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Neurofilament light chains (NfLs) are promising biomarkers of neuroaxonal damage in stroke patients. We investigated the correlations between NfL levels and infarct volume, initial stroke severity, and functional outcomes at discharge in patients with acute ischemic stroke. We prospectively included 15 patients with first-ever acute ischemic stroke and 8 age- and sex-matched healthy controls without other neurological disorders. Serum NfL levels were measured using the single-molecule array (Simoa) technique twice within 24 hours of admission (NfL1D) and on the seventh hospital day (NfL7D) in patients with stroke and once in healthy controls. We assessed the infarct volume on diffusion-weighted magnetic resonance imaging using the free software ITK-SNAP. Serum NfL1D levels in stroke patients were significantly higher (28.4 pg/mL; interquartile range [IQR], 43.0) than in healthy controls (14.5 pg/mL; IQR, 3.2; Pâ =â .005). Temporal pattern analyses demonstrated that NfL7D levels were increased (114.0 pg/mL; IQR, 109.6) compared to NfL1D levels in all stroke patients (Pâ =â .001). There was a strong correlation between NfL7D levels and infarct volume (Râ =â 0.67, Pâ =â .007). The difference between NfL1D and NfL7D (NfLdiff levels) was strongly correlated with the infarct volume (Râ =â 0.63; Pâ =â .013). However, there was no statistically significant correlation between NfL levels and the initial stroke severity or functional outcomes at discharge. NfL levels in the subacute stage of stroke and the NfL difference between admission and 7th day of hospital were correlated with infarct volume in patients with acute ischemic stroke.
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AVC Isquêmico , Acidente Vascular Cerebral , Biomarcadores , Humanos , Infarto , Filamentos Intermediários , Proteínas de Neurofilamentos , Acidente Vascular Cerebral/diagnóstico por imagemRESUMO
OBJECTIVES: To analyze whether CT image normalization can improve 3-year recurrence-free survival (RFS) prediction performance in patients with non-small cell lung cancer (NSCLC) relative to the use of unnormalized CT images. METHODS: A total of 106 patients with NSCLC were included in the training set. For each patient, 851 radiomic features were extracted from the normalized and the unnormalized CT images, respectively. After the feature selection, random forest models were constructed with selected radiomic features and clinical features. The models were then externally validated in the test set consisting of 79 patients with NSCLC. RESULTS: The model using normalized CT images yielded better performance than the model using unnormalized CT images (with an area under the receiver operating characteristic curve of 0.802 vs 0.702, p = 0.01), with the model performing especially well among patients with adenocarcinoma (with an area under the receiver operating characteristic curve of 0.880 vs 0.720, p < 0.01). CONCLUSIONS: CT image normalization may improve prediction performance among patients with NSCLC, especially for patients with adenocarcinoma. KEY POINTS: ⢠After CT image normalization, more radiomic features were able to be identified. ⢠Prognostic performance in patients was improved significantly after CT image normalization compared with before the CT image normalization. ⢠The improvement in prognostic performance following CT image normalization was superior in patients with adenocarcinoma.
Assuntos
Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Tomografia Computadorizada por Raios X/métodos , PrognósticoRESUMO
PROBLEM: Preterm birth (PTB) is a major cause of increased morbidity and mortality in newborns. The main cause of spontaneous PTB (sPTB) is the activation of an inflammatory response as a result of ascending genital tract infection. Despite various studies on the effects of the vaginal microbiome on PTB, a practical method for its clinical application has yet to be developed. METHOD OF STUDY: In this case-control study, 94 Korean pregnant women with PTB (n = 38) and term birth (TB; n = 56) were enrolled. Their cervicovaginal fluid (CVF) was sampled, and a total of 10 bacteria were analyzed using multiplex quantitative real-time PCR (qPCR). The PTB and TB groups were compared, and a PTB prediction model was created using bacterial risk scores using machine learning techniques (decision tree and support vector machine). The predictive performance of the model was validated using random subsampling. RESULTS: Bacterial risk scoring model showed significant differences (P < 0.001). The PTB risk was low when the Lactobacillus iners ratio was 0.812 or more. In groups with a ratio under 0.812, moderate and high risk was classified as a U. parvum ratio of 4.6 × 10-3 . The sensitivity and specificity of the PTB prediction model using bacteria risk score were 71% and 59%, respectively, and 77% and 67%, respectively, when white blood cell (WBC) data were included. CONCLUSION: Using machine learning, the bacterial risk score in CVF can be used to predict PTB.
