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1.
Hum Mutat ; 2019 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-31209999

RESUMO

BRCA1 BRCA2 mutational spectrum in the Middle East, North Africa, and Southern Europe is not well characterized. The unique history and cultural practices characterizing these regions, often involving consanguinity and inbreeding, plausibly led to the accumulation of population-specific founder pathogenic sequence variants (PSVs). To determine recurring BRCA PSVs in these locales, a search in PUBMED, EMBASE, BIC, and CIMBA was carried out combined with outreach to researchers from the relevant countries for unpublished data. We identified 232 PSVs in BRCA1 and 239 in BRCA2 in 25 of 33 countries surveyed. Common PSVs that were detected in four or more countries were c.5266dup (p.Gln1756Profs), c.181T>G (p.Cys61Gly), c.68_69del (p.Glu23Valfs), c.5030_5033del (p.Thr1677Ilefs), c.4327C>T (p.Arg1443Ter), c.5251C>T (p.Arg1751Ter), c.1016dup (p.Val340Glyfs), c.3700_3704del (p.Val1234Glnfs), c.4065_4068del (p.Asn1355Lysfs), c.1504_1508del (p.Leu502Alafs), c.843_846del (p.Ser282Tyrfs), c.798_799del (p.Ser267Lysfs), and c.3607C>T (p.Arg1203Ter) in BRCA1 and c.2808_2811del (p.Ala938Profs), c.5722_5723del (p.Leu1908Argfs), c.9097dup (p.Thr3033Asnfs), c.1310_1313del (p. p.Lys437Ilefs), and c.5946del (p.Ser1982Argfs) for BRCA2. Notably, some mutations (e.g., p.Asn257Lysfs (c.771_775del)) were observed in unrelated populations. Thus, seemingly genotyping recurring BRCA PSVs in specific populations may provide first pass BRCA genotyping platform.

2.
Amyloid ; 25(4): 220-226, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30572722

RESUMO

BACKGROUND: ATTRV30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by amyloid deposition composed of aggregated misfolded TTR monomers with the V30M mutation. The age of onset in patients with ATTRV30M varies in different foci and the mechanism behind it is still unknown. METHODS: The tertiary neurology center following all ATTRV30M patients in Cyprus was used to collect demographic data to estimate; prevalence, incidence, penetrance, anticipation, time from disease onset to diagnosis and transplantation. Ocular, cardiac and leptomeningeal involvement in transplanted patients was explored. Correlation of C1q tagging SNPs with age of disease onset was carried out. RESULTS: Prevalence and incidence for ATTRV30M neuropathy in Cyprus are 5.4/100,000 and 0.3/100,000 respectively. Mean age of onset is 40.6 years and anticipation is 8.3 years. Penetrance reaches 51% and 75% by the ages of 50 and 80 years respectively. In liver transplanted patients rates of ocular, cardiac and leptomeningeal involvement were estimated to be 60%, 20% and 16%, respectively. C1q polymorphisms correlated with age of disease onset. CONCLUSIONS: ATTRV30M neuropathy has a rising prevalence in Cyprus due to improved survival of patients. Late onset complications are becoming a major problem. Complement C1q appears to be a modifier in this disease.


Assuntos
Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genética , Complemento C1q/genética , Genes Modificadores , Mutação , Polimorfismo de Nucleotídeo Único , Pré-Albumina/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Amiloide/química , Estudos de Casos e Controles , Criança , Estudos de Coortes , Chipre/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
3.
Nanomedicine ; 2018 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-30448526

RESUMO

Herein, we maximize the labeling efficiency of cardiac progenitor cells (CPCs) using perfluorocarbon nanoparticles (PFCE-NP) and 19F MRI detectability, determine the temporal dynamics of single-cell label uptake, quantify the temporal viability/fluorescence persistence of labeled CPCs in vitro, and implement in vivo, murine cardiac CPC MRI/tracking that could be translatable to humans. FuGENEHD-mediated CPC PFCE-NP uptake is confirmed with flow cytometry/confocal microscopy. Epifluorescence imaging assessed temporal viability/fluorescence (up to 7days [D]). Nonlocalized murine 19F MRS and cardiac MRI studied label localization in terminal/longitudinal tracking studies at 9.4 T (D1-D8). A 4-8 fold 19F concentration increase is evidenced in CPCs for FuGENE vs. directly labeled cells. Cardiac 19F signals post-CPC injections diminished in vivo to ~31% of their values on D1 by D7/D8. Histology confirmed CPC retention, dispersion, and macrophage-induced infiltration. Intra-cardiac injections of PFCE-NP-labeled CPCs with FuGENE can be visualized/tracked in vivo for the first time with 19F MRI.

