Vloga tiroksina pri karcinogenezi ščitnice

The aimof this study was to test the hypothesis on the protective role of thyroxin administration before and during irradiation on the occurrence of thyroid carcinoma in rats. Application of thyroxin before and during irradiation was expected to decrease production of thyrotropin by the hypophyseal feedback mechanism, caused by radiation damage of thyroid tissue. Stabilizing the thyroid cells in this way during irradiation would thus make them less radiosensitive. In the experiment, we first divided 81 three to fourweek old Wistar strain rats of both sexes into two groups, i.e. thyroxin (T4) and water (H2O). The T4 rats were injected 1% thyroxin solution (0.01 mg/100 g body weight) twice a day for 15 days, while the H2O rats received saline in the same way. After ten days, the two main groups were divided each into two subgroups. The rats from both irradiated subgroups (T4/X and (H2O/X) recieved 10 Gy to the neck area. They were iradiated with a telecobalt machinefor five consecutive days with one direct field. During a two years follow - up, all moribund animals were sacrificed and their thyroid glands taken. The rest of the thyroid glands were taken at the end of the experiment.All glands were pathohistologically analysed. Besides, all suspicious and enlarged extrathyroid organs and tissues were examined and the occurrence of tumors was noted. Pathohistological examination revealed the occurrence of 8 thyroid carcinomas and 7 adenomas in the H2O/X group, and 3 adenomas in the T4/X group. In the iradiated group of rats without thyroxin, significantly (P = 0.01) more thyroid carcinomas occurred than in the irradiated group without thyroxin.Namen študije je bil preveriti hipotezo o zaščitni vlogi dajanja tiroksina podganam pred obsevanjem in po njem, na pojavljanje ščitničnega karcinoma. Dajanje tiroksina pred in med obsevanjem naj bi preko povratne zveze s hipofizo preprečilo povečano izločanje tirotropina, povročeno z radiacijsko okvaro ščitničnega tkiva. Na takšen način stabilizirane celice naj bi bile medobsevanjem manj radiosenzibilne. V poskusu smo 81 podgan seva Wistar obeh spolov, starih 3 do 4 tedne najprej razdelili v dve skupini, v tiroksinsko (T4) in vodno (H2O). Tiroksinski skupini smo 15 dni dvakrat dnevno intraperitonealno injicirali enoodstotno raztopino tiroksina (0.01 mg/100 g telesne teže), vodna skupina pa je na enak način dobivala sterilno fiziološko raztopino. Po 10 dneh smo vsako od osnovnih skupin razdelili v dve podskupinipodgane iz obeh obsevanih podskupin (T4/X in H2O/X) so prejele 10 Gy na področje vratu. Na telekobaltovem aparatu smo jih 5 dni zapored obsevaliz direktnim poljem. Med dveletnim opazovanjem smo sproti žertvovali vse živali v slabem stanju in jim odvzeli ščitnice. Preostale ščitnice smo odvzeli ob koncu poskusa. Vse žleze smo patohistološko analizirali. Poleg tegasmo pregledali vse sumljive in povečane ekstratiroidne organe in tkiva terzabeležili vsa pojavljanja tumorjev. Ugotovili smo, da se je v skupini H2O/X pojavilo 8 ščitničnih karcinomov in 7 adenomov, v skupini T4/X pa trije ščitnični adenomi. V skupini obsevanih podgan brez tiroksina je bila incidencakarcinomov ščitnice statistično signifikantno (P = 0,01) večja kot v obsevani skupini s tiroksinom. Z opisanim poskusom je bila potrjena hipoteza o zaščitni vlogi dajanja tiroksina pred in med obsevanjem pri postiradiacijskiščitnični karcinogenezi pri podganah

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Differential Expression of Several miRNAs and the Host Genes AATK and DNM2 in Leukocytes of Sporadic ALS Patients

Genetic studies have managed to explain many cases of familial amyotrophic lateral sclerosis (ALS) through mutations in several genes. However, the cause of a majority of sporadic cases remains unknown. Recently, epigenetics, especially miRNA studies, show some promising aspects. We aimed to evaluate the differential expression of 10 miRNAs, including miR-9, miR-338, miR-638, miR-663a, miR-124a, miR-143, miR-451a, miR-132, miR-206, and let-7b, for which some connection to ALS was shown previously in ALS culture cells, animal models or patients, and in three miRNA host genes, including C1orf61 (miR-9), AATK (miR-338), and DNM2 (miR-638), in leukocyte samples of 84 patients with sporadic ALS. We observed significant aberrant dysregulation across our patient cohort for miR-124a, miR-206, miR-9, let-7b, and miR-638. Since we did not use neurological controls we cannot rule out that the revealed differences in expression of investigated miRNAs are specific for ALS. Nevertheless, the group of these five miRNAs is worth of additional research in leukocytes of larger cohorts from different populations in order to verify their potential association to ALS disease. We also detected a significant up-regulation of the AAKT gene and down-regulation of the DNM2 gene, and thus, for the first time, we connected these with sporadic ALS cases. These findings open up new research toward miRNAs as diagnostic biomarkers and epigenetic processes involved in ALS. The detected significant deregulation of AAKT and DNM2 in sporadic ALS also represents an interesting finding. The DNM2 gene was previously found to be mutated in Charcot-Marie-Tooth neuropathy-type CMT2M and centronuclear myopathy (CNM). In addition, as recent studies connected AATK and frontotemporal dementia (FTD) and DNM2 and hereditary spastic paraplegia (HSP), these two genes together with our results genetically connect, at least in part, five diseases, including FTD, HSP, Charcot-Marie-Tooth (type CMT2M), CNM, and ALS, thus opening future research toward a better understanding of the cell biology involved in these partly overlapping pathologies

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk

Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1–10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk