Endometriosis - Review Of Current Therapeutic Aproaches For Disease Control

Ендометриозата е хронично естроген-зависимо заболяване, което се характеризира с развитие на ендометриална тъкан извън маточната кухина. В световен мащаб засяга около 10% от жените. Заболяването може да причини дисменорея, хронична тазова болка, диспареуния и инфертилитет. Медикаментозното лечение играе ключова роля в контрола на заболяването. В повечето случаи е наложително лекарствената терапия да бъде комбинирана с хирургична, за да бъде постигнато пълно излекуване. Подходът при избор на подходящо медикаментозно лечение трябва да бъде индивидуализиран, като бъде съобразен с тежестта на ендометриозата, ефикасността на лекарството, страничните му ефекти, желанието на пациентката, възрастта ѝ и репродуктивните ѝ планове. Голяма част от използваните днес лекарства за лечение на ендометриоза целят потискане на овариалната функция. Най-често прилаганите и показващи най-добри резултати са комбинираните орални контрацептиви, аналозите на гонадотропин-освобождаващия хормон и прогестините. Освен тези утвърдени терапии, съвременното лечение включва и нови хормонално и нехормонално-базирани терапевтични подходи, които модулират различни патогенетични механизми. В този обзор ще бъдат разгледани настоящите терапевтични опции - както класическите, така и по-новите, все още неодобрени медикаменти за лечение на ендометриоза.Endometriosis is an estrogen-dependent chronic disease characterized by the presence of endometrial tissue outside the uterine cavity. Globally, it affects about 10% of women worldwide. It causes dysmenorrhea,chronic pelvic pain, dyspareunia, and infertility.Medication treatment plays a key role in disease management. In most cases, medications should be combined with surgery in order to eradicate the disease. The medication treatment should be individualized considering the severity of endometriosis, efficacy of the drug, its side effects, patient`s preferences, age, and reproductive plans. Nowadays, most of the drugs used to treat endometriosis aim to suppress ovarian function. The most widelyused and with the best therapeutic outcomes are the combined oral contraceptives, gonadotropin-releasing hormone agonists, and progestins. In addition to these well-established therapies, new horomonal and non-hormonal therapeutics that modulate various pathogenic pathways are available. We review currently availabletreatment options - the classical ones and the new therapies that are still not approved

NUTRIGENETIC TESTS FOR LIFE-STYLE OPTIMIZATION IN THE BULGARIAN POPULATION - DIFFICULTIES, ADVANCES AND FUTURE PERSPECTIVES

Introduction: Nutrigenetics is a relatively new, but intensively developing scientific field. It aims to improve the quality of life by customizing dietary intake, physical activity and environmental exposures according to the personal genetic variantions.Aim: The aim of the study is to examine the attitude of the Bulgarian society towards nutrigenetic tests and how knowledge of personal genetic data influences current lifestyle choices.Materials and Methods: Seventy-eight Bulgarian probands were tested for the 56 single nucleotide polimorphisms (SNPs) in 52 genes, related to the lipid, carbohydrate, vitamin B and D metabolism, inflammation, oxidative stress, osteoporosis detoxification, PUFA, caffeine and salt responsiveness, predisposition to tendon injuries, as well as genes associated with power and endurance in athletes (DNA Life, Nordic Laboratories). Each proband provided a written informed consent before testing, as well as filled in questionnaires as part of pre-test counseling and then a few months later. Each patient was consulted by a trained genetic counselor. Probands were provided with detailed information about the test, detected polymorphic variants and personalized recommendations for diet, sport and lifestyle changes.Results: The preliminarily results reveal that large portion of the respondents could directly follow the received personal recommendations. In a small number of the patients a chronic disease during the counseling was detected and they were directed to the gastroenterologist for treatment. A significant share of our cohort, found to be predisposed to obesity, insulin resistance and osteoporosis, has already manifested some symptoms and the individuals were referred to a dietitian and endocrinologist, respectively. Patient follow-up, as well as data collection from the questionnaires are ongoing.Conclusion: This study shows that Bulgarians are inclined to do nutrigenetic tests for prevention of socially significant disorders and stresses the need for a trained physician to analyze test results and offer the most suitable lifestyle modifications in order to minimize morbidity risk