4.
Pulm Pharmacol Ther ; 48: 15-21, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29056509

RESUMO

OBJECTIVES: Few studies have examined the potentially therapeutic effect of increasing the production of endogenous nitric oxide (NO) in Primary Ciliary Dyskinesia (PCD) and other chronic respiratory conditions. Nasal NO is low in PCD and has been found to correlate with compromised Ciliary Beat Frequency (CBF). In this study we assessed the effect of increasing l-Arginine, as the substrate of NO synthases, on CBF in biopsies of human respiratory ciliated epithelium. METHODOLOGY: A total of 28 suspect cases with chronic respiratory manifestations referred for PCD diagnostic testing and 8 healthy controls underwent nasal brushing. Obtained epithelial cells were divided between three culture medium 199 solutions, containing different levels of l-Arginine (0.33 mM as baseline, 1 mM and 10 Mm as increased levels). CBF measurements were obtained at 37 °C and 25 °C at 1, 3 and 24 h after sample acquisition. RESULTS: Among a total of 36 recruited subjects, 8 had PCD confirmed (PCD n = 8), 20 had PCD excluded (non-PCD n = 20) and 8 were healthy controls (Healthy Controls = 8). Among PCD subjects, ciliary motility was characterized by rotational (n = 5) or dyskinetic (n = 3) beating. At 37 °C, compared to baseline, higher levels of l-Arginine resulted in up to 9% CBF increase at 1 h (p = 0.007), up to 9% CBF increase at 3 h (p < 0.001) and up to 12% CBF increase at 24 h (p = 0.002). Similar although smaller scale increases were recorded at 25 °C. The effect of l-Arginine was time dependent (interaction p = 0.002) and was similar in PCD patients, non-PCD chronic respiratory patients and healthy controls (interaction p = 0.800). CONCLUSIONS: l-Arginine increases CBF and merits to be evaluated as a potential stimulator of mucociliary clearance in chronic respiratory conditions and congenital ciliary disorders with residual motility. Larger human studies are needed to confirm these findings.

5.
PLoS One ; 12(9): e0183444, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28877188

RESUMO

BACKGROUND: Despite evidence supporting an involvement of mitochondrial dysfunction in the pathogenesis of some neurodegenerative disorders, there are inconsistent findings concerning mitochondrial haplogroups and their association to neurodegenerative disorders, including idiopathic Parkinson's disease (PD). METHODS: To test this hypothesis for the Greek-Cypriot population, a cohort of 230 PD patients and 457 healthy matched controls were recruited. Mitochondrial haplogroup distributions for cases and controls were determined. Association tests were carried out between mitochondrial haplogroups and PD. RESULTS: Mitochondrial haplogroup U was associated with a reduced PD risk in the Cypriot population. After pooling mitochondrial haplogroups together into haplogroup clusters and superclusters, association tests demonstrated a significantly protective effect of mitochondrial haplogroup cluster N (xR) and supercluster LMN for PD risk only in females. In addition, for female PD cases belonging to UKJT and R (xH, xUKJT) haplogroup, the odds of having a later age of onset of PD were 13 and 15 times respectively higher than the odds for female cases with an H haplogroup. CONCLUSION: Statistically significant associations regarding PD risk and PD age of onset were mostly detected for females thus suggesting that gender is a risk modifier between mitochondrial haplogroups and PD status / PD age of onset. The biological mechanisms behind this gender specificity remain to be determined.


Assuntos
Mitocôndrias/metabolismo , Doença de Parkinson/epidemiologia , Doença de Parkinson/metabolismo , Caracteres Sexuais , Idade de Início , Idoso , Estudos de Casos e Controles , Intervalos de Confiança , DNA Mitocondrial/genética , Feminino , Grécia , Haplótipos/genética , Humanos , Masculino , Razão de Chances , Fases de Leitura Aberta/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética
6.
Neurol Neuroimmunol Neuroinflamm ; 4(4): e350, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28473999

