Perspectives For Target Therapy In The Treatment Of Malignant Neoplasms Of The Urinary Bladder

Етиологията, патогенезата и лечението на злокачествените новообразувания на пикочния мехур все още пораждат редица въпроси. Установени са биомаркери, показващи разлики в молекулния образ на инвазивния и неинвазивния уроепителен карцином, които са част от факторите, отговорни за големите вариации в лечението дори и при тумори с еднакъв хистологичен резултат. В момента стандартно прилаганата системна терапия включва различни цитотоксични химиотерапевтични схеми и се основава главно на хистологичната оценка и стадирането на тумора. От май 2016 г. за първи път се разреши прилагането на прицелна терапия при лечение на онкологични зболявания на пикочен мехур. Прицелната терапия се използва за спиране на растежа и разпространението на раковите клетки, посредством потискане на активирани сигнални пътища - най-често на фибробластния, епидермалния и ендотелния растежен фактор. Изборът на „правилното` лекарство се базира до голяма степен върху молекулно-генетичната диагноза на тумора и наличие на специфични биомаркери, показващи възможността за прилагане на едно или друго лекарство.През последните години е постигнат значителен напредък в ерата на молекулната диагностика и прицелната терапия, което неминуемо води до удължаване на преживяемостта на онкопоциентите и подобряване качеството им на живот. В тази статия ние разглеждаме потенциалните и съществуващите възможности за приложение на прецизирана терапия при пациенти с уроепителни тумори.The etiology, pathogenesis and treatment of malignant neoplasms of the bladder still address a number of issues. Several biomarkers have been identified showing differences in the molecular image of invasive and non-invasive uroepithelial carcinoma. These biomarkers are part of the factors responsible for the large variation in treatment even in tumors with the same histological diagnosis. Currently, standard systemic therapy includes various cytotoxic chemotherapy regimens and is based mainly on histological evaluation and tumor progression. Since May 2016, target therapy has been approved for the first time in the treatment of oncological bladder disease. Target therapy is used to stop the growth and spread of cancer cells by suppressing activated signaling pathways - most often fibroblast, epidermal and endothelial growth factor pathways. The choice of „ the right` drug is largely based on the molecular genetic diagnosis of the tumor and the presence of specific biomarkers indicating the applicability of one or another drug.Significant progress has been made in the era of molecular diagnosis and target therapy, which leads to prolonged survival and improved quality of life of oncology patients. In this article, we examine the potential and existing options for the use of precision therapy in patients with uroeptithelial tumors

Susceptibility to Neurodegenerative Disorders: Insights from Paleogenomic Data

Ancient human genome data that has accumulated in recent years can be employed to establish the spatiotemporal trajectories of genetic variants associated with human diseases. Such knowledge might illuminate if and how past adaptations impact contemporary human health and medicine. Scarcely any studies have yet been attempted to evaluate the genetic susceptibility to neurodegenerative disorders in ancient human communities. Using publicly available ancient human genome-wide data the present study evaluates the molecular predisposition to neurodegenerative disorders in ancient human communities. To this end we screened the ancient genome-wide data for the presence of variants unequivocally associated with neurodegenerative disorders in modern populations, and their historical and geographic prevalence was assessed. These variants are two rare variants in the LRRK2 gene associated with Mendelian Parkinson\u27s disease, a pathogenic variant in the CRH gene, associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), and a rare variant in the TREM2 gene, a possible risk modifier associated with Alzheimer\u27s disease. Our assessment of the historical and geographic prevalence indicates differing spatiotemporal frequency dynamics for these clinically significant variants. Neurodegenerative disorders are often with poorly understood pathogenesis that might be elucidated by studying the interaction of past genetic variability with ecological and evolutionary factors such as adverse environmental conditions, specific selective pressures, periods of population isolation and admixture processes. Data on molecular predisposition to neurodegenerative disorders in ancient genomes is instructive to modern medical diagnostic and therapeutic practices

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

Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN)