16p11.2 Duplication Syndrome - a Case Report

16p11.2 duplication syndrome is a rare disorder, often associated with intellectual disability, attention deficit, hyperactivity disorder, and a predisposition to epilepsy and schizophrenia. There are no specific dysmorphic features for this genetic condition, but micro-cephaly, micrognathia and hypertelorism could be present. We report a case of 16p11.2 duplication syndrome which has the typical clinical presentation – slight facial dysmorphism, impaired intellectual development, and autistic behavior. Whole-exome sequencing was performed, but no pathogenic or likely pathogenic mutations were identified. Array comparative genomic hybridization analysis established the diagnosis of 16p11.2 duplication syndrome, which illustrates the importance of this method when diagnosing children with unexplained intellectual disability.&nbsp

Analysis of the expression level of genes associated with the metabolism of exogenous substances and DNA reparation in patients suffering from bladder cancer

IntroductionBladder cancer is a result of the interaction between urine metabolites that come into contact with the bladder mucosa and a certain hereditary predisposition. AimThe aim of the study is to determine the expression level of genes, involved in the metabolism of xenobiotics that are metabolized to substances with carcinogenic potential, as well as the expression levels of genes involved in DNA reparation.Materials and Methods A total of 16 samples from transitional cell bladder cancer were analyzed - four stage pTa, four pT1, five pT2 and three control samples. Expression analysis was done via PAHS-004 Human Cancer Drug Resistance & Metabolism PCR Array on 29 genes, known to take part in DNA reparation and biotransformation of the xenobiotics: APC, ATM, BRCA1, BRCA2, ERCC3, MSH2, XPA, XPC, ARNT, BLMH, CLPTM1L, CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, DHFR, EPHX1, GSK3A, GSTP1, NAT2, SOD1, SULT1E1 (STE) and TPMT. Increased/decreased expression levels were defined by a fivefold change.Results None of the reparative genes showed increased expression. XPA and APC had a decreased expression, ranging from 6 to 30 times, in the highest number of samples: 11 of 13 for XPA and 10 of 13 for APC.Genes related to metabolism of xenobiotics also showed normal or decreased expression. Only three samples from pTa stage showed up-regulation of the CYP3A5 gene, ranging from 6 to 11 times. The rest of the samples showed normal expressions. Only one sample - low differentiated T2 bladder tumor, grade II, stage G3 showed an increased expression of the genes CLPTM1L, CYP1A1 and GSTP1

Expression analysis of bladder tumors for chemotherapeutic drug sensitivity determination

Introduction: Bladder cancer is a multifactorial disease with increasing frequency in the economically developed countries. Aim: The primary endpoint of this study was the evaluation of the genetic image of bladder tumors in connection to common anticancer drugs.Materials and Methods: A total of 50 samples were analyzed. 41 samples were from transitorial cell bladder cancer (stages pTa, pT1 and pT2), 6 samples were from chronic inflammatory process (precancerous) and three - negative controls. The gene expression analysis of 168 genes were carried out with two panels for Cancer Drug Resistance & Metabolism PCR Array, Qiagene (84 genes) and PAHS-507 Z - Human Cancer Drug Targets PCR Array, Qiagene (84 genes).Results: The results showed significant up-regulation of the genes: CYP1A1, CYP3A5, AR, CLPTM1L, CCNE1, MVP, TOP2B, AHR and PPARG in the bladder cancer samples compared to the negative control. A statistically significant difference (p <0.0001) was found in the expression levels of EGFR, ERBB2, ERBB4, ABCC1, ABCC3, ARNT, CYP1A1, CYP3A5, EPHX1, MVP and PPARG genes in muscle invasive (pT2) versus non-invasive bladder tumors (pTa and pT1). These genes are involved in the formation of multi-drug resistance and in the metabolism of steroid hormones, cyclosporins, polycyclic aromatic hydrocarbons, as well as some anticancer drugs like Vincristine, Taxol and Thiopurine. The obtained data show the significance of the genes as possible targets in clinical trials for the treatment of bladder cancer

Whole genome methylation array analysis reveals new aspects in Balkan endemic nephropathy etiology