RESUMO

OBJECTIVE: To assess the potential effect of variants in genes encoding molecules that are implicated in leukocyte trafficking into the CNS on the clinical phenotype of multiple sclerosis (MS). METHODS: A total of 389 Greek MS cases and 336 controls were recruited in 3 MS centers from Cyprus and Greece. We genotyped 147 tagging single nucleotide polymorphisms (SNPs) in 9 genes encoding for P-selectin (SELP), integrins (ITGA4, ITGB1, and ITGB7), adhesion molecules (ICAM1, VCAM1, and MADCAM1), fibronectin 1 (FN1), and osteopontin (SPP1) involved in lymphocyte adhesion and trafficking into the CNS. Clinical end points of the study were age at MS onset and MS severity as measured by the Multiple Sclerosis Severity Score. Permutation testing was applied to all analyses. RESULTS: SNPs rs6721763 of the ITGA4 and rs6532040 of the SPP1 were found to significantly influence disease severity (permutation p values: 3.00e-06 and 0.009884, respectively). SNP rs1250249 of the FN1 had a dose-dependent effect on age at disease onset (permutation p value: 0.0002). CONCLUSIONS: This study provides evidence implicating variants encoding adhesion molecules, responsible for lymphocyte adhesion and trafficking within the CNS, as modifiers of MS disease severity. These genetic biomarkers, which can be available at the time of diagnosis, may be used to assess the biological aggressiveness of the disease and thus guide decisions on treatment.

7.
Int J Prosthodont ; 30(3): 280­285, 2017 May/June.
Artigo em Inglês | MEDLINE | ID: mdl-28319210

RESUMO

Oculo-dento-digital dysplasia (ODDD) is a congenital disorder manifesting with multiple phenotypic abnormalities involving the face, eyes, teeth, and limbs in addition to neurologic symptomatology. This report aims to present a female patient with ODDD who was referred due to extensive oral restorative needs. The presence of hypoplastic enamel triggered further evaluation. Characteristic facies with hypoplastic alae nasi and syndactyly offered greater insight into the phenotype of the syndrome. Clinical suspicion was confirmed by genetic sequencing revealing heterozygous mutation in GJA1. It is important to be aware of genetic disorders associated with characteristic dental malformations to offer appropriate counseling and treatment.


Assuntos
Conexina 43/genética , Anormalidades Craniofaciais/genética , Anormalidades do Olho/genética , Deformidades Congênitas do Pé/genética , Reabilitação Bucal/métodos , Sindactilia/genética , Anormalidades Dentárias/genética , Adulto , Feminino , Humanos , Mutação , Fenótipo
8.
Eur J Nutr ; 56(2): 545-555, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26572891

RESUMO

PURPOSE: Xenobiotic metabolism is related to the interplay between diet and breast cancer (BC) risk. This involves detoxification enzymes, which are polymorphic and metabolise various dietary metabolites. An important characteristic of this pathway is that chemoprotective micronutrients can act not only as substrates but also as inducers for these enzymes. We investigated whether functional GSTP1 (p.Ile105Val-rs1695), NAT2 (590G>A-rs1799930) SNPs and GSTM1 and GSTT1 deletion polymorphisms could modulate the effect of the Mediterranean diet (MD) on BC risk, in Greek-Cypriot women. METHODS: Genotyping was performed on women from the MASTOS case-control study of BC in Cyprus. A 32-item food-frequency questionnaire was used to obtain dietary intake information. A dietary pattern, which closely resembles the MD (high loadings of vegetables, fruit, legumes and fish), was previously derived with principal component analysis and was used as our dietary variable. RESULTS: GSTT1 null genotype increased BC risk compared with the homozygous non-null GSTT1 genotype (OR 1.21, 95 % CI 1.01-1.45). Increasing adherence to the MD reduced BC risk in women with at least one GSTP1 Ile allele (OR for Ile/Ile = 0.84, 95 % CI 0.74-0.95, for Ile/Val = 0.73, 95 % CI 0.62-0.85) or one NAT2 590G allele (OR for 590 GG = 0.73, 95 % CI 0.63-0.83, for 590 GA = 0.81, 95 % CI 0.70-0.94). p interaction values were not, however, statistically significant. CONCLUSION: The homozygous null GSTT1 genotype could be a risk allele for BC among Greek-Cypriot women. The anticarcinogenic effects of the high adherence to MD against BC risk could also be further enhanced when combined with the wild-type alleles of the detoxification GSTP1 or NAT2 SNPs.