Urinary neopterin concentrations in patients with Balkan endemic nephropathy (BEN).BackgroundBalkan endemic nephropathy (BEN) is of great clinical importance in restricted areas of Bulgaria, Serbia, Croatia, Bosnia, Herzegovina, and Romania, since the etiology of BEN is still unknown.MethodsIn urine samples from 48 patients (41 females and 7 males, aged 65.6 ± 6.87years) with BEN living in an endemic area of Vratza district, Bulgaria, neopterin concentrations were measured by high-pressure liquid chromatography (HPLC) and compared with other clinical and laboratory investigations, including creatinine, hemoglobin, and erythrocyte sedimentation rates (ESRs).ResultsUrinary neopterin concentrations were 263 ± 128 (mean ± SD; range, 78 to 786 μmol/mol creatinine), 24 (50%) of BEN patients presented with increased concentrations as compared to the established normal ranges. Average ESRs were increased (1hour, 29.0 ± 14.7mm/hour) and hemoglobin was decreased (109.3 ± 16.4g/L). Hemoglobin correlated inversely with ESRs (rs = -0.787 and –0.780) and creatinine concentrations (r = -0.690, all P < 0.001), but not with neopterin concentrations. Neopterin concentrations also did not correlate with serum creatinine levels. There existed an age relationship of ESR, creatinine, and hemoglobin, but not of neopterin. Neopterin concentrations were slightly lower in five females with low titers of antibodies against local B1 hantavirus strain (P < 0.05).ConclusionThe findings can support an immune-mediated inflammatory process in the pathogenesis of BEN only in a subgroup of patients

Mitochondrial DNA Suggests a Western Eurasian origin for Ancient (Proto-) Bulgarians

Ancient (proto-) Bulgarians have long been thought to as a Turkic population. However, evidence found in the past three decades show that this is not the case. Until now, this evidence does not include ancient mitochondrial DNA (mtDNA) analysis. In order to fill this void, we have collected human remains from the VIII-X century AD located in three necropolises in Bulgaria: Nojarevo (Silistra region) and Monastery of Mostich (Shumen region), both in Northeast Bulgaria and Tuhovishte (Satovcha region) in Southwest Bulgaria. The phylogenetic analysis of 13 ancient DNA samples (extracted from teeth) identified 12 independent haplotypes, which we further classified into mtDNA haplogroups found in present-day European and Western Eurasian populations. Our results suggest a Western Eurasian matrilineal origin for proto-Bulgarians as well as a genetic similarity between proto- and modern Bulgarians. Our future work will provide additional data which will further clarify proto-Bulgarian origins; thereby adding new clues to current understanding of European genetic evolution

Influence of detection of pretreatment cytogenetic abnormalities on first complete remission and survival in adult acute lymphoblastic leukemia

Objective: Treatment of acute lymphoblastic leukemia (ALL) in adults focuses on the initial assessment of the prognostic relevant cytogenetic features as well as a response-guided therapy based on molecular data. We examined the importance of molecular-cytogenetic abnormalities for complete remission (CR) rates and the overall survival (OS) in adult ALLs.Materials and Methods: Conventional cytogenetics and fluorescence in situ hybridization were performed on bone marrow cells from 33 newly-diagnosed ALL adults. Two karyotype categories [standard- risk group- normal karyotype, hyperdiplody and other structural aberrations, and high-risk group-t(11q23)/MLL, t(9;22)/bcr-abl, t(1;19), t(8;14), C-MYC and complex karyotype] and the biologically and clinically relevant ALL ploidy subgroups were prospectively defined.Results: Chromosomal abnormalities were found in 52% of the cases with a high rate of poor-risk translocations - t(9;22), t(8q24), t(11q23), t(1;19). The total CR rate was 67% and the median time for achievement 2.33 months. Male sex, an age below 35 years and the absence of high risk translocations might have contributed to the high CR rates. Female patients, hyperdiplody, low white blood cells (WBC), and random cytogenetic aberrations had the longest OS. OS, 3- and 5-years survival periods were significantly shorter for poor-risk than standard risk group (p=.015, p=.001 and p=.005, respectively).Conclusion: This study emphasizes the lack of influence of cytogenetic aberrations on the CR and the time to achieve CR. However, our observations show that these aberrations are an independent prognostic factor in adult ALL - they allow predicting therapy resistance and the OS time after intensetreatment

