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PubMed | University of Porto and Higher Institute of Advanced Technologies
Type: | Journal: BioMed research international | Year: 2014

The aim of our study was to explore the clinicopathological and prognostic significance of extracellular matrix metalloproteinase inducer (EMMPRIN) expression in oral squamous cell carcinomas (OSCC), and its relation with the proliferative tumor status of OSCC. We examined EMMPRIN and Ki-67 proteins expression by immunohistochemistry in 74 cases with OSCC. Statistical analysis was conducted to examine their clinicopathological and prognostic significance in OSCC. EMMPRIN membrane expression was observed in all cases, with both membrane and cytoplasmic tumor expression in 61 cases (82.4%). EMMPRIN overexpression was observed in 56 cases (75.7%). Moderately or poorly differentiated tumors showed EMMPRIN overexpression more frequently than well-differentiated tumors (P = 0.002). Overexpression of EMMPRIN was correlated with high Ki-67 expression (P = 0.004). In the multivariate analysis, EMMPRIN overexpression reveals an adverse independent prognostic value for cancer-specific survival (CSS) (P = 0.034). Our results reveal that EMMPRIN protein is overexpressed in more than two-thirds of OSCC cases, especially in high proliferative and less differentiated tumors. The independent value of EMMPRIN overexpression in CSS suggests that this protein could be used as an important biological prognostic marker for patients with OSCC. Moreover, the high expression of EMMPRIN makes it a possible therapeutic target in OSCC patients.


PubMed | Fernando Pessoa University, Portuguese Oncology Institute IPOPorto, Higher Institute of Advanced Technologies and King's College London
Type: Journal Article | Journal: Journal of investigative and clinical dentistry | Year: 2016

To assess the awareness and knowledge on oral cancer in a general population of Oporto city, in Portugal.Face-to-face interviews were performed with 1116 individuals, resident in the city of Oporto. Participants socio-demographic information, lifestyle habits and awareness, knowledge and beliefs on oral cancer were ascertained.Breast cancer was the most mentioned being as heard of (69.8%), while oral cancer was one of the least heard of (23.7%). Tobacco was identified as a risk factor by 54.8% of individuals and this knowledge was associated with their education level (P<0.001), dentist visits (P=0.026), and tobacco consumption (P<0.001). Fewer subjects (24.6%) referred to alcohol as a risk factor, and this knowledge was associated with their education level (P=0.020) and dentist visits (P=0.002). More than half the subjects (58.8%) could not identify any sign or symptom of oral cancer.There is a general lack of awareness on oral cancer among this Oporto population. Higher education level and better oral health care were significant factors that identified individuals with a better awareness and knowledge of oral cancer, suggesting that educational measures could be useful for the prevention and early diagnosis of oral cancer in the Portuguese population.


Lima A.,Higher Institute of Advanced Technologies | Lima A.,Portuguese Institute of Oncology of Porto IPO Porto | Lima A.,University of Porto | Seabra V.,Higher Institute of Advanced Technologies | And 6 more authors.
Molecular Biology Reports | Year: 2014

Abstract Thymidylate synthase (TYMS) has three polymorphisms that may modulate thymidylate synthase (TS) expression levels: (1) 28 base pairs (bp) variable number tandem repeat (VNTR) (rs34743033); (2) single nucleotide polymorphism (SNP) C>G at the twelfth nucleotide of the second repeat of 3R allele (rs2853542); and (3) 6 bp sequence deletion (1494del6, rs34489327). This study was conducted to evaluate the influence of TYMS polymorphisms on the survival of Portuguese patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Our results showed no statistically significant differences between VNTR genotypes; although, considering the SNP C>G, homozygotes 3RG presented a better prognostic at 36 months (p = 0.004) and overall survival (p = 0.003) when compared to 2R3RG patients. Patients with "median/high expression genotypes" demonstrated a better survival at 12 months (p = 0.041) when compared to "low expression genotypes". Furthermore, 6 bp- carriers (p = 0.006) showed a better survival at 12 months when compared to 6 bp+ homozygotes patients. When analyzing TYMS haplotypes, better survival at 12 months was observed for patients carrying haplotypes with the 6 bp- allele (2R6 bp-; p = 0.026 and 3RG6 bp-; p = 0.045). This is the first report that evaluates the three major TYMS polymorphisms in the therapeutic outcome of NSCLC in Portugal. According to our results, the TYMS polymorphisms may be useful tools to predict which advanced NSCLC patients could benefit more from platinum-based chemotherapy regimens. © Springer Science+Business Media 2014.