Assuntos
Arilamina N-Acetiltransferase/genética , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Dieta Mediterrânea , Glutationa Transferase/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Idoso , Estudos de Casos e Controles , Chipre/epidemiologia , Registros de Dieta , Inquéritos sobre Dietas , Feminino , Frequência do Gene , Genótipo , Grécia/epidemiologia , Grécia/etnologia , Humanos , Pessoa de Meia-Idade
9.
Mol Nutr Food Res ; 61(4)2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27860207

RESUMO

SCOPE: A high adherence to the Mediterranean diet (MD) was previously associated with a decreased risk of breast cancer (BC) among Greek-Cypriot women. Additionally, particular polymorphisms were shown to modulate this MD-BC association. Herein, we aimed to investigate the effect of polymorphisms-MD interactions on the levels of specific metabolites that could be related to dietary adherence or enzymatic activity, which is itself modulated by polymorphisms. METHODS AND RESULTS: Greek-Cypriot women who were BC controls and had the lowest or the highest MD adherence (vegetables, fruit, legumes, fish) as assessed by principal component analysis (n = 564) were included. Participants were previously genotyped for nine polymorphisms of the one-carbon metabolism, oxidative stress, and xenobiotic metabolism. The serum levels of 14 metabolites that are key players in the aforementioned pathways were measured by UPLC-MS/MS. ANCOVA was used to assess polymorphism-MD interactions on metabolites' levels within a multivariate linear regression model. Statistically significant interactions between GSTM1 (where GST is glutathione S-transferase) deletion polymorphism and MD on flavin mononucleotide and on 5-methyltetrahydrofolate (5-MTHF) concentrations were observed. The MTHFR rs1801133 interacted significantly with MD on 5-MTHF concentration. CONCLUSION: Serum levels of flavin mononucleotide and 5-MTHF were shown to be influenced by interactions between GSTM1 deletion or MTHFR (rs1801133) polymorphisms and a dietary pattern, characteristic of MD.


Assuntos
Neoplasias da Mama/dietoterapia , Dieta Mediterrânea , Metabolômica , Adulto , Idoso , Fabaceae , Feminino , Frutas , Genótipo , Glutationa Transferase/genética , Glutationa Transferase/metabolismo , Grécia , Humanos , Pessoa de Meia-Idade , Estresse Oxidativo , Polimorfismo Genético , Tetra-Hidrofolatos , Verduras
10.
J Cell Mol Med ; 21(5): 993-1012, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27878954

RESUMO

Advances in mass spectrometry technologies have created new opportunities for discovering novel protein biomarkers in systemic lupus erythematosus (SLE). We performed a systematic review of published reports on proteomic biomarkers identified in SLE patients using mass spectrometry-based proteomics and highlight their potential disease association and clinical utility. Two electronic databases, MEDLINE and EMBASE, were systematically searched up to July 2015. The methodological quality of studies included in the review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Twenty-five studies were included in the review, identifying 241 SLE candidate proteomic biomarkers related to various aspects of the disease including disease diagnosis and activity or pinpointing specific organ involvement. Furthermore, 13 of the 25 studies validated their results for a selected number of biomarkers in an independent cohort, resulting in the validation of 28 candidate biomarkers. It is noteworthy that 11 candidate biomarkers were identified in more than one study. A significant number of potential proteomic biomarkers that are related to a number of aspects of SLE have been identified using mass spectrometry proteomic approaches. However, further studies are required to assess the utility of these biomarkers in routine clinical practice.


Assuntos
Biomarcadores/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Espectrometria de Massas/métodos , Proteômica/métodos , Humanos
11.
Clin Chem Lab Med ; 54(12): 1955-1961, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27327131

RESUMO

BACKGROUND: Infections from microorganisms and parasites have been connected with either increased or decreased cancer risk. The objective of this study was to investigate whether infection by Echinococcus granulosus is associated with cancer risk. METHODS: We assembled a pilot retrospective cohort of patients who were diagnosed as being infected by E. granulosus in Cyprus between 1930 and 2011. Age/gender-matched non-infected family members and neighbors were selected as references. Medical history was ascertained from each study subject through in-person interview. Cox proportional hazards regression analysis was performed to assess the association of being infected by E. granulosus with cancer risk. RESULTS: Individuals with prior infection by E. granulosus (n=249) were more likely to have cancer compared to those without infection (n=753), 11.65% vs. 8.37% (p=0.0492). Survival analysis also showed that subjects with prior infection had a higher risk for developing cancer. The hazards ratio (HR) was 1.595, [95% confidence interval (CI) between 1.008 and 2.525]. The risk ratio did not change significantly (HR=1.536; 95% CI: 0.965-2.445) after adjusting for gender, year of birth, smoking status, alcohol consumption, and family history of cancer. CONCLUSIONS: Our study suggests that infection by E. granulosus may increase cancer risk. If this observation can be confirmed independently, further investigation of the mechanisms underlying the association is warranted.


