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1.
Chem Res Toxicol ; 35(10): 1805-1808, 2022 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-35482010

RESUMO

In the course of studies on the enhancement of 1,2-dibromoethane-induced DNA base pair mutations by O6-alkylguanine-DNA alkyltransferase (AGT, MGMT), we discovered the facile reaction of AGT with an abasic site in DNA, leading to covalent cross-linking. The binding of AGT differs from the mechanism reported for the protein HMCES; instead it appears to involve formation of a stable thioglycoside. Facile cross-linking was also observed with the protease papain, which like AGT has a low pKa cysteine, and the tripeptide glutathione.


Assuntos
Dibrometo de Etileno , Tioglicosídeos , Cisteína , DNA/metabolismo , Reparo do DNA , Glutationa , O(6)-Metilguanina-DNA Metiltransferase/metabolismo , Papaína/metabolismo , Compostos de Sulfidrila
2.
Oncotarget ; 8(41): 69456-69464, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-29050216

RESUMO

Although rare, mucoepidermoid carcinoma (MEC) is one of the most common malignant salivary gland tumors. The presence of the t(11;19)(q21;p13) translocation in a subset of MECs has raised interest in genomic aberrations in MEC. In the present study we conducted genome-wide copy-number-aberration analysis by micro-array comparative-genomic-hybridization on 27 MEC samples. Low/intermediate-grade MECs had significantly fewer copy-number-aberrations compared to high-grade MECs (low vs high: 3.48 vs 30; p = 0.0025; intermediate vs high: 5.7 vs 34.5; p = 0.036). The translocation-negative MECs contained more copy-number-aberrations than translocation-positive MECs (average amount of aberrations 15.9 vs 2.41; p =0.04). Within all 27 MEC samples, 16p11.2 and several regions on 8q were the most frequently gained regions , while 1q23.3 was the most frequently detected loss. Low/intermediate-grade MEC samples had copy-number-aberrations in chromosomes 1, 12 and 16, while high-grade MECs had a copy-number-aberration in 8p. The most commonly observed copy-number-aberration was the deletion of 3p14.1, which was observed in 4 of the translocation-negative MEC samples. No recurrent copy-number-aberrations were found in translocation-positive MEC samples. Based on these results, we conclude that MECs may be classified as follows: (i) t(11;19)(q21;p13) translocation-positive tumors with no or few chromosomal aberrations and (ii) translocation-negative tumors with multiple chromosomal aberrations.

3.
Arch Oral Biol ; 82: 121-126, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28628803

RESUMO

OBJECTIVES: The aberrant expression of mucins and mucin-type carbohydrates has been described in many types of cancer, including mucoepidermoid carcinoma (MEC), a malignant salivary gland tumor. In this study, we examined the aberrant expression patterns of mucins (MUC1, MUC4, MUC5AC and MUC5B), simple mucin-type carbohydrate antigens (Tn, sialyl-Tn and T) and mature carbohydrate antigens (Lewisa and sulfo-Lewisa antigens) in MEC originating from the parotid gland, which normally does not secrete mucins. DESIGN: We conducted an immunohistochemical study to investigate the presence of mucins and carbohydrates in 24 MEC samples originating from the parotid gland and in surrounding normal tissue of the same gland in comparison 6 samples of normal salivary glands. The expression levels were compared with respect to the histological grading. Furthermore, 24 MEC samples from non-parotid salivary glands were included. RESULTS: We observed loss of topology of membrane-bound MUC1 and MUC4, and de novo expression of MUC5AC, MUC5B and sialyl-Tn in MEC that originated in the parotid gland. Furthermore, mucins MUC1, MUC4 and carbohydrate antigens Tn, sialyl-Tn, T, Lewisa and sulfo-Lewisa were overexpressed in MEC samples compared to surrounding normal salivary gland tissues. MUC1 was expressed in both low- and high grade MECs, whereas MUC4 was not expressed in high grade MECs of the parotid gland. CONCLUSION: During the development of MEC in the parotid gland, the genes for gel-forming secretory mucins are switched on. Besides these MEC tissues overexpress short oligosaccharides, suggesting that the glycosylation machinery is altered.