Assuntos
Colo do Útero/microbiologia , Aprendizado de Máquina , Microbiota/fisiologia , Nascimento Prematuro/microbiologia , Vagina/microbiologia , Adulto , Líquidos Corporais/microbiologia , Estudos de Casos e Controles , Feminino , Humanos , Gravidez , Fatores de RiscoRESUMO
Grammatical Error Correction (GEC) is the task of detecting and correcting various grammatical errors in texts. Many previous approaches to the GEC have used various mechanisms including rules, statistics, and their combinations. Recently, the performance of the GEC in English has been drastically enhanced due to the vigorous applications of deep neural networks and pretrained language models. Following the promising results of the English GEC tasks, we apply the Transformer with Copying Mechanism into the Korean GEC task by introducing novel and effective noising methods for constructing Korean GEC datasets. Our comparative experiments showed that the proposed system outperforms two commercial grammar check and other NMT-based models.
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Idiopathic normal-pressure hydrocephalus (iNPH) is an uncommon neurological disorder with no known pathological hallmarks. INPH may share common degenerative pathways with other neurological diseases, such as Alzheimer's disease (AD). However, the reversible properties of iNPH may share differing pathophysiological mechanisms with other diseases. This study aimed at assessing the diagnostic value of plasma chitinase 3-like 1 (CHI3L1) protein levels as a disease-specific biomarker for iNPH. We selected both iNPH and AD patients as well as normal and disease control subjects from an enrolled dementia registry. A total of 121 AD, 80 iNPH, 13 idiopathic Parkinson's disease, and 23 mild cognitive impairment patients with 83 healthy controls were included in the final analysis. The Aß42, total tau, and phosphorylated tau levels within the cerebrospinal fluid, as well as plasma levels of CHI3L1, were measured using commercially available enzyme-linked immunosorbent assay kits. CHI3L1 levels for iNPH patients were higher than those of the other groups. Analysis of covariance adjusting for age showed significantly increased plasma CHI3L1 levels in iNPH patients than in the controls (p < 0.001). CHI3L1 plasma levels may be useful in differentiating iNPH patients from healthy individuals.
Assuntos
Proteína 1 Semelhante à Quitinase-3/sangue , Hidrocefalia de Pressão Normal , Biomarcadores/sangue , HumanosRESUMO
It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels >250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers.
Assuntos
Diabetes Mellitus Experimental/patologia , Armadilhas Extracelulares/metabolismo , Hormônio Liberador de Gonadotropina/efeitos adversos , Cicatrização , Animais , Citrulinação/efeitos dos fármacos , Modelos Animais de Doenças , Armadilhas Extracelulares/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/agonistas , Células HL-60 , Histonas/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Neutrófilos/ultraestrutura , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Receptores LHRH/metabolismo , Cicatrização/efeitos dos fármacosRESUMO
Non-thermal plasma (NTP) has many functional activities such as, sterilization, wound healing and anti-cancer activity. Despite of its wide spread biomedical application, the effect of NTP on immune cells and allergic response has not been well studied. In this study, we determined whether NTP suppresses mast cell activation, which is important for allergic response, and ameliorates an atopic dermatitis (AD)-like skin inflammatory disease in mice. Exposure to NTP-treated medium during mast cell activation inhibited the expression and production of IL-6, TNF-α and suppressed NF-κB activation. We also investigated whether NTP treatment ameliorates house dust mite (HDM)-induced AD-like skin inflammation in mice. NTP treatment inhibited increases in epidermal thickness and recruitment of mast cells and eosinophils, which are important cell types in AD pathogenesis. In addition, Th2 cell differentiation was induced by application of HDM and the differentiation was also inhibited in the draining lymph node of NTP-treated mice. Finally, the expression of AD-related cytokines and chemokines was also decreased in NTP-treated mice. Taken together, these results suggest that NTP might be useful in the treatment of allergic skin diseases, such as AD.