Assuntos
Equinococose/complicações , Neoplasias/complicações , Neoplasias/parasitologia , Idoso , Animais , Estudos de Coortes , Chipre , Equinococose/parasitologia , Feminino , Humanos , Masculino , Projetos Piloto , Análise de Regressão , Estudos Retrospectivos , Fatores de Risco
12.
Oncol Lett ; 11(1): 471-473, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26834852

RESUMO

Fanconi anemia (FA) is a rare disorder characterized by multiple congenital malformations, progressive bone marrow failure and susceptibility to malignancies. Biallelic mutations in the breast cancer 2, early onset (BRCA2) gene are responsible for the FA-D1 subgroup, which accounts for ~3% of all the FA cases. Patients with biallelic BRCA2 mutations generally display a more severe phenotype, with earlier onset and increased incidence of leukaemia and other solid tumors, than other patients with FA. In the present report, the first Cypriot patient with FA-D1 is described, which is the fifth case of a homozygote for the same null allele reported thus far, and the third known case of neuroblastoma in association with FA-D1.

13.
Eur J Nutr ; 55(4): 1535-44, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26130326

RESUMO

PURPOSE: Oxidative stress arises due to a cellular imbalance in oxidants and antioxidants and/or due to an altered activity of antioxidant enzymes, caused by SNPs. Oxidative stress increases susceptibility to breast cancer (BC) risk, and we previously showed that the Mediterranean diet (MD), which is rich in antioxidants, reduces BC risk in Greek-Cypriot women. Here, we investigated the effect of MnSOD (p.Val16Ala, rs4880) and CAT (-262C>T, rs1001179) SNPs on the association between the MD and BC risk in the case-control study of BC MASTOS in Cyprus. METHODS: Dietary intake data were obtained using a 32-item food frequency questionnaire, from which a dietary pattern was previously derived, using principal component analysis. This pattern included high loadings of vegetables, fruit, legumes and fish, a combination that closely resembles the MD and was used as our dietary variable. RESULTS: High vegetable intake lowered BC risk in women with at least one MnSOD Val allele (ORHigh vs. Low for Val/Val = 0.56, 95 % CI 0.35-0.88, for Val/Ala = 0.57, 95 % CI 0.39-0.82), or one CAT -262C allele (ORHigh vs. Low for -262CC = 0.66, 95 % CI 0.47-0.92, for -262CT = 0.53, 95 % CI 0.35-0.81). High fish intake conferred a decreased BC risk of CAT -262CC women (ORQ4 vs. Q1 0.66, 95 % CI 0.47-0.92) compared with the CAT -262TT women and low fish intake (ORQ2 vs. Q1 2.79, 95 % CI 1.08-7.17). Additionally, high fish intake reduced BC risk in MnSOD Val/Val women (ORQ4 vs. Q1 0.63, 95 % CI 0.40-0.98). p interaction values were, however, not statistically significant. CONCLUSION: Our results demonstrate that the antioxidative effects of the MD against BC risk may be enhanced by the wild-type alleles of the MnSOD or CAT SNPs among Greek-Cypriot women.


Assuntos
Neoplasias da Mama/genética , Catalase/genética , Dieta Mediterrânea , Polimorfismo de Nucleotídeo Único , Superóxido Dismutase/genética , Adulto , Idoso , Alelos , Animais , Antioxidantes/farmacologia , Neoplasias da Mama/epidemiologia , Estudos de Casos e Controles , Fabaceae , Feminino , Peixes , Frutas , Interação Gene-Ambiente , Técnicas de Genotipagem , Grécia , Humanos , Pessoa de Meia-Idade , Avaliação Nutricional , Estresse Oxidativo/efeitos dos fármacos , Fatores de Risco , Alimentos Marinhos , Verduras
14.
Respir Med ; 109(3): 347-56, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25698650

RESUMO

BACKGROUND: Despite the manifestations of primary ciliary dyskinesia (PCD) in early life, the diagnosis is often much delayed. Since 1998 in Cyprus, we have established the only national diagnostic and clinical referral center for PCD. OBJECTIVE: To review the phenotypic features at presentation of PCD patients in Cyprus in relation to age at diagnosis, with emphasis on previously lobectomised patients. METHODS: The medical records of the diagnosed PCD patients were retrospectively reviewed to obtain clinical data on presentation. RESULTS: Thirty patients, aged 13.9 years (range 0.1, 58.4 years), were diagnosed with PCD. Twelve of them presented after the age of 18. The most common manifestations were chronic cough (100%), chronic rhinorrhea (96.7%), sputum production (92.9%), laterality defects (63.3%), a history of pneumonia (53.3%) and neonatal respiratory distress (50%). A history of lobectomy in the past was recorded in 16.7% (5 patients). Patients who presented in adulthood had significantly higher frequency of lobectomy (41.7% vs 0%, p-value = 0.006) and had more frequently low FEV1 (58.3% vs 0%, p-value = 0.015) than those who presented before. Serial measurements of FEV1 and FVC indicated significantly lower intercepts in lobectomised compared to the adult non-lobectomised patients both in terms of FEV1 (-4.90 vs -1.80, p-value = 0.022) and FVC (-5.43 vs -1.91, p-value = 0.029) z-score levels. Change in FEV1 and FVC across time was not statistically significant in either group. CONCLUSIONS: PCD often remains undiagnosed up to adulthood accompanied by appearance of advanced lung disease. Performance of lobectomies seems to be a poor prognostic factor for PCD in adulthood.


Assuntos
Síndrome de Kartagener/patologia , Pneumonectomia , Adolescente , Adulto , Biópsia , Índice de Massa Corporal , Doença Crônica , Tosse/etiologia , Chipre/epidemiologia , Diagnóstico Tardio , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Síndrome de Kartagener/complicações , Síndrome de Kartagener/diagnóstico , Síndrome de Kartagener/epidemiologia , Síndrome de Kartagener/cirurgia , Masculino , Sistemas Computadorizados de Registros Médicos , Pessoa de Meia-Idade , Pneumonectomia/métodos , Prevalência , Estudos Retrospectivos , Fatores de Risco , Espirometria
15.
Genes Nutr ; 10(2): 453, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25604861

RESUMO

Single-nucleotide polymorphisms (SNPs) within genes of the one-carbon metabolism pathway have been shown to interact with dietary folate intake to modify breast cancer (BC) risk. Our group has previously demonstrated that the Mediterranean dietary pattern, rich in beneficial one-carbon metabolism micronutrients, protects against BC in Greek-Cypriot women. We aimed to investigate whether SNPs in the MTHFR (rs1801133 and rs1801131) and MTR (rs1805087) genes modify the effect of the Mediterranean dietary pattern on BC risk. Dietary intake data were obtained using a 32-item food-frequency questionnaire. A dietary pattern specific to the Greek-Cypriot population, which closely resembles the Mediterranean diet, was derived using principal component analysis (PCA) and used as our dietary variable. Genotyping was performed on subjects from the MASTOS study, a case-control study of BC in Cyprus, using TaqMan assays. Adjusted odds ratios (ORs) were estimated using logistic regression analyses. High adherence to the PCA-derived Mediterranean dietary pattern further reduced BC risk with increasing number of variant MTHFR 677T alleles (ORQ4vs.Q1 for 677TT = 0.37, 95 % CI 0.20-0.69, for 677 CT = 0.60, 95 % CI 0.42-0.86). Additionally, high adherence to the Mediterranean dietary pattern decreased BC risk in subjects with at least one MTR 2756A allele (ORQ4vs.Q1 for 2756AA = 0.59, 95 % CI 0.43-0.81, for 2756AG = 0.59, 95 % CI 0.39-0.91) and in subjects with the MTHFR 1298CC genotype (ORQ4vs.Q1 0.44, 95 % CI 0.30-0.65). Overall P-interaction values, however, were not statistically significant. Our study suggests that these MTHFR and MTR SNPs may act as effect modifiers, highlighting their biological significance in the association between Mediterranean diet, the one-carbon metabolism pathway and BC.