Background Balkan endemic nephropathy (BEN) represents a chronic progressive interstitial nephritis in striking correlation with uroepithelial tumours of the upper urinary tract. The disease has endemic distribution in the Danube river regions in several Balkan countries. DNA methylation is a primary epigenetic modification that is involved in major processes such as cancer, genomic imprinting, gene silencing, etc. The significance of CpG island methylation status in normal development, cell differentiation and gene expression is widely recognized, although still stays poorly understood. Methods We performed whole genome DNA methylation array analysis on DNA pool samples from peripheral blood from 159 affected individuals and 170 healthy individuals. This technique allowed us to determine the methylation status of 27 627 CpG islands throughout the whole genome in healthy controls and BEN patients. Thus we obtained the methylation profile of BEN patients from Bulgarian and Serbian endemic regions. Results Using specifically developed software we compared the methylation profiles of BEN patients and corresponding controls and revealed the differently methylated regions. We then compared the DMRs between all patient-control pairs to determine common changes in the epigenetic profiles. SEC61G, IL17RA, HDAC11 proved to be differently methylated throughout all patient-control pairs. The CpG islands of all 3 genes were hypomethylated compared to controls. This suggests that dysregulation of these genes involved in immunological response could be a common mechanism in BEN pathogenesis in both endemic regions and in both genders. Conclusion Our data propose a new hypothesis that immunologic dysregulation has a place in BEN etiopathogenesis. Keywords: Epigenetics; Whole genome array analysis; Balkan endemic nephropath

MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy

Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups

Association between endometrial microbiome and implantation success in women with frozen embryo transfer: results of a prospective cohort study

AbstractThe aim of this prospective study was to compare the endometrial microbiome between pregnant and non-pregnant women after frozen embryo transfer (FET) with euploid embryos. Endometrial biopsies were collected from 30 women during the mid-luteal phase in a natural cycle. FET was performed with euploid embryos up to 3 months after the biopsy. Endometrial microbiota composition was analysed using 16S rRNA (v4-v5 region) next generation sequencing (NGS). The analysis of different clinical outcomes after the biopsy (no pregnancy (n = 14), and ultrasound confirmed pregnancy (n = 16)) revealed differences in the endometrial microbiome composition. In total, 271 distinct bacterial species and 668 bacterial genera were identified. The number of unique species found in non-pregnant women was 62 (22.88%), while in the patients who became pregnant after FET it was 39 (14.39%). Among them, bacteria with high frequency of occurrence such as Bacteroides spp., Cutibacterium granulosum, Isoptericola spp., Acetomicrobium spp., Marivivens spp. and Syntrophomonas spp. were found only in non-pregnant patients, while Bosea spp. was present only in pregnant women. The analysis of bacteria relative abundance revealed that Lactobacillus genus was not significantly different between the studied groups. In contrast, Serratia marcescens, Staphylococcus spp., Glutamicibacter spp. and Delftia spp. were significantly enriched in the non-pregnant group. In conclusion, specific bacteria taxa had higher relative abundance in the endometrium of patients with implantation failure after FET with euploid embryos. We hypothesize that an appropriate treatment for optimization of endometrial microbiome content in women with diagnosed microbiome dysbiosis could be beneficial for improvement of pregnancy rates

Novel genes and variants associated with longevity in Bulgarian centenarians revealed by whole exome sequencing DNA pools: a pilot study

Aim: To determine specific genetic loci that might be associated with longevity in Bulgarian population by analyzing exome pool-seq data from centenarians and a control group.Methods: We performed whole-exome sequencing of two DNA pools, set up of 32 Bulgarian centenarians and 61 young healthy controls, respectively, and 59935 quality filtered variants were concurrently detected in both pools. Fisher’s exact test was employed to establish the significance of allele frequency difference between the pools.Results: Forty seven variants showed significantly higher allele frequency in the centenarian compared to the control pool, and these can be considered to be positively associated with longevity in Bulgarian populaton. Based on their assigned functional role, three genes containing three of these variants were further investigated. These genes, RNF43, WNK1 and NADSYN1, are involved in evolutionary conserved processes with well ascertained association with longevity, i.e., Wnt signaling pathway, insulin/IGF-1 signal pathway and redox balancing processes, respectively. For the remaining genes exhibiting variants with significantly higher allele frequency in the Bulgarian centenarian pool there is not enough evidence about their functional role in determining longevity and further research is needed.Conclusion: The results confirm the importance of studying centenarians in different populations to discover those combinations of variants that associate with longer health span