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1.
Oncotarget ; 10(19): 1760-1774, 2019 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-30956756

RESUMO

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.

2.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.


Assuntos
Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Complexo Principal de Histocompatibilidade/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Antígenos HLA/genética , Humanos , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único
3.
EBioMedicine ; 32: 93-101, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29859855

RESUMO

Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31-1.72; p = 7.75 × 10-9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression.


Assuntos
Adenocarcinoma/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
4.
J Thorac Dis ; 10(12): 6660-6669, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30746211

RESUMO

Background: Idiopathic pulmonary fibrosis (IPF) has common risk factors with cancer and significant similarities in the pathobiology process, both diseases having poor outcomes. Immune checkpoint PD-L1 has become the target of checkpoint inhibitory therapy that unleashes antitumor T cells and has revolutionized cancer treatment. This is a pilot study exploring membrane immune checkpoint PD-L1 expression in human IPF lung tissue samples and its soluble form, soluble PD-L1 (sPD-L1) plasma concentrations in IPF patients, in order to investigate potential role of PD-L1 as an IPF biomarker. Methods: Twelve human IPF lung tissue samples (formalin-fixed, paraffin-embedded) obtained by surgical biopsy, have been tested for PD-L1 expression by PD-L1 IHC 22C3 pharmDx assay, while plasma samples for examination of sPD-L1 forms, PD-L1 (B7-H1/CD274) blood concentration, originated from 23 patients with IPF who did not undergo surgical biopsy. Results: Membrane PD-L1 expression in IPF lung tissue samples was positive to overexpression of PD-L1 in 9 samples out of 12. Only very few cells in the interstitium have shown a discrete PD-L1 expression, but not of a membrane type. As for sPD-L1 forms, we have found elevated concentrations of sPD-L1 in the serum of IPF patients 314.3 ng/L (117.7-483.1 ng/L), significantly higher compared with healthy control group 91.0 ng/L (52.4-119.7 ng/L), P<0.01. Conclusions: For IPF with PD-L1 expression on alveolar macrophages, further studies are necessary to elucidate this phenomenon. Serum sPD-1/PD-L1 is easily detected in clinical practice and should be further evaluated as a potential prognostic or/and predictive biomarker in IPF.

5.
Clin Exp Rheumatol ; 36(1): 56-61, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28770705

RESUMO

OBJECTIVES: The aim of this study was to investigate association between pulmonary and skin manifestations in a large group of patients with primary antiphospholipid syndrome (PAPS) as well as their connection with antiphospholipid antibodies. METHODS: Our prospective study comprises of 390 patients with primary APS. Antiphospholipid antibody (aPL) analysis included detection of aCL (IgG/IgM), ß2GPI (IgG/IgM) and LA. Distinct pulmonary and skin associations were determined, as well as their associations with aPL. RESULTS: In PAPS patients the presence of LA was more common in PTE (p=0.005) and in pulmonary microthrombosis (p=0.003). We revealed statistical significance considering the presence of aCL IgM and pulmonary microthrombosis (p=0.05). Skin ulcerations correlated with positive titres aCL IgM and ß2 GPI IgM (p=0.03 and 0.04, respectively), while pseudovasculitis correlated with positive titres ß2 GPI IgM (p=0.02). PAPS patients were more more likely to develop pulmonary thromboembolisam if they had livedo reticularis (p=0.005), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.01), superficial cutaneous necrosis (p=0.005), and digital gangrene (p=0.02). Patients were also more prone to pulmonary microthrombosis if they already had livedo reticularis (p=0.03), skin ulcerations (p=0.007), pseudovasculitic lesions (p=0.05), superficial cutaneous necrosis (p=0.006), and digital gangrene (p=0.02). CONCLUSIONS: There is strong link between some pulmonary and skin manifestations in PAPS patients, suggesting complexity and evolutionary nature of APS. The presence of skin manifestations may be a high risk factor for several types of serious pulmonary manifestations in PAPS. Certain aPL types are associated with distinct pulmonary and skin manifestation, suggesting their predictive role.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/imunologia , Pneumopatias/imunologia , Dermatopatias/imunologia , Adulto , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/diagnóstico , Síndrome Antifosfolipídica/epidemiologia , Biomarcadores/sangue , Feminino , Humanos , Pneumopatias/sangue , Pneumopatias/diagnóstico , Pneumopatias/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Embolia Pulmonar/sangue , Embolia Pulmonar/imunologia , Fatores de Risco , Sérvia/epidemiologia , Testes Sorológicos , Dermatopatias/sangue , Dermatopatias/diagnóstico , Dermatopatias/epidemiologia , Dermatopatias Vasculares/sangue , Dermatopatias Vasculares/imunologia , Úlcera Cutânea/sangue , Úlcera Cutânea/imunologia
6.
Carcinogenesis ; 39(3): 336-346, 2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29059373