16.
PLoS One ; 9(8): e105501, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25133505

RESUMO

Lynch syndrome is the most common form of hereditary colorectal cancer and is caused by germline mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. Mutation carriers have an increased lifetime risk of developing colorectal cancer as well as other extracolonic tumours. The aim of the current study was to evaluate the frequency and distribution of mutations in the MLH1, MSH2 and MSH6 genes within a cohort of Cypriot families that fulfilled the revised Bethesda guidelines. The study cohort included 77 patients who fulfilled at least one of the revised Bethesda guidelines. Mutational analysis revealed the presence of 4 pathogenic mutations, 3 in the MLH1 gene and 1 in the MSH2 gene, in 5 unrelated individuals. It is noted that out of the 4 pathogenic mutations detected, one is novel (c.1610delG in exon 14 of the MLH1) and has been detected for the first time in the Cypriot population. Overall, the pathogenic mutation detection rate in our patient cohort was 7%. This percentage is relatively low but could be explained by the fact that the sole criterion for genetic screening was compliance to the revised Bethesda guidelines. Larger numbers of Lynch syndrome families and screening of the two additional predisposition genes, PMS2 and EPCAM, are needed in order to decipher the full spectrum of mutations associated with Lynch syndrome predisposition in Cyprus.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Proteínas Nucleares/genética , Adolescente , Adulto , Estudos de Coortes , Chipre/epidemiologia , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Adulto Jovem
17.
Crit Rev Clin Lab Sci ; 51(5): 280-90, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24901807

RESUMO

Ubiquitination, a fundamental post-translational modification (PTM) resulting in the covalent attachment of ubiquitin (Ub) to a target protein, is currently implicated in several key cellular processes. Although ubiquitination was initially associated with protein degradation, it is becoming increasingly evident that proteins labeled with polyUb chains of specific topology and length are activated in an ever-expanding repertoire of specific cellular processes. In addition to their involvement in the classical protein degradation pathways they are involved in DNA repair, kinase regulation and nuclear factor-κB (NF-κB) signaling. The sorting and processing of distinct Ub signals is mediated by small protein motifs, known as Ub-binding domains (UBDs), which are found in proteins that execute disparate biological functions. The involvement of UBDs in several biological pathways has been revealed by several studies which have highlighted the vital role of UBDs in cellular homeostasis. Importantly, functional impairment of UBDs in key regulatory pathways has been related to the development of pathophysiological conditions, including immune disorders and cancer. In this review, we present an up-to-date account of the crucial role of UBDs and their functions, with a special emphasis on their functional impairment in key biological pathways and the pathogenesis of several human diseases. The still under-investigated topic of Ub-UBD interactions as a target for developing novel therapeutic strategies against many diseases is also discussed.


Assuntos
Síndromes de Imunodeficiência , Ubiquitina , Ubiquitinação/fisiologia , Humanos , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/fisiopatologia , Modelos Moleculares , Estrutura Terciária de Proteína , Transdução de Sinais , Ubiquitina/química , Ubiquitina/metabolismo , Ubiquitina/fisiologia
18.
PLoS One ; 9(4): e93400, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24695549

RESUMO

The identification of variants of unknown clinical significance (VUS) in the BRCA1 gene complicates genetic counselling and causes additional anxiety to carriers. In silico approaches currently used for VUS pathogenicity assessment are predictive and often produce conflicting data. Furthermore, functional assays are either domain or function specific, thus they do not examine the entire spectrum of BRCA1 functions and interpretation of individual assay results can be misleading. PolyPhen algorithm predicted that the BRCA1 p.Ser36Tyr VUS identified in the Cypriot population was damaging, whereas Align-GVGD predicted that it was possibly of no significance. In addition the BRCA1 p.Ser36Tyr variant was found to be associated with increased risk (OR = 3.47, 95% CI 1.13-10.67, P = 0.02) in a single case-control series of 1174 cases and 1109 controls. We describe a cellular system for examining the function of exogenous full-length BRCA1 and for classifying VUS. We achieved strong protein expression of full-length BRCA1 in transiently transfected HEK293T cells. The p.Ser36Tyr VUS exhibited low protein expression similar to the known pathogenic variant p.Cys61Gly. Co-precipitation analysis further demonstrated that it has a reduced ability to interact with BARD1. Further, co-precipitation analysis of nuclear and cytosolic extracts as well as immunofluorescence studies showed that a high proportion of the p.Ser36Tyr variant is withheld in the cytoplasm contrary to wild type protein. In addition the ability of p.Ser36Tyr to co-localize with conjugated ubiquitin foci in the nuclei of S-phase synchronized cells following genotoxic stress with hydroxyurea is impaired at more pronounced levels than that of the p.Cys61Gly pathogenic variant. The p.Ser36Tyr variant demonstrates abrogated function, and based on epidemiological, genetic, and clinical data we conclude that the p.Ser36Tyr variant is probably associated with a moderate breast cancer risk.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Variação Genética/genética , Linhagem Celular , Núcleo Celular/genética , Citoplasma/genética , Feminino , Aconselhamento Genético/métodos , Predisposição Genética para Doença/genética , Genótipo , Células HEK293 , Humanos , Risco
19.
Crit Rev Clin Lab Sci ; 51(3): 138-48, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24588712

