Transcriptome profiling of mice testes following low dose irradiation

BACKGROUND: Radiotherapy is used routinely to treat testicular cancer. Testicular cells vary in radio-sensitivity and the aim of this study was to investigate cellular and molecular changes caused by low dose irradiation of mice testis and to identify transcripts from different cell types in the adult testis. METHODS: Transcriptome profiling was performed on total RNA from testes sampled at various time points (n = 17) after 1 Gy of irradiation. Transcripts displaying large overall expression changes during the time series, but small expression changes between neighbouring time points were selected for further analysis. These transcripts were separated into clusters and their cellular origin was determined. Immunohistochemistry and in silico quantification was further used to study cellular changes post-irradiation (pi). RESULTS: We identified a subset of transcripts (n = 988) where changes in expression pi can be explained by changes in cellularity. We separated the transcripts into five unique clusters that we associated with spermatogonia, spermatocytes, early spermatids, late spermatids and somatic cells, respectively. Transcripts in the somatic cell cluster showed large changes in expression pi, mainly caused by changes in cellularity. Further investigations revealed that the low dose irradiation seemed to cause Leydig cell hyperplasia, which contributed to the detected expression changes in the somatic cell cluster. CONCLUSIONS: The five clusters represent gene expression in distinct cell types of the adult testis. We observed large expression changes in the somatic cell profile, which mainly could be attributed to changes in cellularity, but hyperplasia of Leydig cells may also play a role. We speculate that the possible hyperplasia may be caused by lower testosterone production and inadequate inhibin signalling due to missing germ cells

Gut microbiota profiles of autism spectrum disorder and attention deficit/hyperactivity disorder:A systematic literature review

Accumulating evidence has implicated an involvement of the gut-brain axis in autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD), however with highly diverse results. This systematic review aims to describe and evaluate studies investigating the gut microbiota composition in individuals with ASD or ADHD and to evaluate if variations in gut microbiota are associated with these disorders. Twenty-four articles were identified in a systematic literature search of PubMed and Embase up to July 22, 2019. They consisted of 20 studies investigating ASD and four studies investigating ADHD. For ASD, several studies agreed on an overall difference in β-diversity, although no consistent bacterial variation between all studies was reported. For ADHD, the results were more diverse, with no clear differences observed. Several common characteristics in gut microbiota function were identified for ASD compared to controls. In contrast, highly heterogeneous results were reported for ADHD, and thus the association between gut microbiota composition and ADHD remains unclear. For both disorders, methodological differences hampered the comparison of studies

Functional megalin is expressed in renal cysts in a mouse model of adult polycystic kidney disease

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive growth of cysts and a decline of renal function. The clinical feasibility of the number of potential disease-modifying drugs is limited by systemic adverse effects. We hypothesize that megalin, a multiligand endocytic receptor expressed in the proximal tubule, may be used to facilitate drug uptake into cysts, thereby allowing for greater efficacy and fewer side effects. METHODS: The cyst expression of various tubular markers, including megalin and aquaporin 2 (AQP2), was analysed by immunohistochemistry (IHC) of kidney sections from the ADPKD mouse model (PKD1(RC/RC)) at different post-natal ages. The endocytic function of megalin in cysts was examined by IHC of kidney tissue from mice injected with the megalin ligand aprotinin. RESULTS: Cyst lining epithelial cells expressing megalin were observed at all ages; however, the proportion decreased with age. Concomitantly, an increasing proportion of cysts revealed expression of AQP2, partial expression of megalin and/or AQP2 or no expression of the examined markers. Endocytic uptake of aprotinin was evident in megalin-positive cysts, but only in those that remained connected to the renal tubular system. CONCLUSIONS: Megalin-expressing cysts were observed at all ages, but the proportion decreased with age, possibly due to a switch in tubular origin, a merging of cysts of different tubular origin and/or a change in the expression pattern of cyst lining cells. Megalin expressed in cysts was functional, suggesting that megalin-mediated endocytosis is a potential mechanism for drug targeting in ADPKD if initiated early in the disease

Development of a Precision Medicine Workflow in Hematological Cancers, Aalborg University Hospital, Denmark

Within recent years, many precision cancer medicine initiatives have been developed. Most of these have focused on solid cancers, while the potential of precision medicine for patients with hematological malignancies, especially in the relapse situation, are less elucidated. Here, we present a demographic unbiased and observational prospective study at Aalborg University Hospital Denmark, referral site for 10% of the Danish population. We developed a hematological precision medicine workflow based on sequencing analysis of whole exome tumor DNA and RNA. All steps involved are outlined in detail, illustrating how the developed workflow can provide relevant molecular information to multidisciplinary teams. A group of 174 hematological patients with progressive disease or relapse was included in a non-interventional and population-based study, of which 92 patient samples were sequenced. Based on analysis of small nucleotide variants, copy number variants, and fusion transcripts, we found variants with potential and strong clinical relevance in 62% and 9.5% of the patients, respectively. The most frequently mutated genes in individual disease entities were in concordance with previous studies. We did not find tumor mutational burden or micro satellite instability to be informative in our hematologic patient cohort

Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor

The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the first analysis of the X chromosome. Eight new loci mapping to 2q14.2, 3q26.2, 4q35.2, 7q36.3, 10q26.13, 15q21.3, 15q22.31, and Xq28 achieved genome-wide significance (P < 5 × 10−8). Most loci harbor biologically plausible candidate genes. We refined previously reported associations at 9p24.3 and 19p12 by identifying one and three additional independent SNPs, respectively. In aggregate, the 39 independent markers identified to date explain 37% of father-to-son familial risk, 8% of which can be attributed to the 12 new signals reported here. Our findings substantially increase the number of known TGCT susceptibility alleles, move the field closer to a comprehensive understanding of the underlying genetic architecture of TGCT, and provide further clues to the etiology of TGCT

Learning to live together: mutualism between self-splicing introns and their hosts

Group I and II introns can be considered as molecular parasites that interrupt protein-coding and structural RNA genes in all domains of life. They function as self-splicing ribozymes and thereby limit the phenotypic costs associated with disruption of a host gene while they act as mobile DNA elements to promote their spread within and between genomes. Once considered purely selfish DNA elements, they now seem, in the light of recent work on the molecular mechanisms regulating bacterial and phage group I and II intron dynamics, to show evidence of co-evolution with their hosts. These previously underappreciated relationships serve the co-evolving entities particularly well in times of environmental stress