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Background Structural rearrangements of chromosomal band 19q13 are a non-random cytogenetic abnormality in thyroid adenomas and adenomatous goiters and lead to an expression of miRNAs of the chromosome 19 microRNA cluster C19MC. Normally, expression of these miRNAs is silenced except for embryonic stem cells and the placenta where they represent the majority of miRNAs not only in the trophoblast but also in exosomes derived from it. Presentation of the hypothesis We have advanced the hypothesis that as part of the feto-maternal communication miRNAs of C19MC serve immunomodulatory functions in the placenta and confer a growth advantage to thyroid nodules by protecting them against autoimmune attacks. More precisely, the exosomes containing these miRNAs may specifically target immune cells in their local environment as well as systemically by transferring their cargo to recipient cells. Within these target cells the transferred miRNAs can interact with mRNAs of the recipient cells thereby suppressing their immune-specific functions. Testing the hypothesis Experiments used to demonstrate the immunomodulatory capacity of placenta-derived exosomes can be modified by transfecting the target cells with those miRNAs of C19MC represented in placental exosomes. Implications of the hypothesis Mimics of C19MC-derived miRNAs might develop to useful drug candidates for the treatment of autoimmune disease as e.g. rheumatoid arthritis and Sjögren’s syndrome and for the prevention of transplant rejection. In case of tumor entities with elevated expression of C19MC miRNAs these miRNAs may be interesting targets for treatment with appropriate antagonists.

miRNAs of the largest human miRNA gene cluster at all, i.e., C19MC, are almost exclusively expressed in the placenta. Nevertheless, only little is known about the interindividual variation of their expression and even about possible influence of gestational age, conflicting data is reported as well as for miRNAs of the much smaller miR-371-3 cluster. Our present study aims at the analyses of the expression of miRNAs from both clusters at different times of pregnancy, possible differences between placenta samples obtained from spontaneous or induced abortions in the first trimester, and the possible variation of miRNA expression at different sites within same placentas. miR-371a-3p, miR-372-3p, miR-373-3p, miR-517a-3p, and miR-520c-3p were quantified in 85 samples and miR-371a-3p was quantified in maternal serum samples taken immediately before delivery. While for miRNA-517a-3p and miR-520c-3p the expression increased with increasing gestational age, the present study revealed strong interindividual differences in the expression of miR-371-3 in full-term placental tissue as well as for miRNAs of the C19MC cluster, where the levels differed to a much lesser extent than for the former microRNAs. Also, strong interindividual differences were noted between the serum samples but differences related to the site of the placenta where the sample has been taken from were excluded. For neither of the data from placental tissue, the study revealed differences between the spontaneous and induced abortion group. Thus, the differences do not in general seem to be related to first trimester abortion. It remains to be elucidated whether or not they affect other prenatal processes.

Chromosomal rearrangements of band 19q13.4 are frequent cytogenetic alterations in benign thyroid adenomas. Apparently, these alterations lead to the upregulation of genes encoding microRNAs of two clusters mapping to the breakpoint region, i.e. miR-371-3 and C19MC. Since members of both clusters have been associated with neoplastic growth in other tumor entities the question arises whether or not their upregulation predisposes to malignant transformation of follicular cells of the thyroid. To address this question we have quantified the expression of miR-372 and miR-520c-3p in samples of 114 thyroid cancers including eight anaplastic thyroid carcinomas, 25 follicular thyroid carcinomas, 78 papillary thyroid carcinomas (including 13 follicular variants thereof), two medullary thyroid carcinomas and one oncocytic thyroid carcinoma. Additionally, we quantified miR-371a-3p and miR-519a-3p in selected samples. While in neither of the cases miR-520c-3p and miR-519a-3p were found to be upregulated, one papillary and one anaplastic thyroid carcinoma, respectively, showed upregulation of miR-372 and miR-371a-3p. However, in these cases fluorescence in situ hybridization did not reveal rearrangements of the common breakpoint region as affected in adenomas. Thus, these rearrangements do apparently not play a major role as first steps in malignant transformation of the thyroid epithelium. Moreover, there is no evidence that 19q13.4 rearrangements characterize a subgroup of thyroid adenomas associated with a higher risk to undergo malignant transformation. Vice versa, the mechanisms by which 19q13.4 rearrangements contribute to benign tumorigenesis in the thyroid remain to be elucidated.

BackgroundThe mental health benefits of cannabidiol (CBD) are promising but can be inconsistent, in part due to challenges in defining an individual’s effective dosage. In schizophrenia, alterations in anandamide (AEA) concentrations, an endocannabinoid (eCB) agonist of the eCB system, reflect positively on treatment with CBD. Here, we expanded this assessment to include eCBs alongside AEA congeners, comparing phytocannabinoids and dosage in a clinical setting.MethodsLiquid chromatography-tandem mass spectrometry quantified changes in serum levels of AEA, 2-arachidonoylglycerol (2-AG), alongside AEA-related compounds oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which were attained from two independent, parallel-designed, clinical trials investigating single, oral CBD (600 or 800 mg), delta-9-tetrahydrocannabinol (Δ9-THC, 10 or 20 mg) and combination administration (CBD|800 mg+Δ9-THC|20 mg) in healthy volunteers (HVs, n=75). Concentrations were measured at baseline (t=0), 65 and 160 min post administration.ResultsCBD-led increases in AEA (1.6-fold), OEA and PEA (1.4-fold) were observed following a single 800 mg (pcorr<0.05) but not 600 mg dosage. Declining AEA was observed with Δ9-THC at 10 mg (−1.3-fold) and 20 mg (−1.4-fold) but restored to baseline levels by 160 min. CBD+Δ9-THC yielded the highest increases in AEA (2.1-fold), OEA (1.9-fold) and PEA (1.8-fold) without reaching a maximal response.ConclusionCBD-administered effects towards AEA, OEA and PEA are consistent with phase II trials reporting clinical improvement for acute schizophrenia (CBD≥800 mg). Including Δ9-THC appears to enhance the CBD-induced response towards AEA and its congeners. Our results warrant further investigations into the potential of these lipid-derived mediators as metabolic measures for CBD dose prescription and co-cannabinoid administration.