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Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Gases em Plasma/farmacologia , Animais , Quimiocinas/metabolismo , Citocinas/metabolismo , Dermatite Atópica/terapia , Modelos Animais de Doenças , Eosinófilos/metabolismo , Hipersensibilidade/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Gases em Plasma/metabolismo , Pele/patologia , Células Th2/imunologiaRESUMO
Plasma medicine is an emerging novel therapeutic field. It has been reported that plasma can kill bacteria, promote wound healing and induce apoptosis of tumor cells. However, the effects of plasma on immune cells and immune related skin diseases have not been well studied. In this study, we demonstrated that non-thermal atmospheric plasma (NTP) treatment could inhibit psoriasis-like skin inflammation in mice. NTP treatment in imiquimod-induced psoriasis-like mouse skin inhibited increases in epithelial cell thickness and expression of pro-inflammatory molecules compared to ones without the NTP treatment. In addition, differentiation of Th17 cells, an important cell type for pathogenesis of psoriasis, was inhibited in the NTP-treated mouse lymph nodes. It was also demonstrated that liquid type plasma (LTP), which is also known as indirect plasma, inhibited Th17 cell differentiation in vitro. Other in vitro experiments showed that LTP inhibited bone marrow-derived dendritic cell activation. Interestingly, LTP enhanced PD-L1 expression in HaCaT cells, suggesting that NTP may inhibit unwanted over-activation of T cells through increased PD-L1 expression. Taken together, these results suggest that NTP may be used in treatment of CD4+ T cell-mediated autoimmune diseases such as psoriasis.
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Diferenciação Celular/efeitos da radiação , Inflamação/terapia , Gases em Plasma/uso terapêutico , Psoríase/terapia , Animais , Antígeno B7-H1/genética , Células da Medula Óssea/imunologia , Células da Medula Óssea/efeitos da radiação , Linfócitos T CD4-Positivos/efeitos da radiação , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Imiquimode/toxicidade , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Linfonodos/imunologia , Linfonodos/efeitos da radiação , Camundongos , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Células Th17/imunologia , Células Th17/efeitos da radiaçãoRESUMO
Hepatocytes are used widely as a cell model for investigation of xenobiotic metabolism and the toxic mechanism of drugs. Simvastatin is the first statin drug used extensively in clinical practice for control of elevated cholesterol or hypercholesterolemia. However, it has also been reported to cause adverse effects in liver due to cellular damage. In this study, for proteomic and transcriptomic analysis, rat primary hepatocytes were exposed to simvastatin at IC20 concentration for 24 h. Among a total of 607 differentially expressed proteins, 61 upregulated and 29 downregulated proteins have been identified in the simvastatin-treated group. At the mRNA level, results of transcriptomic analysis revealed 206 upregulated and 41 downregulated genes in the simvastatin-treated group. Based on results of transcriptomic and proteomic analysis, NRF2-mediated oxidative stress response, xenobiotics by metabolism of cytochrome P450, fatty acid metabolism, bile metabolism, and urea cycle and inflammation metabolism pathways were focused using IPA software. Genes (FASN, UGT2B, ALDH1A1, CYP1A2, GSTA2, HAP90, IL-6, IL-1, FABP4, and ABC11) and proteins (FASN, CYP2D1, UG2TB, ALDH1A1, GSTA2, HSP90, FABP4, and ABCB11) related to several important pathways were confirmed by real-time PCR andWestern blot analysis, respectively. This study will provide new insight into the potential toxic pathways induced by simvastatin.