RESUMO

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Fumar/efeitos adversos , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu , Interação Gene-Ambiente , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
7.
Onco Targets Ther ; 10: 4347-4354, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28919784

RESUMO

This paper presents a rare case of an elderly patient treated with erlotinib for disseminated lung adenocarcinoma with poor performance status (Eastern Cooperative Oncology Group performance status [PS]3). This treatment led to a long duration of complete remission according to Response Evaluation Criteria in Solid Tumors 1.1 - almost 7 years (81 months) of progression-free survival (PFS) and overall survival (OS) of 10 years by March 2017. The treatment with erlotinib started in September 2008 and it was well tolerated with no adverse effects. Mutation analyses (real-time polymerase chain reaction method) revealed deletion of EGFR (epidermal growth factor receptor) gene and wild-type Kirsten-ras protein gene in exon 19. In May 2015, the patient relapsed with jaundice and enlarged lymph nodes of the liver hilum, with no other metastasis, PS 2. Biopsy confirmed metastasis of lung adenocarcinoma. EGFR molecular testing did not reveal T790M mutation. Treatment was continued with gemcitabine-cisplatin chemotherapy. A total of six cycles were administered with nearly complete response and Eastern Cooperative Oncology Group performance status 0. Further on, gemcitabine monotherapy has been administered with nearly complete response maintained and OS of 10 years by March 2017. This report describes an extremely rare case of a poor performance patient with advanced metastatic adenocarcinoma harboring EGFR mutation - deletion in exon 19 - who was receiving salvage erlotinib and had a complete response with 81 months of PFS followed by a relapse and subsequent chemotherapy which led to nearly complete response, with an OS of 10 years by March 2017. Such a complete response to tyrosine kinase inhibitor therapy in a poor PS patient, with long PFS and OS achieved, justifies tyrosine kinase inhibitor treatment approach in poor PS patients with EGFR-sensitizing tumors, and furthermore points to the feasibility of administering chemotherapy at the time of relapse.

8.
Thorac Cancer ; 8(5): 393-401, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28671758

RESUMO

BACKGROUND: In spite of the progress made in neoadjuvant therapy for operable non small-cell lung cancer (NSCLC), many issues remain unsolved, especially in locally advanced stage IIIA. METHODS: Retrospective data of 163 patients diagnosed with stage IIIA NSCLC after surgery was analyzed. The patients were divided into two groups: a preoperative chemotherapy group including 59 patients who received platinum-etoposide doublet treatment before surgery, and an upfront surgery group including 104 patients for whom surgical resection was the first treatment step. Adjuvant chemotherapy or/and radiotherapy was administered to 139 patients (85.3%), while 24 patients (14.7%) were followed-up only. RESULTS: The rate of N2 disease was significantly higher in the upfront surgery group ( P < 0.001). The one-year relapse rate was 49.5% in the preoperative chemotherapy group compared to 65.4% in the upfront surgery group. There was a significant difference in relapse rate in relation to adjuvant chemotheraphy treatment ( P = 0.007). The probability of relapse was equal whether radiotherapy was applied or not ( P = 0.142). There was no statistically significant difference in two-year mortality ( P = 0.577). The median survival duration after two years of follow-up was 19.6 months in the preoperative chemotherapy group versus 18.8 months in the upfront surgery group ( P = 0.608 > 0.05). CONCLUSION: There was significant difference in preoperative chemotherapy group regarding relapse rate and treatment outcomes related to the lymph node status comparing to the upfront surgery group. Neoadjuvant/adjuvant chemo-therapy is a part of treatment for patients with stage IIIA NSCLC, but further investigation is required to determine optimal treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/cirurgia , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/patologia , Linfonodos , Masculino , Mediastino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
10.
Wien Med Wochenschr ; 165(15-16): 315-21, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26208475