Lima A.,University of Porto | Bernardes M.,University of Porto | Azevedo R.,University of Porto | Monteiro J.,Higher Institute of Advanced Technologies | And 3 more authors.
Toxicological sciences : an official journal of the Society of Toxicology | Year: 2014

Methotrexate (MTX) is used for rheumatoid arthritis (RA) treatment showing a wide toxicity profile. This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding for MTX transporters with the occurrence of MTX-related toxicity (overall and gastrointestinal). A total of 233 Portuguese RA patients were genotyped for 23 SNPs. Haplotype analyses were performed and a toxicogenetic risk index (TRI) was created for SNPs that revealed to be statistically significant. Regarding MTX overall toxicity, an increased risk was associated to SLC19A1 rs7499 G carriers (p = 0.017), SLC46A1 rs2239907 GG (p = 0.030) and, SLCO1B1 rs4149056 T carriers (p = 0.040) and TT (p = 0.019). TRI revealed that patients with Index 3 were 18-fold more likely to present an adverse drug reaction when compared to those with Index 1 (p = 0.001). For MTX gastrointestinal toxicity, results demonstrated an increased risk associated with SLC19A1 rs7499 G carriers (p = 0.012) and GG (p = 0.045), SLC19A1 rs1051266 G carriers (p = 0.034), SLC19A1 rs2838956 A carriers (p = 0.049) and, SLCO1B1 rs4149056 T carriers (p = 0.042) and TT (p = 0.025). Haplotype analyses showed association between GGAG haplotype for SLC19A1 rs7499, rs1051266, rs2838956 and rs3788200 with MTX gastrointestinal toxicity (p = 0.029). TRI revealed that patients with Index 4 were 9-fold more likely to present a gastrointestinal disorder when compared to those with Index 1 (p = 0.020). This study demonstrated that SLC19A1, SLC46A1 and SLCO1B1 genotypes may help to identify patients with increased risk of MTX-related overall toxicity and that SLC19A1 and SLCO1B1 genotypes, and SLC19A1 haplotypes may help to identify patients with increased risk of MTX-related gastrointestinal toxicity. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.


PubMed | University of Porto and Higher Institute of Advanced Technologies
Type: | Journal: BioMed research international | Year: 2014

Methotrexate (MTX), the most used drug in rheumatoid arthritis (RA) treatment, showing variability in clinical response, is often associated with genetic polymorphisms. This study aimed to elucidate the role of methylenetetrahydrofolate reductase (MTHFR) C677T and aminoimidazole carboxamide adenosine ribonucleotide transformylase (ATIC) T675C polymorphisms and clinicopathological variables in clinical response to MTX in Portuguese RA patients.Study included 233 RA patients treated with MTX for at least six months. MTHFR C677T and ATIC T675C polymorphisms were genotyped and clinicopathological variables were collected. Statistical analyses were performed and binary logistic regression method adjusted to possible confounding variables.Multivariate analyses demonstrated that MTHFR 677TT (OR = 4.63; P = 0.013) and ATIC 675T carriers (OR = 5.16; P = 0.013) were associated with over 4-fold increased risk for nonresponse. For clinicopathological variables, noncurrent smokers (OR = 7.98; P = 0.001), patients positive to anti-cyclic citrullinated peptide (OR = 3.53; P = 0.004) and antinuclear antibodies (OR = 2.28; P = 0.045), with higher health assessment questionnaire score (OR = 2.42; P = 0.007), and nonsteroidal anti-inflammatory drug users (OR = 2.77; P = 0.018) were also associated with nonresponse. Contrarily, subcutaneous administration route (OR = 0.11; P < 0.001) was associated with response.Our study suggests that MTHFR C677T and ATIC T675C genotyping combined with clinicopathological data may help to identify patients whom will not benefit from MTX treatment and, therefore, assist clinicians in personalizing RA treatment.


PubMed | University of Porto and Higher Institute of Advanced Technologies
Type: Journal Article | Journal: Toxicological sciences : an official journal of the Society of Toxicology | Year: 2014