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Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Proteínas/metabolismo , Sinvastatina/efeitos adversos , Animais , Bile/metabolismo , Western Blotting , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida/métodos , Sistema Enzimático do Citocromo P-450/metabolismo , Ácidos Graxos/metabolismo , Perfilação da Expressão Gênica , Hepatite/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Proteínas/genética , Proteômica/métodos , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Sinvastatina/toxicidade , Software , Ureia/metabolismoRESUMO
Cisplatin is used widely for treatment of a variety of cancer diseases. Recently, however, the use of cisplatin is restricted because of its adverse effects such as hepatotoxicity. There is no study with current proteomics technology to evaluate cisplatin-induced hepatotoxicity, even if some studies have reported on the hepatotoxicity. In this study, proteomic as well as genomic analyses have been used for identification of proteins and genes that respond to cisplatin treatment in rat primary hepatocytes. To investigate the hepatotoxic effects of cisplatin, rat primary hepatocytes were treated with an IC(20) concentration for 24 h. From proteomic analysis based on label-free quantitation strategy, cisplatin induced 76 up-regulated and 19 down-regulated proteins among 325 distinct proteins. In the mRNA level, genomic analysis revealed 72 up-regulated and 385 down-regulated genes in the cisplatin-treated group. Based on these two analyses, 19 pathways were commonly altered, whereas seven pathways were identified only by proteomic analysis, and 19 pathways were identified only by genomic analysis. Overall, this study explained the mechanism of cisplatin-induced hepatotoxicity with two points of view: well known pathways including drug metabolism, fatty acid metabolism, and glycolysis/TCA cycle and little known pathways including urea cycle and inflammation metabolism, for hepatotoxicity of other toxic agents. Up-regulated proteins detected by proteomic analysis in the cisplatin-treated group: FBP1 (fructose 1,6-bisphosphatase 1), FASN (fatty acid synthase), CAT (catalase), PRDX1 (peroxiredoxin-1), HSPD1 (60-kDa heat shock protein), MDH2 (malate dehydrogenase 2), and ARG1 (arginase 1), and also down-regulated proteins in the cisplatin-treated group: TPM1 (tropomyosin 1), TPM3 (tropomyosin 3), and CTSB (cathepsin B), were confirmed by Western blot analysis. In addition, up-regulated mRNAs detected by microarray analysis in the cisplatin-treated group: GSTA2, GSTT2, YC2, TXNRD1, CYP2E1, CYP2C13, CYP2D1, ALDH17, ARG1, ARG2, and IL-6, and also down-regulated mRNAs: CYP2C12, CYP26B1, TPM1, and TPM3, were confirmed by RT-PCR analysis. In case of PRDX1, FASN, and ARG1, they were further confirmed by immunofluorescence analysis. Through the integrated proteomic and genomic approaches, the present study provides the first pathway map related to cisplatin-induced hepatotoxicity, which may provide new insight into the mechanism of hepatotoxicity.
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Antineoplásicos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cisplatino/toxicidade , Hepatócitos/efeitos dos fármacos , Animais , Células Cultivadas , Perfilação da Expressão Gênica , Hepatócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Proteômica , RNA Mensageiro/metabolismo , RatosRESUMO
This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNP) in DNA repair genes to determine the relationship between polymorphisms and the survival outcome of patients with early stage non-small-cell lung cancer (NSCLC). Three hundred and ten consecutive patients with surgically resected NSCLC were enrolled. Forty-eight SNP in 27 DNA repair genes were genotyped and their associations with overall survival (OS) and disease-free survival (DFS) were analyzed. Individually, six SNP exhibited significant associations with survival outcome. When the six SNP were combined, OS and DFS decreased as the number of bad genotypes increased (P(trend) <0.0001 for both). Patients with three, and four or five bad genotypes had a significantly worse OS and DFS compared with those carrying zero or one bad genotypes (adjusted hazard ratio [aHR] for OS=3.53, 95% confidence interval [CI]=1.25-9.97, P=0.02, and aHR for DFS=3.31, 95% CI=1.41-7.76, P=0.006; and aHR for OS=5.47, 95% CI=1.87-16.00, P=0.002, and aHR for DFS=4.42, 95% CI=1.82-10.74, P=0.001, respectively). These findings suggest that the six SNP identified can be used as prognostic markers for patients with surgically resected early stage NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/genética , Reparo do DNA/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Idoso , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Frequência do Gene , Genótipo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteína 2 Homóloga a MutS/genética , Estadiamento de Neoplasias , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética , Prognóstico , Proteínas Supressoras de Tumor/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X , Proteína Grupo D do Xeroderma Pigmentoso/genéticaRESUMO
One of major challenges in the drug delivery lies in the development of nanoparticles that are effectively delivered to targeted cells and release their payload over an extended period to achieve a clinical response. In this paper, we report a new family of biocompatible and biodegradable polymer, termed polyoxalate that degrades hydrolytically into nontoxic byproducts. Polyoxalate was synthesized from a simple one-step polymerization reaction of 1,4-cyclohexanedimethanol and oxalyl chloride and had a MW of approximately 11000 Da. This polymer was designed to degrade by water hydrolysis into 1,4-cyclohexanedimethanol and oxalic acid, which can be easily removed from a body. Polyoxalate had a hydrophobic backbone and was formulated into nanoparticles with a mean diameter of 600 nm, which is suitable for drug delivery involving phagocytosis by macrophages. Polyoxalate nanoparticles were readily taken up by RAW 264.7 macrophage cells and HEK (human embryonic kidney) 293 cells and exhibited a minimal cytotoxicity in a time- and dose-dependent manner. In comparison with PLGA nanoparticles, polyoxalate nanoparticles had a significantly higher cell viability. We anticipated that the ease of synthesis and excellent biocompatibility make polyoxalate highly potent for numerous applications in drug delivery.
