected (rs1409314, rs4752219, rs4752220, rs7091672 and rs10510050) and 5 non-positively selected SNPs (rs10886342, rs11198804, rs2275112, rs10787899 and rs4752269) were identified in the LRH test. However, none of them was correlated with the platinum-based chemotherapy response. In contrast, 4 of the positively selected SNPs (rs1409314, rs4752219, rs4752220 and rs7091672) were significantly correlated with the toxicities tested (neutropenia, anemia, thrombocytopenia, emesis and hepatotoxicity). In addition, rs10510050 was significantly correlated with thrombocytopenia, emesis and hepatotoxicity. None of the 5 non-positively selected SNPs was correlated with the 5 toxicities. CONCLUSION: The positively selected SNPs of eIF3a are significantly correlated with platinum-based chemotherapy toxicities in Chinese NSCLC patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Fator de Iniciação 3 em Eucariotos/genética , Neoplasias Pulmonares/tratamento farmacológico , Compostos Organoplatínicos/efeitos adversos , Compostos de Platina/efeitos adversos , Polimorfismo de Nucleotídeo Único , Povo Asiático/genética , Carcinoma Pulmonar de Células não Pequenas/etnologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Distribuição de Qui-Quadrado , China/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Feminino , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Farmacogenética , Fenótipo , Fatores de Risco , Resultado do TratamentoRESUMO
This study aims to investigate the influence of ATP7B genetic polymorphism to platinum-based chemotherapy in Chinese Han lung cancer patients. A total of 338 Chinese Han lung cancer patients were enrolled in this study. All patients underwent at least two cycles of platinum-based chemotherapy. Four tag SNPs of ATP7B (rs1061472, rs9535826, rs7999812, and rs9535828) were selected to evaluate their impacts to platinum-based chemotherapy in these patients. ATP7B rs9535828 and rs9535826 were found to be associated with platinum resistance in Chinese Han lung cancer patients. Patients with A allele in ATP7B rs9535828 presented an increased susceptibility to platinum drugs (OR 1.96, 95 % CI 1.17-3.30, p < 0.01). Patients with G allele in ATP7B rs9535826 had the highest susceptibility to platinum drugs (OR 2.05, 95 % CI 1.19-3.52, p < 0.01). Our findings suggest that ATP7B genetic polymorphisms could affect the therapeutic efficacy of platinum-based chemotherapy, and ATP7B gene might be considered as predictive markers for the efficacy evaluation of platinum-based chemotherapy in Chinese Han lung cancer patients.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Transporte de Cátions/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , ATPases Transportadoras de Cobre , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Platina/uso terapêuticoRESUMO
The aim of the present study was to investigate the association of genetic polymorphisms in high mobility group box 1 and 2 (HMGB1 and HMGB2, respectively) with platinum-based chemotherapy responses in Chinese lung cancer patients. In total, 338 Chinese lung cancer patients (154 responders and 184 non-responders) were recruited to the study. All patients received at least two cycles of first-line platinum-based chemotherapy. Three tagging single nucleotide polymorphisms (SNPs) of HMGB1 and two tagging SNPs of HMGB2 were detected in patients. We found that rs1412125 and rs2249825 of HMGB1 were significantly associated with the platinum-based chemotherapy response in both recessive and genotypic models. In addition, rs1412125 showed significant association with platinum-based chemotherapy response for the subgroup of patients aged >55 years in additive, recessive and genotypic models. No significant associations were detected between other SNPs and the platinum-based chemotherapy response. The HMGB1 SNPs (rs1412125 and rs2249825) were associated with platinum-based chemotherapy responses in Chinese lung cancer patients. In conclusion, HMGB1 SNPs may serve as potential biomarkers for predicting the efficacy of platinum-based chemotherapy.
Assuntos
Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Proteína HMGB1/metabolismo , Proteína HMGB2/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Polimorfismo Genético , Antineoplásicos/uso terapêutico , Feminino , Marcadores Genéticos , Genótipo , Proteína HMGB1/genética , Proteína HMGB2/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Platinum-based chemotherapy toxicity is always one of the serious problems from which lung cancer patients suffer. The genetic polymorphism of WISP1 was revealed to be associated with susceptibility and platinum-based chemotherapy response in our previous studies. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with platinum-based chemotherapy toxicity in lung cancer patients. A total of 412 lung cancer patients were enrolled in this study, and 28 polymorphisms of the WISP1 gene were genotyped by SequenomMassARRAY. We found that WISP1 polymorphisms (rs2929965, rs2929969, rs2929970, rs2929973 and rs754958) were related to the overall chemotherapy toxicity of lung cancer in subgroup analyses. Rs16904853, rs2929970, rs2977549 and rs2977551 (p = 0.021, 0.028, 0.024, 0.048, respectively) polymorphisms were significantly associated with hematologic toxicity. Rs2929946, rs2929970, rs2977519, rs2977536, rs3739262 and rs754958 (p = 0.031, 0.046, 0.029, 0.016, 0.042, 0.035, respectively) polymorphisms were significantly associated with the gastrointestinal toxicity of lung cancer. Genotypes of WISP1 may be novel and useful biomarkers for predicting platinum-based chemotherapy toxicity in lung cancer patients.