Assuntos
Antígenos Glicosídicos Associados a Tumores/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Mucina-5AC/metabolismo , Mucina-5B/metabolismo , Neoplasias Parotídeas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Criança , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade
5.
PLoS One ; 10(11): e0142264, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26544193

RESUMO

BACKGROUND: Currently, clinical examination, ultrasound scanning (with or without fine needle aspiration cytology), preoperative CT-scan and MRI are available for the differential diagnosis of parotid gland swelling. A preliminary non-invasive salivary diagnostic tool may be helpful in the clinical decision making process. Altered salivary micro-RNA (miRNA) expression levels have been observed in saliva from patients with various cancers. Therefore, we investigated miRNA expression levels in saliva samples from patients with a parotid gland neoplasm using Human miRNA cards in comparison to controls. RESULTS: In the discovery phase, eight miRNAs were identified having different expression levels in patients compared to controls. In the validation phase, the differences in miRNA expression levels between patients and controls were confirmed for seven out of eight discovered miRNAs (p < 0.001). A combination of two miRNAs yielded a receiver-operator-characteristics curve with an AUC of 0.94 (95% CI: 0.87-1.00; sensitivity 91%; specificity 86%). Validation of discovered miRNAs in segregated collected parotid saliva revealed that expression of these miRNAs differ between whole saliva and parotid saliva. CONCLUSIONS: A two miRNA combination can predict the presence of a parotid gland neoplasm. Furthermore, this study suggested that the identified, patient-specific, salivary miRNAs were not derived from the parotid gland itself.


Assuntos
Biomarcadores Tumorais/metabolismo , MicroRNAs/metabolismo , Neoplasias Parotídeas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Citodiagnóstico/métodos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Glândula Parótida/metabolismo , Glândula Parótida/patologia , Neoplasias Parotídeas/metabolismo , Saliva/metabolismo
6.
Clin Cancer Res ; 19(11): 3032-8, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23575476

RESUMO

PURPOSE: This study was conducted to explore the differences in salivary microRNA (miRNA) profiles between patients with malignant or benign parotid gland tumors as a potential preoperative diagnostic tool of tumors in the salivary glands. EXPERIMENTAL DESIGN: Whole saliva samples from patients with malignant (n = 38) or benign (n = 29) parotid gland tumors were obtained from the Salivary Gland Tumor Biorepository (SGTB). After total RNA isolation, human miRNA cards were used for miRNA profiling. The differential miRNA expression was analyzed using two-sided Wilcoxon test. Quantitative real-time PCR (qRT-PCR) was used to validate selected miRNAs in an independent sample set. Receiver-operating characteristics curve and probability of malignancy was exploited to evaluate the diagnostic power of the validated miRNAs. RESULTS: With miRNA profiling, 57 of 750 investigated miRNAs were differently expressed, of which 54 showed higher miRNA expression in samples from patients with malignant tumors than those from patients with benign tumors. Validating the expression in an independent sample set of 9 miRNAs revealed indeed higher expression of miRNAs in malignant samples compared with benign samples. The expression of 6 validated miRNAs was statistically significantly different between the two groups (P < 0.05). A four miRNA combination was able to discriminate between saliva samples from patients with malignant tumors from those of patients with benign parotid gland tumors (sensitivity 69%, specificity 95%). CONCLUSIONS: Salivary miRNA profiles differ in saliva from patients with malignant from saliva from patients with a benign parotid gland tumor. These preliminary results are promising to develop a noninvasive diagnostic tool for diagnosing tumors in the salivary glands.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias Parotídeas/diagnóstico , Neoplasias Parotídeas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Espaço Extracelular , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reprodutibilidade dos Testes , Saliva/química
7.
J Biotechnol ; 139(1): 12-8, 2009 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18984015

RESUMO

Cytochrome P450 (P450) 2A6 is able to catalyze indole hydroxylation to form the blue dye indigo. The wild-type P450 2A6 enzyme was randomly mutated throughout the whole open reading frame and screened using 4-chloroindole hydroxylation, a substituted indole selected from 30 indole compounds for enhanced color development. Mutants with up to 5-fold increases of catalytic efficiency (k(cat)/K(m)) and 2-fold increases in k(cat) were selected after two rounds of screening. Important residues located both in (e.g., Thr305) and outside the active site (e.g., Ser224) were identified. The study utilized a better substrate for "indigo assay" to obtain new information on the structure-functional relationship of P450 2A6 that was not revealed by previous mutagenesis studies with this enzyme.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Indóis/metabolismo , Hidrocarboneto de Aril Hidroxilases/química , Citocromo P-450 CYP2A6 , Bases de Dados de Proteínas , Escherichia coli , Humanos , Hidroxilação , Índigo Carmim , Cinética , Membranas/metabolismo , Modelos Químicos , Modelos Moleculares , Mutagênese , Análise de Sequência de Proteína
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