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Materiais Biocompatíveis , Portadores de Fármacos , Nanopartículas , Ácido Oxálico/química , Animais , Linhagem Celular , Humanos , Cinética , Camundongos , Microscopia Eletrônica de Varredura , FagocitoseRESUMO
PURPOSE: The polymorphisms in microRNA (miRNA) machinery genes and miRNA-containing genomic regions may play an important role in cancer development and prognosis. Accordingly, the present study analyzed the single nucleotide polymorphisms (SNPs) of miRNA-related genes and their impact on the prognosis for patients with colorectal cancer. METHODS: Four hundred and twenty-six consecutive patients with surgically treated colorectal adenocarcinoma were enrolled. The genomic DNA was extracted from fresh colorectal tissue and 40 polymorphisms of miRNA-related genes determined using a real-time PCR genotyping assay. RESULTS: In a univariate analysis, the progression-free survival of the patients with the combined mir492 C/G and G/G genotype was significantly worse than that of the patients with the mir492 C/C genotype (rs2289030) (P value = 0.0426), although there was no difference in the overall survival. However, no association was noted between the SNPs of the miRNA-related genes evaluated and survival in a multivariate analysis. CONCLUSIONS: None of the 40 miRNA-related gene polymorphisms investigated in this study was found to be an independent prognostic marker for Korean patients with surgically resected colorectal cancer. However, further studies are warranted to clarify the role of miRNA-related gene polymorphisms as a prognostic biomarker for colorectal cancer patients.
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Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
The Bcl-2 protein inhibits apoptosis (programmed cell death) of hematopoietic stem cells induced by a variety of noxious stimuli, thus mediating chemoresistance and decreasing chemosensitivity. Higher Bcl-2 expression correlates to an adverse outcome following therapy for acute myeloid leukemia (AML). The current study determined whether a BCL2 gene single nucleotide polymorphism (SNP) could affect treatment outcomes in 99 AML patients excluding acute promyelocytic leukemia. Two genotypes were tested, including BCL2 -938 C>A (rs2279115) and +21 A>G (rs1801018). Neither the -938 C>A nor the +21 A>G BLC2 genotype was associated with complete remission (CR) rates following chemotherapy. The -938 A>C BCL2 genotype did not affect leukemia-free survival (LFS), event-free survival (EFS) or overall survival (OS). However, of interest, the BCL2 +21 A>G genotype correlated with LFS, EFS and OS: The group with the +21 AA genotype had a significantly longer median LFS (p<0.001) or EFS (p=0.004), and OS (p=0.04). The multivariate analyses confirmed that this BCL2 gene SNP is an independent prognostic factor for LFS (p=0.05, HR 1.83, 95% C.I. [1.02-3.45]) and EFS (p=0.02, HR 3.13 [1.34-6.43]), but not for OS (p=0.1). This data suggests the involvement of a Bcl-2-mediated mechanism in the development of chemoresistance in AML.