Methotrexate (MTX) is used for rheumatoid arthritis (RA) treatment showing a wide toxicity profile. This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding for MTX transporters with the occurrence of MTX-related toxicity (overall and gastrointestinal). A total of 233 Portuguese RA patients were genotyped for 23 SNPs. Haplotype analyses were performed and a toxicogenetic risk index (TRI) was created for SNPs that revealed to be statistically significant. Regarding MTX overall toxicity, an increased risk was associated to SLC19A1 rs7499 G carriers (p = 0.017), SLC46A1 rs2239907 GG (p = 0.030) and, SLCO1B1 rs4149056 T carriers (p = 0.040) and TT (p = 0.019). TRI revealed that patients with Index 3 were 18-fold more likely to present an adverse drug reaction when compared to those with Index 1 (p = 0.001). For MTX gastrointestinal toxicity, results demonstrated an increased risk associated with SLC19A1 rs7499 G carriers (p = 0.012) and GG (p = 0.045), SLC19A1 rs1051266 G carriers (p = 0.034), SLC19A1 rs2838956 A carriers (p = 0.049) and, SLCO1B1 rs4149056 T carriers (p = 0.042) and TT (p = 0.025). Haplotype analyses showed association between GGAG haplotype for SLC19A1 rs7499, rs1051266, rs2838956 and rs3788200 with MTX gastrointestinal toxicity (p = 0.029). TRI revealed that patients with Index 4 were 9-fold more likely to present a gastrointestinal disorder when compared to those with Index 1 (p = 0.020). This study demonstrated that SLC19A1, SLC46A1 and SLCO1B1 genotypes may help to identify patients with increased risk of MTX-related overall toxicity and that SLC19A1 and SLCO1B1 genotypes, and SLC19A1 haplotypes may help to identify patients with increased risk of MTX-related gastrointestinal toxicity.


PubMed | Higher Institute of Advanced Technologies
Type: Journal Article | Journal: Molecular biology reports | Year: 2014

Thymidylate synthase (TYMS) has three polymorphisms that may modulate thymidylate synthase (TS) expression levels: (1) 28 base pairs (bp) variable number tandem repeat (VNTR) (rs34743033); (2) single nucleotide polymorphism (SNP) C>G at the twelfth nucleotide of the second repeat of 3R allele (rs2853542); and (3) 6 bp sequence deletion (1494del6, rs34489327). This study was conducted to evaluate the influence of TYMS polymorphisms on the survival of Portuguese patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based chemotherapy. Our results showed no statistically significant differences between VNTR genotypes; although, considering the SNP C>G, homozygotes 3RG presented a better prognostic at 36 months (p=0.004) and overall survival (p=0.003) when compared to 2R3RG patients. Patients with median/high expression genotypes demonstrated a better survival at 12 months (p=0.041) when compared to low expression genotypes. Furthermore, 6 bp- carriers (p=0.006) showed a better survival at 12 months when compared to 6 bp+ homozygotes patients. When analyzing TYMS haplotypes, better survival at 12 months was observed for patients carrying haplotypes with the 6 bp- allele (2R6 bp-; p=0.026 and 3RG6 bp-; p=0.045). This is the first report that evaluates the three major TYMS polymorphisms in the therapeutic outcome of NSCLC in Portugal. According to our results, the TYMS polymorphisms may be useful tools to predict which advanced NSCLC patients could benefit more from platinum-based chemotherapy regimens.


PubMed | University of Porto and Higher Institute of Advanced Technologies
Type: Journal Article | Journal: PloS one | Year: 2014

Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients.Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches.Considering TYMS genotypes, 3R3R (p=0.005, OR=2.34), 3RC3RG (p=0.016, OR=3.52) and 6bp- carriers (p=0.011, OR=1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp- carriers (p=0.016, OR=2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp- alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes.Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences.


PubMed | University of Parma and Higher Institute of Advanced Technologies
Type: | Journal: Case reports in dentistry | Year: 2015

Central odontogenic fibroma is a very rare benign odontogenic tumour characterized by a fibrous mature stroma with variable strands or islands of inactive-looking odontogenic epithelium. Our aim is to report a case of a central odontogenic fibroma and describe the clinical usefulness of Er:YAG laser for the surgical treatment of this tumour. A 74-year-old woman presented with an expansive lesion located in a mandible with multilocular and mixed radiographic appearance. A conservative excision using Er:YAG laser was performed. Complete removal was obtained. There were no postoperative complications. The histopatologic features were consistent with the diagnosis of central odontogenic fibroma of rich-epithelium type. No recurrence was observed during follow-up.


PubMed | Higher Institute of Advanced Technologies
Type: Journal Article | Journal: Pharmacogenomics | Year: 2014

Methotrexate (MTX) is used in low doses to treat a variety of diseases. Although the mechanism responsible for its therapeutic action is unknown, MTX membrane transport proteins (influx and/or efflux) can be major determinants of pharmacokinetics, adverse drug reactions and clinical response profiles. With progess in pharmacogenomics, the improvement of the prediction of patients therapeutic outcome treated with low doses of MTX will offer a powerful tool for the translation of transporter SNPs into clinical practice and will be essential to sustain a breakthrough in the field of personalized medicine. Therefore, this paper provides an update on the current data on SNPs in genes encoding low-dose MTX membrane transport proteins and their relevance as possible biomarkers of MTX therapeutic outcome.

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