Assuntos
Antineoplásicos/toxicidade , Proteínas de Sinalização Intercelular CCN/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Platina/toxicidade , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Membranous nephropathy (MN) and IgA nephropathy (IgAN) are the most common primary glomerulopathies worldwide. The systemic metabolic changes in the progression of MN and IgAN are not fully understood. METHODS: A total of 87 and 70 patients with MN and IgAN, respectively, and 30 healthy controls were enrolled in this study. Untargeted metabolomics was performed to explore the differential metabolites and metabolic pathways in the early stage of MN and IgAN. To judge the diagnostic ability of biomarkers, receiver operating characteristic curve analysis (ROC) were performed. RESULTS: Principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA) suggested that patients with MN and IgAN showed an obvious separation trend from the healthy controls. In addition, 155 and 148 metabolites were identified to be significantly altered in the MN and IgAN groups, respectively. Of these, 70 metabolites were markedly altered in both disease groups; six metabolites, including L-tryptophan, L-kynurenine, gamma-aminobutyric acid (GABA), indoleacetaldehyde, 5-hydroxyindoleacetylglycine, and N-alpha-acetyllysine, showed the opposite tendency. The most affected metabolic pathways included the amino acid metabolic pathways, citrate cycle, pantothenate and CoA biosynthesis, and hormone signaling pathways. CONCLUSIONS: Substantial metabolic disorders occurred during the progression of MN and IgAN. L-tryptophan, L-kynurenine, GABA, indoleacetaldehyde, 5-hydroxyindoleacetylglycine, and N-alpha-acetyllysine may show potential as biomarkers for the identification of MN and IgAN.
Assuntos
Glomerulonefrite por IGA , Glomerulonefrite Membranosa , Humanos , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite Membranosa/diagnóstico , Cinurenina , Triptofano , Biomarcadores , Ácido gama-AminobutíricoRESUMO
In this study, we aimed to investigate the expression of OX40, OX40L, PD-1 and PD-L1 in patients with unexplained recurrent spontaneous abortion (URSA) compared to normal pregnancies (NP). A total of 50 patients who were diagnosed with URSA and 41 NP were recruited to this study. Real-time polymerase chain reaction (RT-PCR) was used to determine the expression of OX40, OX40L, PD-1 and PD-L1 in decidual tissues; Immunohistochemistry (IHC) was conducted to characterize the distribution of the involved genes in decidual tissues; Double immunofluorescence staining was used to prove the localization of the involved genes in decidual tissues. The concentrations of OX40L and PD-L1 in plasma were measured with enzyme-linked immunosorbent assay (ELISA). The expression of OX40L in the decidua of URSA patients was significantly increased compared to that in the NP group, while the expression of PD-L1 in the URSA group was decreased compared to that in the NP group. Both proteins are localized in the decidual stroma as analyzed by double immunofluorescence staining. The staining results were confirmed at the mRNA level of decidual tissues, while the mRNA level of peripheral blood showed no significant difference. In conclusion, the results suggest that decidual stromal cells may promote the interaction with OX40 on T cells by upregulating the expression of OX40L and reduce the interaction with PD-1 on T cells by downregulating the expression of PD-L1 in URSA patients, which may interfere with the immune tolerance of the maternal-fetal interface, leading to poor pregnancy outcomes.