RESUMO

Infectious agents have been associated with cancer due to activation of pro-carcinogenic inflammatory processes within their host. Several reports, however, indicate that specific pathogens may be able to elicit anti-tumor immune responses that can lead to protection from tumorigenesis or cancer regression. Amongst these "beneficial" pathogens are some helminthic parasites that have already been connected with prevention of autoimmune diseases and allergies, immune conditions increasingly associated with cancer. Even though helminths have co-existed with humans and their ancestors for millions of years, investigations of their impact on human (patho)physiology are relatively new and the functions of components that can explain the helminth bi-directional influence on carcinogenesis are not well understood. This review aims to discuss evidence for the helminth-induced immune, genetic, epigenetic, proteomic, hormonal and metabolic changes that may ultimately mediate the potential pro- or anti-carcinogenic role of helminths. This overview may serve future investigations in clarifying the tumorigenic role of the most common helminthic parasites. It may also inspire the development of anti-cancer regimens and vaccines, in parallel to ongoing efforts of using helminth-based components for the prevention and/or treatment of autoimmune diseases and allergies.


Assuntos
Carcinogênese/patologia , Helmintíase/patologia , Helmintos/isolamento & purificação , Neoplasias/parasitologia , Animais , Interações Hospedeiro-Parasita , Humanos , Inflamação/parasitologia
20.
J Proteome Res ; 12(12): 5696-708, 2013 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-24106833

RESUMO

Matched healthy and diseased tissues from breast cancer patients were analyzed by quantitative proteomics. By comparing proteomic profiles of fibroadenoma (benign tumors, three patients), DCIS (noninvasive cancer, three patients), and invasive ductal carcinoma (four patients), we identified protein alterations that correlated with breast cancer progression. Three 8-plex iTRAQ experiments generated an average of 826 protein identifications, of which 402 were common. After excluding those originating from blood, 59 proteins were significantly changed in tumor compared with normal tissues, with the majority associated with invasive carcinomas. Bioinformatics analysis identified relationships between proteins in this subset including roles in redox regulation, lipid transport, protein folding, and proteasomal degradation, with a substantial number increased in expression due to Myc oncogene activation. Three target proteins, cofilin-1 and p23 (increased in invasive carcinoma) and membrane copper amine oxidase 3 (decreased in invasive carcinoma), were subjected to further validation. All three were observed in phenotype-specific breast cancer cell lines, normal (nontransformed) breast cell lines, and primary breast epithelial cells by Western blotting, but only cofilin-1 and p23 were detected by multiple reaction monitoring mass spectrometry analysis. All three proteins were detected by both analytical approaches in matched tissue biopsies emulating the response observed with proteomics analysis. Tissue microarray analysis (361 patients) indicated cofilin-1 staining positively correlating with tumor grade and p23 staining with ER positive status; both therefore merit further investigation as potential biomarkers.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Cofilina 1/genética , Fibroadenoma/genética , Regulação Neoplásica da Expressão Gênica , Adulto , Idoso , Amina Oxidase (contendo Cobre)/genética , Amina Oxidase (contendo Cobre)/isolamento & purificação , Amina Oxidase (contendo Cobre)/metabolismo , Transporte Biológico , Biomarcadores Tumorais/isolamento & purificação , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Estudos de Casos e Controles , Cofilina 1/isolamento & purificação , Cofilina 1/metabolismo , Feminino , Fibroadenoma/diagnóstico , Fibroadenoma/metabolismo , Fibroadenoma/patologia , Perfilação da Expressão Gênica , Humanos , Metabolismo dos Lipídeos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oxirredução , Complexo de Endopeptidases do Proteassoma/metabolismo , Dobramento de Proteína , Proteólise , Proteômica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Análise Serial de Tecidos
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