RESUMO

The aim of the study was to assess the expression and significance of HER2 and HER3, and Ile/Val single nucleotide polymorphism (SNP) of HER2 in lung cancer patients. Thirty seven cases of lung cancer were investigated immunohistochemically for HER2 and HER3 expression. PCR followed by restriction fragment length polymorphism (RFLP) was used to analyze the presence of HER-2 SNP at codon 655 in 20 samples. The results were compared with clinical and pathological parameters of investigated patients.We found that 100% of the cases were negative for HER2, 29.7% were with moderate or strong HER3 expression and 70.3% of the tumors-without or with low expression for HER3. Lymph node metastasis were found in 40% of HER3 positive cases (χ(2) = 4.752; p = 0.029). Moderately-differentiated tumors do not express neither of investigated markers (χ(2) = 6.719; p = 0.035). HER2 RFLP-PCR analysis showed genotype AG in five patients (25%) and the rest of 15 cases (75%) had АА (Ile/Ile) genotype. Patients with metastasis had genotype АА (Ile/Ile) in 80% and genotype AG (Ile/Val) in 20% (χ(2) = 2.857; p = 0.091).Our results indicate that SNP in HER2 codon 655 and investigation of HER2 and HER3 expression could be helpful to outline the prognosis for patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma/genética , Códon/genética , Regulação da Expressão Gênica/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Idoso , Feminino , Humanos , Isoleucina/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição/genética , Prognóstico , Estatística como Assunto , Valina/genética
11.
Clin Exp Rheumatol ; 33(4): 531-6, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26088955

RESUMO

OBJECTIVES: The aim of this study was to analyse prevalence and type of pulmonary manifestations in patients with primary antiphospholipid syndrome (PAPS), their association to antiphospholipid antibody (aPL) type and localisation of peripheral vascular thrombosis, and possible relationship to existing cardiac manifestations. METHODS: Our cross-sectional study comprised 318 PAPS patients, enrolled in the study as the Serbian APS Registry. aPL analysis included detection of aCL (IgG/IgM), ß2GPI (IgG/IgM) and LA, served to evaluate associations with cardiac and pulmonary manifestations. RESULTS: In patients with pulmonary embolism and infarction, we observed significant prevalence of myocardial infarction (p=0.044), unstable angina pectoris (p=0.001), venous thrombosis (p=0.007) arterial thrombosis (p=0.0001), deep venous thrombosis of the low extremities (p=0.008), and superficial thrombophlebitis of the low extremities (p=0.023). Patients with primary pulmonary hypertension were more prone to unstable angina pectoris (p=0.009), while patients with secondary pulmonary hypertension were more prone to venous thrombosis (p=0.04) and deep venous thrombosis of the inferior extremities (p=0.04). Patients with pulmonary microthrombosis were more prone to unstable angina pectoris (p=0.026), arterial thrombosis (p=0.002), venous thrombosis (p=0.001), deep venous thrombosis of the inferior extremities (p=0.001), and superficial thrombophlebitis of the inferior extremities (p=0.001). The presence of LA was significantly higher in patients with pulmonary embolism and infarction (p=0.001), secondary pulmonary hypertension (p=0.032), and pulmonary microthrombosis (p=0.001). CONCLUSIONS: Presence of LA was associated with distinct pulmonary manifestations in the Serbian APS cohort. There is a strong link between some cardiovascular and pulmonary manifestations in PAPS patients, suggesting complexity and evolutionary nature of PAPS.


Assuntos
Síndrome Antifosfolipídica , Doenças Cardiovasculares , Hipertensão Pulmonar , Embolia Pulmonar , Trombose , Adulto , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/epidemiologia , Síndrome Antifosfolipídica/imunologia , Síndrome Antifosfolipídica/fisiopatologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Transversais , Feminino , Humanos , Hipertensão Pulmonar/epidemiologia , Hipertensão Pulmonar/etiologia , Inibidor de Coagulação do Lúpus/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/etiologia , Fatores de Risco , Sérvia/epidemiologia , Trombose/classificação , Trombose/epidemiologia , Trombose/etiologia , beta 2-Glicoproteína I/imunologia
12.
Case Rep Pulmonol ; 2014: 282196, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24782938

RESUMO

Intestinal type of lung adenocarcinoma (ILADC) was initially described by Tsao and Fraser in 1991. Morphology and immunophenotype of ILADC are the same as in colorectal adenocarcinoma. Rectocolonoscopy must be performed to exclude colorectal origin of adenocarcinoma. Colorectal adenocarcinoma claimed to be genetically similar to an ILADC. Patients. We describe 24- and 26-year-old patients of both genders who went under surgery because of a lung tumor mass detected on CT scan. ILADC was diagnosed on resected lung specimens. According to positivity of Cytokeratin20, CDX-2, and Villin, respectively, and negativity of Cytokeratin7, TTF-1, Napsin-A, SurfactantB, MUC-1, and MUC-2, respectively, ILADC was diagnosed. KRAS mutation was detected in tumor tissue of the male patient. Conclusion. Rectocolonoscopy is the only relevant method for distinguishing the intestinal type of lung adenocarcinoma from metastatic colorectal carcinoma because immunohistochemistry and detection of mutation status are frequently the same in both types of adenocarcinoma. More investigations are needed for further understanding of ILADC in purpose of personalized lung carcinoma therapy particularly introducing detection of mutation status, especially in younger patients.

13.
Isr Med Assoc J ; 16(3): 162-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24761704

RESUMO

BACKGROUND: Antiphospholipid syndrome (APS, also known as Hughes syndrome) may manifest itself as a primary or secondary disease, most commonly with systemic lupus erythemathosus (SLE) and various cardiac manifestations. OBJECTIVES: To report the first results from the Serbian National Cohort study, which was started in January 2000. METHODS: Our study included 374 patients: 260 primary APS patients and 114 SLE patients with secondary APS. Antiphospholipid antibody (aPL) analysis included detection of anticardiolipin antibodies (aCL) (immunoglobulin G and M), beta2-glycoprotein 1, and lupus anticoagulant. Echocardiography was performed in all patients, and data on myocardial infarction, unstable angina, chronic cardiomyopathy and acute heart failure were collected. RESULTS: There were 30.7% secondary APS patients and 9.2% primary APS patients with pseudo-infective endocarditis (P = 0.0001). Cardiac manifestations were observed in 28.7% of patients who had more than one type of antibody (category I), in 24.1% with category IIa, in 23.1% with category IIb, and in 27.8% with category IIc (P = 0.78). Age was confirmed as a significant factor for cardiac manifestations in APS patients (52.3 and 43.3 years, respectively, P = 0.001). aCL IgG and IgM positivity was related to valvular changes in all APS patients and high levels of those antibodies increased the risk of these manifestations. CONCLUSIONS: Patients with secondary APS had a higher prevalence ofvalvular lesions, and some aPL types and high levels of aPL were risk factors for specific cardiac manifestations in APS patients.


Assuntos
Anticorpos Anticardiolipina/imunologia , Anticorpos Antifosfolipídeos/imunologia , Síndrome Antifosfolipídica/complicações , Cardiopatias/epidemiologia , Adulto , Fatores Etários , Síndrome Antifosfolipídica/imunologia , Estudos de Coortes , Ecocardiografia , Feminino , Cardiopatias/imunologia , Cardiopatias/fisiopatologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Sérvia , beta 2-Glicoproteína I/imunologia
14.
Clin Exp Rheumatol ; 31(5): 756-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23899875

RESUMO

OBJECTIVES: The aim of this study was to investigate the association between non-thrombotic neurological and cardiac manifestations in patients with antiphospholipd syndrome (APS), as well as their connection with type and level of antiphospholipid antibodies. METHODS: Our prospective study comprises 333 patients: 218 with primary and 115 with secondary APS. Antiphospholipid antibody (aPL) analysis included detection of aCL(IgG/IgM), ß2GPI(IgG/IgM) and LA and served to evaluate associations with distinct neurological manifestations. RESULTS: The presence of aCL IgG was more common (p=0.001) in SAPS and LA in PAPS patients (p=0.002). High ß2GPI IgM levels (>100PLU/ml) were more common in epilepsy (p=0.00001) in PAPS, and in transient ischaemic attack (p=0.029) in SAPS. High ß2GPI IgG levels (>100PLU/ml) were more common in epilepsy (p=0.035) in SAPS. Chorea, migraine and epilepsy occurred more often in SAPS and headache and depression in PAPS. We found statistical significance considering the presence of aCL IgG and acute ischaemic encephalopathy in SAPS, aCL IgM and epilepsy in SAPS, aCL IgM and migraine in PAPS, ß2GPI IgG and chorea in SAPS and ß2GPI IgM and TIA and epilepsy in PAPS. LA was linked to depression, transient global amnaesia and migraine in PAPS. Patients with non-stable angina pectoris were more likely to develop TIA in both PAPS and SAPS, epilepsy and transient global amnaesia in PAPS and acute ischaemic encephalopathy in SAPS. Patients with valve vegetations were more prone to epilepsy and depression. CONCLUSIONS: Certain aPL type and levels are associated with distinct neurological non-thrombotic manifestation, suggesting their predictive role. There is strong link between some non-thrombotic neurological and cardiac manifestations in APS patients, suggesting the complexity and evolutionary nature of APS.