Assuntos
Aborto Habitual , Receptor de Morte Celular Programada 1 , Gravidez , Humanos , Feminino , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Aborto Habitual/genética , Decídua , RNA MensageiroRESUMO
INTRODUCTION: This study aimed to study the expression and function of kisspeptin during human uterine decidualization in recurrent spontaneous abortion (RSA) and the underlying mechanism. METHODS: All patients were recruited from the Clinical Reproductive Center of the Second Affiliated Hospital of Soochow University. Mice models of RSA (CBA/J × DBA/2) and normal pregnancy (CBA/J × BALB/c) were established, respectively. Kisspeptin expression in the serum and decidual tissues of women with RSA were detected. The function of kisspeptin during decidualization in human endometrial stromal cells (HESCs) was assessed by enhancing and silencing kisspeptin expression. CBA/J × DBA/2 pregnant mice were injected with kisspeptin polypeptide, kisspeptin receptor blocker, and expression of decidualization markers was observed. The regulation of ERK1/2 signalling pathway were verified. RESULTS: Serum kisspeptin levels were significantly lower in patients with RSA than in normal pregnant individuals, as was the expression of kisspeptin, p-ERK, and decidualization indicators in the decidua. Additionally, kisspeptin inhibition downregulated the expression of decidualization markers in HESCs. In mice with RSA, kisspeptin was significantly downregulated, and p-ERK expression at the maternal-foetal interface was significantly decreased. Moreover, exogenous kisspeptin supplementation improved the levels of IGFBP-1 and dPRL, upregulated p-ERK expression, and reduced the abortion rate. DISCUSSION: Kisspeptin is involved in promoting uterine decidualization via the ERK1/2 signalling pathway.
Assuntos
Aborto Habitual , Aborto Espontâneo , Gravidez , Humanos , Feminino , Camundongos , Animais , Aborto Espontâneo/metabolismo , Decídua/metabolismo , Kisspeptinas/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos DBA , Camundongos Endogâmicos CBA , Aborto Habitual/metabolismo , Células Estromais/metabolismoRESUMO
AIMS: The programmed death- (PD-) 1/PD-1 ligand (PD-L) pathway plays an important role in regulating T cell activation and maintaining peripheral tolerance. Accumulated studies showed that PD-1/PD-L1 pathway was involved in the development of type 1 diabetes (T1DM). Since the genetic background of type 1 diabetes differs greatly among the different population, we aim to investigate the association of genetic polymorphisms in PD-1 and PD-L1 with T1DM susceptibility in Chinese population. METHODS: In total, 166 T1DM patients and 100 healthy controls were enrolled into the study. Genomic DNA was extracted from 4 mL peripheral blood samples collected from each subject. Genotyping of 8 selected SNPs of PD-1 and PD-L1 was carried out by the pyrosequencing PSQ 24 System using PyroMark Gold reagents (QIAGEN). RESULTS: SNP rs4143815 in PD-L1 was significantly associated with T1DM. People carrying the C allele of rs4143815 suffering less risk of T1DM and T1DM patients with G/G genotype showed higher levels of autoantibody (AAB) positive incidence compared with C allele carriers. No significant associations were found in other SNPs. CONCLUSIONS: Our results indicate that rs4143815 of PD-L1 is significantly associated with T1DM and may serve as a new biomarker to predict the T1DM susceptibility.
Assuntos
Antígeno B7-H1/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Receptor de Morte Celular Programada 1/genética , Adolescente , Adulto , Alelos , China , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Chemotherapy toxicity is a serious problem from which non-small cell lung cancer (NSCLC) patients suffer. The mismatch repair (MMR) system is associated with platinum-based chemotherapy toxicity in NSCLC patients. In this study, we aimed to investigate the relationship between genetic polymorphisms in the MMR pathway and platinum-based chemotherapy toxicity in NSCLC patients. METHODS: A total of 220 Chinese lung cancer patients who received at least two cycles of platinum-based chemotherapy were recruited for this study. Toxicity was evaluated in each patient after two cycles of chemotherapy. A total of 44 single nucleotide polymorphisms were selected to investigate their associations with platinum-based chemotherapy toxicity. RESULTS: MutS homolog 2 (MSH2) rs6544991 [odds ratio (OR) 2.98, 95% confidence interval (CI) 1.20-7.40, P = 0.019] was associated with gastrointestinal toxicity in the dominant model; MSH3 rs6151627 (OR 2.38, 95% CI 1.23-4.60, P = 0.010), rs6151670 (OR 2.05, 95% CI 1.07-3.93, P = 0.031), and rs7709909 (OR 2.38, 95% CI 1.23-4.64, P = 0.010) were associated with hematologic toxicity in the dominant model. Additionally, MSH5 rs805304 was significantly associated with overall toxicity (OR 2.21, 95% CI 1.19-4.09, P = 0.012), and MSH5 rs707939 was significantly associated with both overall toxicity (OR 0.42, 95% CI 0.23-0.76, P = 0.004) and gastrointestinal toxicity (OR 0.44, 95% CI 0.20-0.96, P = 0.038) in the dominant model. CONCLUSION: Genetic polymorphisms in the MMR pathway are potential clinical markers for predicting chemotherapy toxicity in NSCLC patients.