Assuntos
Genes bcl-2/genética , Leucemia Mieloide Aguda/diagnóstico , Polimorfismo Genético , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Genótipo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease entity due to diverse clinical outcomes to treatment. Most anticancer agents, regardless of their distinct mechanisms of action, ultimately kill cancer cells by inducing apoptosis. Accordingly, the present study analyzed the impact of polymorphisms of apoptosis-related genes on outcome in DLBCL patient treated with R-CHOP. PATIENTS AND METHODS: Ninety patients with DLBCL treated with R-CHOP were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and 22 polymorphisms of 18 apoptosis-related genes were assessed using a polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: All the evaluable patients were responsive to R-CHOP. The multivariate analysis showed that the AA genotype of lymphotoxin alpha (LTA) C804A (rs1041981) and GG genotype of RIPK1 G83A (rs2272990) were significantly correlated with a worse time to progression (TTP) compared with the combined C/A and C/C genotype and the combined G/A and A/A genotype (hazard ratio [HR]=7.92; 95% confidence interval [CI]=1.42-44.18; P=0.018 and HR=20.02; 95% CI=1.59-251.52; P value=0.018, respectively), whereas no association was observed between the other polymorphisms and TTP. CONCLUSION: The polymorphisms of LTA (rs1041981) and RIPK1 (rs2272990) may correlate with TTP in patients with DLBCL treated with R-CHOP.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfotoxina-alfa/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Ciclofosfamida/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Feminino , Frequência do Gene , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prognóstico , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Rituximab , Fatores de Tempo , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto JovemRESUMO
PURPOSE: This study was conducted to determine the impact of potentially functional polymorphisms in the CASPASE (CASP) genes on the survival of early-stage non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Four hundred eleven consecutive patients with surgically resected NSCLC were enrolled. Nine potentially functional polymorphisms in the CASP3, CASP7, CASP8, CASP9, and CASP10 genes were investigated. The genotype and haplotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. RESULTS: Patients with the rs2227310 GG genotype had a significantly decreased OS and DFS compared with patients with the CC + CG genotype (adjusted hazard ratio [aHR] for OS, 1.67; 95% CI, 1.19 to 2.35; P = .003; aHR for DFS, 1.62; 95% CI, 1.19 to 2.22; P = .002). The rs4645981C>T genotype also had a significant effect on OS and DFS (under a recessive model; aHR for OS, 2.00; 95% CI, 1.04 to 3.85; P = .04; aHR for DFS, 2.76; 95% CI, 1.58 to 4.80; P = .0003). When the rs2227310 and rs4645981 genotypes were combined, patients with one or two bad genotypes had worse OS and DFS compared with those who had zero bad genotypes (aHR for OS, 1.75; 95% CI, 1.25 to 2.45; P = .001; aHR for DFS, 1.66; 95% CI, 1.23 to 2.26; P = .001). CONCLUSION: The CASP7 rs2227310 and CASP9 rs4645981 polymorphisms may affect survival in early-stage NSCLC. The analysis of these polymorphisms can help identify patients at high risk for a poor disease outcome.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Caspases/genética , Neoplasias Pulmonares/genética , Polimorfismo Genético , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Taxa de SobrevidaRESUMO
OBJECTIVE: The present study analyzed the functional insertion/deletion polymorphism in the promoter region of NFKB1 gene and their impact on the prognosis for patients with gastric adenocarcinoma. METHODS: Four hundred and seventy two consecutive patients with curatively resected gastric adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tissue and the -94 insertion/deletion ATTG polymorphism of NFKB1 determined using a polymerase chain reaction-restriction fragment length polymorphism assay. RESULTS: The NFKB1 promoter gene polymorphism was successfully amplified in 97.8% of the cases. There were no sexual differences in relation to the genotype and allele. No correlation was observed between the frequency of the genotype or allele and the T, N or M stage. The multivariate survival analysis showed no association between the NFKB1 -94 insertion/deletion promoter polymorphism and the disease-free survival or overall survival of the patients with gastric cancer. CONCLUSIONS: The functional NFKB1 promoter polymorphism was not found to be a prognostic marker for Korean patients with surgically resected gastric adenocarcinoma.