Comparative 1H NMR Metabolomic Urinalysis of People Diagnosed with Balkan Endemic Nephropathy, and Healthy Subjects, in Romania and Bulgaria: A Pilot Study

1H NMR spectroscopy of urine has been applied to exploring metabolomic differences between people diagnosed with Balkan endemic nephropathy (BEN), and treated by haemodialysis, and those without overt renal disease in Romania and Bulgaria. Convenience sampling was made from patients receiving haemodialysis in hospital and healthy controls in their village. Principal component analysis clustered healthy controls from both countries together. Bulgarian BEN patients clustered separately from controls, though in the same space. However, Romanian BEN patients not only also clustered away from controls but also clustered separately from the BEN patients in Bulgaria. Notably, the urinary metabolomic data of two people sampled as Romanian controls clustered within the Romanian BEN group. One of these had been suspected of incipient symptoms of BEN at the time of selection as a ‘healthy’ control. This implies, at first sight, that metabolomic analysis can be predictive of impending morbidity before conventional criteria can diagnose BEN. Separate clustering of BEN patients from Romania and Bulgaria could indicate difference in aetiology of this particular silent renal atrophy in different geographic foci across the Balkans

Genetic Differences between Five European Populations

Aims: We sought to examine the magnitude of the differences in SNP allele frequencies between five European populations (Scotland, Ireland, Sweden, Bulgaria and Portugal) and to identify the loci with the greatest differences. Methods: We performed a population-based genome-wide association analysis with Affymetrix 6.0 and 5.0 arrays. We used a 4 degrees of freedom χ2 test to determine the magnitude of stratification for each SNP. We then examined the genes within the most stratified regions, using a highly conservative cutoff of p < 10–45. Results: We found 40,593 SNPs which are genome-wide significantly (p ≤ 10–8) stratified between these populations. The largest differences clustered in gene ontology categories for immunity and pigmentation. Some of the top loci span genes that have already been reported as highly stratified: genes for hair color and pigmentation (HERC2, EXOC2, IRF4), the LCT gene, genes involved in NAD metabolism, and in immunity (HLA and the Toll-like receptor genes TLR10, TLR1, TLR6). However, several genes have not previously been reported as stratified within European populations, indicating that they might also have provided selective advantages: several zinc finger genes, two genes involved in glutathione synthesis or function, and most intriguingly, FOXP2, implicated in speech development. Conclusion: Our analysis demonstrates that many SNPs show genome-wide significant differences within European populations and the magnitude of the differences correlate with the geographical distance. At least some of these differences are due to the selective advantage of polymorphisms within these loci

Association study in the 5q31-32 linkage region for schizophrenia using pooled DNA genotyping

<p>Abstract</p> <p>Background</p> <p>Several linkage studies suggest that chromosome 5q31-32 might contain risk loci for schizophrenia (SZ). We wanted to identify susceptibility genes for schizophrenia within this region.</p> <p>Methods</p> <p>We saturated the interval between markers D5S666 and D5S436 with 90 polymorphic microsatellite markers and genotyped two sets of DNA pools consisting of 300 SZ patients of Bulgarian origin and their 600 parents. Positive associations were followed-up with SNP genotyping.</p> <p>Results</p> <p>Nominally significant evidence for association (p < 0.05) was found for seven markers (D5S0023i, IL9, RH60252, 5Q3133_33, D5S2017, D5S1481, D5S0711i) which were then individually genotyped in the trios. The predicted associations were confirmed for two of the markers: D5S2017, localised in the <it>SPRY4-FGF1 </it>locus (p = 0.004) and IL9, localized within the IL9 gene (p = 0.014). Fine mapping was performed using single nucleotide polymorphisms (SNPs) around D5S2017 and IL9. In each region four SNPs were chosen and individually genotyped in our full sample of 615 SZ trios. Two SNPs showed significant evidence for association: rs7715300 (p = 0.001) and rs6897690 (p = 0.032). Rs7715300 is localised between the <it>TGFBI </it>and <it>SMAD5 </it>genes and rs6897690 is within the <it>SPRY4 </it>gene.</p> <p>Conclusion</p> <p>Our screening of 5q31-32 implicates three potential candidate genes for SZ: <it>SMAD5</it>, <it>TGFBI </it>and <it>SPRY4</it>.</p