Assuntos
Antineoplásicos/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/tratamento farmacológico , Proteína 2 Homóloga a MutS/genética , Polimorfismo de Nucleotídeo Único , Idoso , Antineoplásicos/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Reparo de Erro de Pareamento de DNA , Intervalo Livre de Doença , Feminino , Técnicas de Genotipagem , Humanos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Proteína 3 Homóloga a MutS , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Lung cancer is the leading cause of cancer deaths in the world. The toxicity of platinum-based chemotherapy is a main reason limiting its clinical effects. RAC1, as a member of the Rho family of small guanosine triphosphatases (GTPases), was reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Its potential of becoming a drug target in cancer treatment has been investigated in recent years. The aim of this study was to investigate the association between genetic polymorphisms and platinum-based chemotherapy toxicity. METHODS: We enrolled 317 lung cancer patients randomly. Nineteen polymorphisms of HSP genes and Rho family genes were genotyped by Sequenom MassARRAY. The logistic regression was performed by PLINK to compare the relevance of polymorphisms and toxicity outcome. RESULTS: We found that the polymorphisms of RAC1 rs836554, rs4720672, and rs12536544 were significantly associated with platinum-based chemotherapy toxicity (p = 0.018, p = 0.044, and p = 0.021, respectively). CONCLUSIONS: RAC1 rs836554, rs4720672, and rs12536544 polymorphisms may be novel and useful genetic markers to predict the toxicity induced by platinum-based chemotherapy in lung cancer patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas de Choque Térmico/genética , Neoplasias Pulmonares/tratamento farmacológico , Proteínas rac1 de Ligação ao GTP/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Feminino , Genótipo , Humanos , Modelos Logísticos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Platina/administração & dosagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Platinum-based chemotherapy is the first-line treatment of non-small cell lung cancer (NSCLC); it is therefore important to discover biomarkers that can be used to predict the efficacy and toxicity of this treatment. Four important transporter genes are expressed in the kidney, including organic cation transporter 2 (OCT2), multidrug and toxin extrusion 1 (MATE1), ATP-binding cassette subfamily B member 1 (ABCB1), and ATP-binding cassette subfamily C member 2 (ABCC2), and genetic polymorphisms in these genes may alter the efficacy and adverse effects of platinum drugs. This study aimed to evaluate the association of genetic polymorphisms of these transporters with platinum-based chemotherapy response and toxicity in NSCLC patients. METHODS: A total of 403 Chinese NSCLC patients were recruited for this study. All patients were newly diagnosed with NSCLC and received at least two cycles of platinum-based chemotherapy. The tumor response and toxicity were evaluated after two cycles of treatment, and the patients' genomic DNA was extracted. Seven single-nucleotide polymorphisms in four transporter genes were selected to investigate their associations with platinum-based chemotherapy toxicity and response. RESULTS: OCT2 rs316019 was associated with hepatotoxicity (P = 0.026) and hematological toxicity (P = 0.039), and MATE1 rs2289669 was associated with hematological toxicity induced by platinum (P = 0.016). In addition, ABCC2 rs717620 was significantly associated with the platinum-based chemotherapy response (P = 0.031). ABCB1 polymorphisms were associated with neither response nor toxicity. CONCLUSION: OCT2 rs316019, MATE1 rs2289669, and ABCC2 rs717620 might be potential clinical markers for predicting chemotherapy toxicity and response induced by platinum-based treatment in NSCLC patients. Trial registration Chinese Clinical Trial Registry ChiCTR-RNC-12002892.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Doenças Hematológicas/induzido quimicamente , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adulto , Idoso , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel , Feminino , Seguimentos , Genótipo , Haplótipos/genética , Doenças Hematológicas/patologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Associada à Farmacorresistência Múltipla , Estadiamento de Neoplasias , Transportador 2 de Cátion Orgânico , Pemetrexede/administração & dosagem , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem , Adulto Jovem , GencitabinaRESUMO
BACKGROUND: Platinum-based chemotherapy is the main treatment method for lung cancer patients. The genetic polymorphisms of Wnt-inducible signaling pathway protein 1 (WISP1) were reported to be associated with the development of diverse lung diseases. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response in Chinese lung cancer patients. MATERIALS AND METHODS: A total of 556 lung cancer patients and 254 healthy controls were enrolled onto this study. The 28 polymorphisms of the WISP1 gene were genotyped by the Sequenom MassARRAY system. RESULTS: We found that WISP1 rs16893344, rs2977530, rs2977537, and rs62514004 (P = .009, .033, .049, and .036, respectively) polymorphisms were related to susceptibility of lung cancer; and WISP1 rs11778573 (P = .023, nonsmokers), rs16893344 (P = .013, ≥ 50 years old), rs2977536 (P = .039, ≥ 50 years old; P = .044, nonsmokers; P = .047, non-small-cell lung cancer, respectively), rs2977549 (P = .013, smokers), and rs62514004 (P = .033, ≥ 50 years old) polymorphisms were significantly associated with platinum-based chemotherapy response in lung cancer patients. CONCLUSION: Genotypes of WISP1 may be novel and useful biomarkers for diagnosis of lung cancer and evaluation of platinum-based chemotherapy response in lung cancer patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Sinalização Intercelular CCN/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , Povo Asiático/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Platina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Resultado do TratamentoRESUMO
