Comparative Analysis of Different Definitions of Amyloid-ß Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer.

Amyloid-ß (Aß) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aß pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer's continuum is critical. Here, we compare different Aß classification approaches and we show their performance in detecting pathophysiological changes downstream Aß pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer's continuum. Participants underwent Aß PET and CSF biomarkers assessment. We classified participants as Aß -positive using five approaches: (1) CSF Aß42 < 1098 pg/ml; (2) CSF Aß42/40 < 0.071; (3) Aß PET Centiloid > 12; (4) Aß PET Centiloid > 30 or (5) Aß PET Positive visual read. We assessed the correlations between Aß biomarkers and compared the prevalence of Aß positivity. We determined which approach significantly detected associations between Aß pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aß-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aß-positive but PET Aß-negative than CSF Aß-negative but PET Aß-positive. The CSF Aß 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aß-positive group. Altogether, we highlight the need for sensitive Aß -classifications to study the preclinical Alzheimer's continuum. Approaches that define Aß positivity based on optimal discrimination of symptomatic Alzheimer's disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer.

CpG island methylation of TMS1/ASC and CASP8 genes in cervical cancer.

BACKGROUND: Gene silencing associated with aberrant methylation of promoter region CpG islands is an acquired epigenetic alteration that serves as an alternative to genetic defects in the inactivation of tumor suppressor and other genes in human cancers. AIMS: This study describes the methylation status of TMS1/ASC and CASP8 genes in cervical cancer. We also examined the prevalence of TMS1/ASC and CASP8 genes methylation in cervical cancer tissue and none--neo plastic samples in an effort to correlate with smoking habit and clinicopathological features. METHOD: Target DNA was modified by sodium bisulfite, converting all unmethylated, but not methylated, cytosines to uracil, and subsequently amplified by Methylation Specific (MS) PCR with primers specific for methylated versus unmethylated DNA. The PCR product was detected by gel electrophoresis and combined with the clinical records of patients. RESULTS: The methylation pattern of the TMS1/ASC and CASP8 genes in specimens of cervical cancer and adjacent normal tissues were detected (5/80 (6.2%), 3/80 (3.75%)-2/80 (2.5%), 1/80 (1.2%) respectively). No statistical differences were seen in the extent of differentiation, invasion, pathological type and smoking habit between the methylated and unmethylated tissues (P > 0.05). CONCLUSION: The present study conclude that the frequency of TMS1/ASC and CASP8 genes methylation in cervical cancer are rare (< 6%), and have no any critical role in development of cervical cancer.

Effect of NBS1 gene polymorphism on the risk of cervix carcinoma in a northern Indian population.

Cervical cancer is one of the most common neoplastic diseases affecting women, with a worldwide incidence of almost half a million cases. A history of smoking and use of oral contraceptives have been confirmed to be risk factors for cervical cancer. Genetic susceptibility and immune response, especially impaired cellular immune response, may well be related to the development of cervical cancer. NBS1 is one of the key proteins participating in the recognition and repair of double-strand breaks that may lead to genomic instability and cancer if unrepaired. The objective of the present study was therefore to investigate NBS1 Glu185Gln gene polymorphisms and the risk of cervix cancer in a northern Indian population. We found that passive smokers having particular NBS1 genotypes (Glu/Gln, Gln/Gln or Glu/Gln + Gln/Gln)have an increased risk of developing cervix cancer (OR 5.21, p=0.000001; OR 4.60, p=0.001; OR 5.10, p=0.0000009, respectively).The risk was increased 2.4-fold in oral contraceptive users with a Glu/Gln genotype. We conclude that the risk of cervical cancer is increased in passive smokers and in users of oral contraceptives with certain NBS1 genotypes.

Expression and polimorphism of IFN-gamma gene in patients with cervical cancer.

BACKGROUND: Cervical cancer, the second most common malignancy in women worldwide, is almost invariably associated with infection by human papillomavirus (HPV). However, although many women are infected with high-risk types of HPV, only a subset of infected women will ever develop cervical cancer. Several studies suggested that immunological components play a key role in the development of cervical cancer. Interferon gamma (IFN-gamma ) is a cytokine produced by activated T cells and natural killer (NK) cells that enhances cellular immune responses by increasing T-cell cytotoxicity and NK cell activity. AIM: To study single nucleotide polymorphism (SNP), T to A, located at the +874 position and measure IFN-gamma messenger RNA (mRNA) at the tumor site. METHODS: DNA was isolated from peripheral blood of 200 patients with cervical cancer and 200 healthy controls. The allele polymorphism at position +874 in the IFN-gamma gene was studied by ARMS-PCR (Amplification Refractory Mutation System) and measured IFN-gamma mRNA at the tumor site by means of a semi-quantitative polymerase chain reaction (sqRT-PCR) assay. RESULTS: It was observed that genotypes AT and AA + AT increase the risk of cervical cancer (OR = 3.3, 95% CI - 2.05-5.2, P

Association of Fas-670 gene polymorphism with risk of cervical cancer in North Indian population.

OBJECTIVES: Cervical cancer is the second most common cancer among women in the world, with approximately 470,000 new cases and 231,000 deaths occurring each year. Incidence is greater in developing countries such as India, where this is the most common female malignancy with almost 100,000 new cases each year. Apoptosis must be considered as a safe mechanism that controls the integrity of the cell erasing abnormal clones and it is likely that failure of apoptosis constitutes a key factor responsible for tumor formation, progression and resistance to drugs. The Fas gene plays a key role in regulation of apoptotic cell death and corruption of this signaling pathway has been shown to participate in immune escape and tumorgenesis. STUDY DESIGN: A single-nucleotide polymorphism at -670 of Fas gene promoter (A/G) was examined in a total of 400 blood samples from normal healthy women and cervical cancer patients, using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Significant association was observed for AG (OR = 3.0, 95% CI = (1.68-5.09, p < 0.001) and combined AG+GG (OR = 2.54, 95% CI = 1.47-4.40, p < 0.001) genotype with risk of cervical cancer. Heterozygous genotype (AG) in SCC showed a highly significant association with risk of cervical cancer (OR = 2.57, 95% CI = 1.47-4.50 p <0.001). Similarly, combined AG+GG genotype had a 2.25-fold risk for SCC patients (OR = 2.25, 95% CI = 1.30-3.90, p < 0.001). There was high increase risk of cervical cancer in passive smokers with AG and combined (AG+GG) genotypes (OR = 4.6, 95% CI = 2.07-10.32, p < 0.001 - OR = 4.9, 95% CI = 2.20-10.32, p < 0.001), respectively. CONCLUSION: This is the first study to provide evidence for the association of a Fas -670 (A/G) gene polymorphism with the risk of cervical cancer in a North Indian population.