Assuntos
Síndrome Antifosfolipídica/complicações , Cardiopatias/etiologia , Doenças do Sistema Nervoso/etiologia , Adulto , Idoso , Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Progressão da Doença , Feminino , Cardiopatias/sangue , Cardiopatias/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/sangue , Doenças do Sistema Nervoso/imunologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Sérvia
15.
Clin Exp Rheumatol ; 31(2): 234-42, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23306109

RESUMO

OBJECTIVES: The aim of this study was to investigate the importance of aPL type and level for non-criteria-related events in APS patients. METHODS: Our study included 374 patients: 260 with PAPS and 114 with APS associated with systemic lupus erythematosus (SLE). RESULTS: We discovered significant connection between migraine and LA absence, livedo reticularis and aCL-IgG, skin ulcerations with aCL-IgG and anti-ß2GPI-IgM, pseudovasculitis lesions with aCL-IgG, aCL-IgM and anti-ß2GPI-IgM, and thrombocytopenia with aCL-IgM, aCL-IgG and anti-ß2GPI-IgG. Thrombocytopenia occurred more frequently in patients with more than one aPL. In PAPS, epilepsy correlated with ß2GPI-IgM, migraine with aCL-IgM, and thrombocytopenia with aCL-IgM, aCL-IgG, anti ß2GPI-IgG and LA. Skin ulcerations occurred more frequently in IIc category patients and in patients with high levels of aCL-IgG and anti ß2GPI-IgG. Livedo reticularis was more prominent in PAPS with high levels of aCL-IgG. Significantly higher prevalence of thrombocytopenia was observed in patients with high levels of aCL-IgG and anti ß2GPI-IgG. Epilepsy was related to high levels of anti ß2GPI-IgM and thrombocytopenia in the SAPS was correlated with aCL-IgG. Skin ulcerations were more prevalent in aCL-IgM positive SAPS patients and epilepsy more frequently in SAPS patients with high levels of anti ß2GPI-IgG. CONCLUSIONS: Our study showed that certain aPL type with certain level correlated with non-criteria manifestations, suggesting their predictive role.


Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/epidemiologia , Síndrome Antifosfolipídica/imunologia , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Anticorpos Anticardiolipina/sangue , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/diagnóstico , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Livedo Reticular/epidemiologia , Livedo Reticular/imunologia , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/imunologia , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Sérvia/epidemiologia , Úlcera Cutânea/epidemiologia , Úlcera Cutânea/imunologia , Trombocitopenia/epidemiologia , Trombocitopenia/imunologia , Vasculite/epidemiologia , Vasculite/imunologia , beta 2-Glicoproteína I/imunologia
17.
Tohoku J Exp Med ; 229(1): 29-34, 2013 01.
Artigo em Inglês | MEDLINE | ID: mdl-23221145

