Specific aspects of researching the oncogenesis and metastatasing potential of laringeal squamous cell carcinoma

Malignant tumor metastasizing, comprised of several consecutive steps beginning with local cancer cell invasion, is a key factor which compromises the prognosis of cancer patients and is responsible for 90% of the lethal outcome. 2/3 of our diagnosed patients show with locally advanced process and/or metastatic disease (stage III/IV).Researching key molecular and cellular mechanisms tied to development and metastasizing of laryngeal squamous cell carcinoma is of clinical importance to developing and using molecular target therapy.Based on popular literature studies the emphasize was put on the following genes: TP53, CDKN2A – accentuating on exons 1,2,3, and PIK3CA – exons 9, 20, as primarily connected to the higher mutation potential of laryngeal squamous cell carcinoma.Researching the genetic similarity between carcinoma and metastasis could potentially help understanding the genotype and mutation potential of Head and Neck squamous cell carcinomas. The practical potential use of this knowledge is the developing of predictive markers and better therapeutic algorithms for diagnosed patients. ---------------------------------------------------------------------- Туморното метастазиране, включващо няколко последователни стъпки, започвайки от инвазия на раковите клетки в околните тъкани, е ключовият фактор, който компрометира прогнозата на раково болните пациенти и отговаря за 90% от смъртността. 2/3 от диагностицираните пациенти са с локално авансирал процес и/ или метастатична болест (стадий III или IV).Проучването на молекулярни и клетъчни механизми, водещи до формирането и метастазирането на плоскоклетъчния карцином от ларингеален произход, би било от клинична полза за разработването на молекулярна таргетна терапия.На базата на обширен литературен обзор акцентът е поставен върху следните гени – TP53, CDKN2A – exons 1,2,3 and PIK3CA – exons 9, 20, като потенциални отговорници за повишаване метастатичния потенциал на плосколетъчния карцином от ларингеален произход.Изследването на генетично сродство между карцином и метастаза би имало теоретичен принос към опознаването на генотипа и мутационния статус на плоскоклетъчните карциноми на глава и шия, чийто практически потенциал се изразява като прогностична стойност за преживяемостта на онкоболните и подобряване на терапевтичния алгоритъм при диагностицирани пациенти

Changes in gene expression of EGFR and LAD1 in patients with metastatic squamous cell laryngeal carcinoma

..

Range of values for lipid accumulation product (LAP) in healthy residents of the European north of Russia

BACKGROUND: Obesity is a major health problem in modern society and its prevalence throughout the world has reached the epidemic level. The unfavorable outcomes of obesity are associated with a high risk of numerous diseases due to metabolic disorders. Finding of diagnostic criteria for early detection of obesity is a priority in biomedical research. Therefore, of particular interest is the new visceral obesity marker – lipid accumulation product (LAP). Meanwhile, to date, the reference values for LAP are not defined, and data on sex- and age-related changes are contradictory. AIMS: The aim of this study was to determine the variation range, sex and age differences in LAP values in healthy subjects. MATERIALS AND METHODS: The study was conducted on apparently healthy subjects (455 men and 286 women) aged 20–59 years selected at routine examinations at the base of the central clinic in Arkhangelsk. Examination of subjects consisted of physical examination with measurement of anthropometric and clinical parameters, filling out a questionnaire, and evaluation of serum lipid levels. RESULTS: The LAP values in the subjects varied in a wide range (0.5–156.5 cm×mmol/l in men; 0.4 to 116.2 cm×mmol/l in women), but at the same they in 75% of the participants did not exceed 30 cm×mmol/l. Sex differences in LAP with the prevalence of values in men were observed in the age groups up to 40 years old, later they disappeared. LAP in men and women increased with age, but these changes were unequal. The LAP values increased to reach a plateau in men up to 30 years of age and in women up to 40 years of age. CONCLUSIONS: LAP is a combined index that simultaneously reflects distribution of adipose tissue and changes in blood lipids, and is considered a marker of obesity associated with the risk of metabolic disorders. This study was the first to determine the variation range, sex differences and age dynamics for LAP in the apparently healthy subjects

Activation of melanocortin receptors MC1 and MC5 attenuates retinal damage in experimental diabetic retinopathy