Assuntos
Subunidade p50 de NF-kappa B/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Estudos de Viabilidade , Feminino , Deleção de Genes , Humanos , Coreia (Geográfico) , Masculino , Pessoa de Meia-Idade , Mutagênese Insercional , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Prognóstico , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Rituximab may overcome bcl-2-mediated chemoresistance through the inhibition of interleukin-10 (IL-10)-mediated loops, thus down-regulating bcl-2 expression. We examined the effects of genetic variation in BCL2/IL10 gene loops on treatment outcomes of diffuse large B-cell lymphoma when treated with either CHOP or rituximab plus CHOP (R-CHOP) chemotherapy. EXPERIMENTAL DESIGN: Four genotypes were tested including BCL2 -938 C>A (rs2279115), +21 A>G (rs1801018), IL10 -819 T>C (rs1800871), and -592 A>C (rs1800872) in patients receiving either R-CHOP (n = 125) or CHOP (n = 110). RESULTS: IL10 SNPs, -819 TT/TC or -592 AA/AC genotypes correlated with improved CHOP response rates (P = 0.04). Neither polymorphism separately influenced the failure-free survival (FFS) or overall survival in patients, but the IL10 haplotype was associated with treatment outcomes after R-CHOP for FFS (P = 0.03) or progression (P = 0.007), whereas the -938 AA BCL2 genotype significantly affected overall survival (P = 0.04). An interactive effect between BCL2 and IL10 SNPs was significant in the group with both -938 AA BCL2 genotype and 1 to 2 copies of CC IL10 haplotype. This group showed a better FFS (P = 0.01) and a lower probability of progression (P = 0.004) compared with other genotype groups when treated with R-CHOP chemotherapy. CONCLUSIONS: These data indicated that R-CHOP chemotherapy resistance in diffuse large B-cell lymphoma may involve interactions between the BCL2 and IL10 genes.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Genes bcl-2 , Interleucina-10/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Genótipo , Haplótipos , Humanos , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prednisona/administração & dosagem , Rituximab , Vincristina/administração & dosagemRESUMO
Microvessel injury is associated with the development of graft-versus-host disease (GVHD), whereas high levels of posttransplantation vascular endothelial growth factor (VEGF) have a protective effect on severe acute GVHD (aGVHD) and transplantation-related mortality. The current study aimed to determine the impact of VEGFA gene single-nucleotide polymorphisms (SNPs) on the risk of aGVHD after allogeneic stem cell transplantation (SCT). Using polymerase chain reaction and restriction fragment length polymorphism, 4 VEGFA SNPs- -2578 C>A (rs699947), -460 T>C (rs833061), +405 G>C (rs2010963), and +936 C>T (rs3025039)-were analyzed in 98 recipients. Strong linkage disequilibrium was noted among loci -2578, -460, and +405, but not among these loci and locus +936. Accordingly, 4 haplotypes were generated based on the genotypes of -2578, -460, and +405: CTC (47.9%), CTG (26.7%), ACG (24.2%), and CCC (1.0%). The group with low VEGF production (ie, +936CT genotype and 2 copies of the ACG haplotype) had a higher incidence of aGVHD. Significant associations were found between the risk of grade 2-4 aGVHD and the +936 CT (P = .006), -2578 AA (P = .003), and -460 CC (P = .002) genotypes and the ACG haplotype (P = .003). No association between the VEGFA SNPs and chronic GVHD was observed. The VEGFA SNPs might predict a lower risk of aGVHD. Our findings suggest that VEGF may have a protective role in the pathogenesis of aGVHD.
Assuntos
Doença Enxerto-Hospedeiro/genética , Desequilíbrio de Ligação , Transplante de Células-Tronco , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Haplótipos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Fatores de Risco , Transplante Homólogo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Increased angiogenesis, mediated by vascular endothelial growth factor (VEGF), was associated with poor prognosis in acute myeloid leukaemia (AML) patients. The current study investigated the impact of VEGF gene (VEGFA) single nucleotide polymorphisms (SNPs) on treatment outcomes for AML. Four VEGFA SNPs were analysed for -2578C>A (rs699947), -460T>C (rs833061), +405G>C (rs2010963) and +936 C>T (rs3025039) loci in 138 AML patients. The +936 CC/CT genotype showed strong correlation with favourable leukaemia-free survival (LFS) at 2 years (51.3%) versus with +936 CC genotype (33.6%, P = 0.03). Strong linkage disequilibrium was noted among loci -2578, -460 and +405, but not with +936. Accordingly, four haplotypes were generated based on the genotypes of -2578, -460 and +405 as follows: CTC (40.2%), CTG (35.0%), ACG (22.0%) and ATC (1.2%). The LFS and event-free survival (EFS) inversely correlated with CTG haplotype (P = 0.03 for LFS; P = 0.05 for EFS). We scored the VEGFA polymorphism marker based on +936 C>T genotype and CTG haplotype for -2578, -460 and +405, which demonstrated a good correlation with the treatment outcomes: LFS (P = 0.01), EFS (P = 0.03) and overall survival (P = 0.01). The VEGFA +936 C>T genotype and CTG haplotype seemed to have an additive effect to predict the prognosis in AML patients.