The eukaryotic translation initiation factor 3a (eIF3a) is one of the core subunits of the translation initiation complex eIF3, responsible for ribosomal subunit joining and mRNA recruitment to the ribosome. Our previous study identified that it was correlated with platinum response in lung cancer. The current study aims to test the hypothesis that eIF3a may affect the drug response and prognosis of ovarian cancer patients receiving platinum-based chemotherapy by regulating xeroderma pigmentosum complementation group C (XPC) and p27(Kip1). Immunohistochemistry and western blot was used to determine the expression of eIF3a in 126 human ovarian cancer tissues followed by association analysis of eIF3a expression with patient's response and survival. Ectopic over-expression and RNA interference knockdown of eIF3a were carried out in A2780/cisplatin (DDP) and its parental A2780 cells, respectively, to determine the effect of altered eIF3a expression on cellular response to cisplatin by employing MTT assay. Western Blot analyses were also carried out to determine the regulation of eIF3a on XPC and p27(Kip1). eIF3a expression was associated with response of ovarian cancer patients to DDP-based chemotherapy and their survival. Overexpression and knockdown of eIF3a increased and decreased the cellular response to cisplatin in A2780/DDP and A2780 cells, respectively. In addition, XPC and p27(Kip1) were down regulated by eIF3a. eIF3a improves ovarian cancer patients' response to DDP-based chemotherapy via down regulating XPC and p27(Kip1).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fator de Iniciação 3 em Eucariotos/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Linhagem Celular Tumoral , Inibidor de Quinase Dependente de Ciclina p27/genética , Proteínas de Ligação a DNA/genética , Relação Dose-Resposta a Droga , Fator de Iniciação 3 em Eucariotos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Modelos de Riscos Proporcionais , Interferência de RNA , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Transfecção , Resultado do TratamentoRESUMO
In this study, we aimed to explore the long noncoding RNA expression pattern in squamous cell lung cancer (SQCC) on a genome-wide scale. Total RNAs were extracted from 16 lung SQCC patients' normal and matched lung cancer tissues by Trizol reagent. The expression level of genome-wide scale lncRNA and mRNA was determined by microarray. qRT-PCR was used to validate the lncRNA expression level in 47 patients. Data analyses were performed using R and Bioconductor. A total of 2,748 up and 852 down regulated probes were identified to be significantly and differentially expressed in tumor tissues. The annotation result of their co-expressed mRNAs showed that the most significantly related category of GO analysis was development and differentiation, while the most significantly related pathway was cell cycle. Subgroup analysis identified that 46 and 18 probes were specifically differentially expressed in smoking and moderately differentiated tumors, respectively. Our study indicated that clusters of lncRNAs were significantly and differentially expressed in SQCC compared with normal tissues in the same subject. They may exert a significant role in lung cancer development and could be potential targets for future treatment of SQCC.
Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , RNA Longo não Codificante/metabolismo , Adulto , Idoso , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Genoma Humano , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Lung cancer is one of the most common cancers and is the leading cause of death worldwide. Platinum-based chemotherapy is the main treatment method in lung cancer patients. Our previous studies indicated that single nucleotide polymorphisms (SNPs) in some transporter genes played important role in platinum-based chemotherapy efficacy. The aim of this study was to investigate the association of SNPs in transporter genes and platinum-based chemotherapy efficacy. The main polymorphisms on transporters OCT2, LRP, AQP2, AQP9 and TMEM205 genes were genotyped in 338 lung cancer patients. The rs195854 in genotypic model, rs896412 in genotypic and recessive models for all subjects showed significant association with chemotherapy response. In stratification analysis, TMEM205 rs896412, OCT2 rs1869641 and rs195854, AQP9 rs1516400 and AQP2 rs7314734 showed significant relation to chemotherapy response. In conclusion, the genetic polymorphisms in OCT2, AQP2, AQP9 and TMEM205 may contribute to chemotherapy response in lung cancer patients.