Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Reflection of neuroblastoma intratumor heterogeneity in the new OHC-NB1 disease model

Accurate modeling of intratumor heterogeneity presents a bottleneck against drug testing. Flexibility in a preclinical platform is also desirable to support assessment of different endpoints. We established the model system, OHC-NB1, from a bone marrow metastasis from a patient diagnosed with MYCN-amplified neuroblastoma and performed whole-exome sequencing on the source metastasis and the different models and passages during model development (monolayer cell line, 3D spheroid culture and subcutaneous xenograft tumors propagated in mice). OHC-NB1 harbors a MYCN amplification in double minutes, 1p deletion, 17q gain and diploid karyotype, which persisted in all models. A total of 80–540 single-nucleotide variants (SNVs) was detected in each sample, and comparisons between the source metastasis and models identified 34 of 80 somatic SNVs to be propagated in the models. Clonal reconstruction using the combined copy number and SNV data revealed marked clonal heterogeneity in the originating metastasis, with four clones being reflected in the model systems. The set of OHC-NB1 models represents 43% of somatic SNVs and 23% of the cellularity in the originating metastasis with varying clonal compositions, indicating that heterogeneity is partially preserved in our model system.     

Drug‐induced photosensitivity: culprit drugs,potential mechanisms and clinical consequences

Drug‐induced photosensitivity, the development of phototoxic or photoallergic reactions due to pharmaceuticals and subsequent exposure to ultraviolet or visible light, is an adverse effect of growing interest. This is illustrated by the broad spectrum of recent investigations on the topic, ranging from molecular mechanisms and culprit drugs through epidemiological as well as public health related issues to long‐term photoaging and potential photocarcinogenic consequences. The present review summarizes the current state of knowledge on the topic while focusing on culprit drugs and long‐term effects. In total, 393 different drugs or drug compounds are reported to have a photosensitizing potential, although the level of evidence regarding their ability to induce photosensitive reactions varies markedly among these agents. The pharmaceuticals of interest belong to a wide variety of drug classes. The epidemiological risk associated with the use of photosensitizers is difficult to assess due to under‐reporting and geographical differences. However, the widespread use of photosensitizing drugs combined with the potential photocarcinogenic effects reported for several agents has major implications for health and safety and suggests a need for further research on the long‐term effects.     

Cross‐sectional and longitudinal association of sports participation,media consumption and motor competence in youth

The beneficial associations of physical activity (PA) and sports with motor competence have been well documented. Similarly, high media time has been associated with poor motor competence. Limited information, however, is available on the combined effects of sport participation and media consumption on motor competence. The present study followed 213 Austrian middle‐school students (57% male; age at baseline: 10.4 ± 0.6 years) over a 4‐year period. Annual assessments included the German Motor Test 6‐18, along with self‐reported participation in club sports, time spent watching TV and using the computer. There were no interaction effects between sports participation and media time on motor competence. Club sports participation, however, was associated with higher motor competence, while there was an inverse association between media time and motor competence. Further, motor competence affected future participation in club sports while club sports had limited effects on subsequent motor development. High media time, on the other hand, impaired subsequent motor development, while effects of motor competence on media time were limited. Taken together, these results emphasize the importance of motor competence in the facilitation of sports participation during adolescence. Accordingly, a wide variety of movement experiences should be provided at young ages to promote motor development. In addition, the detrimental effects of media time on motor competence warrant that sedentary behaviors are targeted separately, particularly in youth not participating in sports.     

Cardiomyocyte microvesicles: proinflammatory mediators after myocardial ischemia?

Myocardial infarction is a frequent complication of cardiovascular disease leading to high morbidity and mortality worldwide. Elevated C-reactive protein (CRP) levels after myocardial infarction are associated with heart failure and poor prognosis. Cardiomyocyte microvesicles (CMV) are released during hypoxic conditions and can act as mediators of intercellular communication. MicroRNA (miRNA) are short non-coding RNA which can alter cellular mRNA-translation. Microvesicles (MV) have been shown to contain distinct patterns of miRNA from their parent cells which can affect protein expression in target cells. We hypothesized that miRNA containing CMV mediate hepatic CRP expression after cardiomyocyte hypoxia. H9c2-cells were cultured and murine cardiomyocytes were isolated from whole murine hearts. H9c2- and murine cardiomyocytes were exposed to hypoxic conditions using a hypoxia chamber. Microvesicles were isolated by differential centrifugation and analysed by flow cytometry. Next-generation-sequencing was performed to determine the miRNA-expression profile in H9c2 CMV compared to their parent cells. Microvesicles were incubated with a co-culture model of the liver consisting of THP-1 macrophages and HepG2 cells. IL-6 and CRP expression in the co-culture was assessed by qPCR and ELISA. CMV contain a distinct pattern of miRNA compared to their parent cells including many inflammation-related miRNA. CMV induced IL-6 expression in THP-1 macrophages alone and CRP expression in the hepatic co-culture model. MV from hypoxic cardiomyocytes can mediate CRP expression in a hepatic co-culture model. Further studies will have to show whether these effects are reproducible in-vivo.

     

Loss of mitochondrial ClpP,Lonp1, and Tfam triggers transcriptional induction of Rnf213, a susceptibility factor for moyamoya disease

neurogenetics - Human RNF213, which encodes the protein mysterin, is a known susceptibility gene for moyamoya disease (MMD), a cerebrovascular condition with occlusive lesions and compensatory...