We hypothesize that melanocortin receptors (MC) could activate tissue protective circuit in a model of streptozotocin- (STZ-) induced diabetic retinopathy (DR) in mice. At 12–16 weeks after diabetes induction, fluorescein angiography (FAG) revealed an approximate incidence of 80% microvascular changes, typical of DR, in the animals, without signs of vascular leakage. Occludin progressively decreased in the retina of mice developing retinopathy. qPCR of murine retina revealed expression of two MC receptors, Mc1r and Mc5r. The intravitreal injection (5 \u1d707L) of the selective MC1 small molecule agonist BMS-470539 (33 \u1d707mol) and the MC5 peptidomimetic agonist PG-901 (7.32 nM) elicited significant protection with regular course and caliber of retinal vessels, as quantified at weeks 12 and 16 after diabetes induction. Mouse retina homogenate settings indicated an augmented release of IL-1\u1d6fc, IL-1\u1d6fd, IL-6, MIP-1\u1d6fc, MIP-2\u1d6fc, MIP-3\u1d6fc, and VEGF from diabetic compared to nondiabetic mice. Application of PG20N or AGRP and MC5 and MC1 antagonist, respectively, augmented the release of cytokines, while the agonists BMS-470539 and PG-901 almost restored normal pattern of these mediators back to nondiabetic values. Similar changes were quantified with respect to Ki-67 staining. Finally, application of MC3-MC4 agonist/antagonists resulted to be inactive with respect to all parameters under assessment

Targeted Sequencing of Candidate Regions Associated with Sagittal and Metopic Nonsyndromic Craniosynostosis

Craniosynostosis (CS) is a major birth defect in which one or more skull sutures fuse prematurely. We previously performed a genome-wide association study (GWAS) for sagittal nonsyndromic CS (sNCS), identifying associations downstream from BMP2 on 20p12.3 and intronic to BBS9 on 7p14.3; analyses of imputed variants in DLG1 on 3q29 were also genome-wide significant. We followed this work with a GWAS for metopic non-syndromic NCS (mNCS), discovering a significant association intronic to BMP7 on 20q13.31. In the current study, we sequenced the associated regions on 3q29, 7p14.3, and 20p12.3, including two candidate genes (BMP2 and BMPER) near some of these regions in 83 sNCS child-parent trios, and sequenced regions on 7p14.3 and 20q13.2-q13.32 in 80 mNCS child-parent trios. These child-parent trios were selected from the original GWAS co-horts if the probands carried at least one copy of the top associated GWAS variant (rs1884302 C allele for sNCS; rs6127972 T allele for mNCS). Many of the variants sequenced in these targeted regions are strongly predicted to be within binding sites for transcription factors involved in crani-ofacial development or bone morphogenesis. Variants enriched in more than one trio and predicted to be damaging to gene function are prioritized for functional studies

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

Alcohol consumption and prostate cancer incidence and progression: A Mendelian randomisation study

Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In this study, we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival. We analysed data from 23,868 men with prostate cancer and 23,051 controls from 25 studies within the international PRACTICAL Consortium. Study-specific associations of 68 single nucleotide polymorphisms (SNPs) in 8 alcohol-metabolising genes (Alcohol Dehydrogenases (ADHs) and Aldehyde Dehydrogenases (ALDHs)) with prostate cancer diagnosis and prostate cancer-specific mortality, by grade, were assessed using logistic and Cox regression models, respectively. The data across the 25 studies were meta-analysed using fixed-effect and random-effects models. We found little evidence that variants in alcohol metabolising genes were associated with prostate cancer diagnosis. Four variants in two genes exceeded the multiple testing threshold for associations with prostate cancer mortality in fixed-effect meta-analyses. SNPs within ALDH1A2 associated with prostate cancer mortality were rs1441817 (fixed effects hazard ratio, HRfixed  = 0.78; 95% confidence interval (95%CI):0.66,0.91; p values = 0.002); rs12910509, HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.003); and rs8041922 (HRfixed  = 0.76; 95%CI:0.64,0.91; p values = 0.002). These SNPs were in linkage disequilibrium with each other. In ALDH1B1, rs10973794 (HRfixed  = 1.43; 95%CI:1.14,1.79; p values = 0.002) was associated with prostate cancer mortality in men with low-grade prostate cancer. These results suggest that alcohol consumption is unlikely to affect prostate cancer incidence, but it may influence disease progression