RESUMO

Patients suffering from autoimmune rheumatic diseases have significantly higher risk of developing various infections compared to the healthy population. Our study included patients suffering from systemic lupus erythematosus (n = 30), rheumatoid arthritis (n = 37) or Sjögren's syndrome (n = 32), with stable underlying diseases status. In November 2010, 47 patients, including 35 subjects vaccinated annually during 2006-2010, received immunization against influenza with trivalent inactivated split vaccine, whereas 52 patients did not accept proposed vaccination in that period. The presence of viral (primarily influenza) and bacterial infections, parameters of disease activity (from the date of vaccination until April 2011), and titers of antibodies against A H1N1 were then monitored in vaccinated and unvaccinated patients. We have identified the importance of predisposing factors for influenza occurrence (i.e. previous respiratory infections and vaccinations in last five years, age, sex, type of disease and duration, medications, smoking) in those groups of patients. The incidence of influenza or bacterial complications (bronchitis) among vaccinated patients was significantly lower, compared to the non-vaccinated group. Importantly, there was no case of exacerbation of the underlying disease. The last vaccination in 2010 reduced the risk of influenza by 87%, but previous bacterial infections (bronchitis and pneumonia) increased influenza risk significantly. In the present study, we have shown the efficiency, sufficient immunogenicity and safety of modern influenza vaccine application in patients suffering from systemic lupus erythematosus, rheumatoid arthritis or Sjögren's syndrome.


Assuntos
Artrite Reumatoide/complicações , Vírus da Influenza A Subtipo H1N1/imunologia , Vacinas contra Influenza/farmacologia , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Lúpus Eritematoso Sistêmico/complicações , Síndrome de Sjogren/complicações , Anticorpos Antivirais/sangue , Estudos Transversais , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Incidência , Vacinas contra Influenza/administração & dosagem , Influenza Humana/complicações , Masculino , Fatores de Risco , Resultado do Tratamento
18.
Pathol Oncol Res ; 19(1): 129-33, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22923000

RESUMO

The actual nature of spindle cell carcinoma has been debated extensively because of its rarity. It carries a poor prognosis, even when early-stage disease is diagnosed and resected. In view of the rarity and the significance of the histological diagnosis, we report a patient with rapidly progressing spindle cell lung carcinoma with soft tissue metastasis. Diagnosis was confirmed by immunohistochemistry finding. Analysis of the TP53 gene mutations by polymerase chain reaction and DNA sequencing revealed insertion of single thymine resulting in frameshift mutation in the exon 8. Prognosis of spindle cell lung carcinoma might be determined by the sarcoma component of the tumor and, based on that, we wonder if this type of lung carcinoma could be followed-up and treated by strategies for soft tissue sarcomas, because of its rapid, sarcomatous type of growth, beside the properly lung carcinoma oncological treatment.


Assuntos
Carcinoma/terapia , Neoplasias Pulmonares/terapia , Sarcoma/terapia , Adulto , Sequência de Bases , Carcinoma/genética , Carcinoma/imunologia , Carcinoma/patologia , Feminino , Humanos , Imunofenotipagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Dados de Sequência Molecular , Mutação , Recidiva Local de Neoplasia , Prognóstico , Sarcoma/genética , Sarcoma/imunologia , Sarcoma/patologia , Tomografia Computadorizada por Raios X , Proteína Supressora de Tumor p53/genética
20.
Epigenetics ; 7(6): 559-66, 2012 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-22522909

RESUMO

Epigenetic alterations are a common event in lung cancer and their identification can serve to inform on the carcinogenic process and provide clinically relevant biomarkers. Using paired tumor and non-tumor lung tissues from 146 individuals from three independent populations we sought to identify common changes in DNA methylation associated with the development of non-small cell lung cancer. Pathologically normal lung tissue taken at the time of cancer resection was matched to tumorous lung tissue and together were probed for methylation using Illumina GoldenGate arrays in the discovery set (n = 47 pairs) followed by bisulfite pyrosequencing for validation sets (n = 99 pairs). For each matched pair the change in methylation at each CpG was calculated (the odds ratio), and these ratios were averaged across individuals and ranked by magnitude to identify the CpGs with the greatest change in methylation associated with tumor development. We identified the top gene-loci representing an increase in methylation (HOXA9, 10.3-fold and SOX1, 5.9-fold) and decrease in methylation (DDR1, 8.1-fold). In replication testing sets, methylation was higher in tumors for HOXA9 (p < 2.2 × 10 (-16) ) and SOX1 (p < 2.2 × 10 (-16) ) and lower for DDR1 (p < 2.2 × 10 (-16) ). The magnitude and strength of these changes were consistent across squamous cell and adenocarcinoma tumors. Our data indicate that the identified genes consistently have altered methylation in lung tumors. Our identified genes should be included in translational studies that aim to develop screening for early disease detection.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Metilação de DNA , Epigênese Genética , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Loci Gênicos , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/genética , Neoplasias de Células Escamosas/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos
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