IBD syndromes such as Crohn's disease and ulcerative colitis result from the inflammation of specific intestinal segments. Although many studies have reported on the regenerative response of intestinal progenitor and stem cells to tissue injury, very little is known about the response of differentiated lineages to inflammatory cues. Here, we show that acute inflammation of the mouse small intestine is followed by a dramatic loss of Lgr5 stem cells. Instead, Paneth cells re-enter the cell cycle, lose their secretory expression signature, and acquire stem-like properties, thus contributing to the tissue regenerative response to inflammation. Stem cell factor secretion upon inflammation triggers signaling through the c-Kit receptor and a cascade of downstream events culminating in GSK3β inhibition and Wnt activation in Paneth cells. Hence, the plasticity of the intestinal epithelium in response to inflammation goes well beyond stem and progenitor cells and extends to the fully differentiated and post-mitotic Paneth cells.

AXIN1 mutations are observed in 8–10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing β-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear β-catenin accumulation nor clearly enhanced expression of β-catenin target genes. Here, using nine HCC lines, we show that AXIN1 mutation or siRNA mediated knockdown contributes to enhanced β-catenin signaling in all AXIN1-mutant and non-mutant lines, also confirmed by reduced signaling in AXIN1-repaired SNU449 cells. Both AXIN1 and AXIN2 work synergistically to control β-catenin signaling. While in the AXIN1-mutant lines, AXIN2 is solely responsible for keeping signaling in check, in the non-mutant lines both AXIN proteins contribute to β-catenin regulation to varying levels. The AXIN proteins have gained substantial interest in cancer research for a second reason. Their activity in the β-catenin destruction complex can be increased by tankyrase inhibitors, which thus may serve as a therapeutic option to reduce the growth of β-catenin-dependent cancers. At concentrations that inhibit tankyrase activity, some lines (e.g. HepG2, SNU398) were clearly affected in colony formation, but in most cases apparently independent from effects on β-catenin signaling. Overall, our analyses show that AXIN1 inactivation leads to enhanced β-catenin signaling in HCC cell lines, questioning the strong statements that have been made in this regard. Enhancing AXIN activity by tankyrase monotherapy provides however no effective treatment to affect their growth exclusively through reducing β-catenin signaling.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) have been identified in bacteria, archaea and mitochondria of plants, but not in eukaryotes. Here, we report the discovery of 12,572 putative CRISPRs randomly distributed across the human chromosomes, which we termed hCRISPRs. By using available transcriptome datasets, we demonstrate that hCRISPRs are distinctively expressed as small non-coding RNAs (sncRNAs) in cell lines and human tissues. Moreover, expression patterns thereof enabled us to distinguish normal from malignant tissues. In prostate cancer, we confirmed the differential hCRISPR expression between normal adjacent and malignant primary prostate tissue by RT-qPCR and demonstrate that the SHERLOCK and DETECTR dipstick tools are suitable to detect these sncRNAs. We anticipate that the discovery of CRISPRs in the human genome can be further exploited for diagnostic purposes in cancer and other medical conditions, which certainly will lead to the development of point-of-care tests based on the differential expression of the hCRISPRs.

Background The survival of glioblastoma patients is poor. Median survival after diagnosis is 15 months, despite treatment involving surgical resection, radiotherapy and/or temozolomide chemotherapy. Identification of novel targets and stratification strategies of glioblastoma patients to improve patient survival is urgently needed. Whole genome sequencing (WGS) is the most comprehensive means to identify such DNA-level targets. We report a unique set of WGS samples along with comprehensive analyses of the glioblastoma genome and potential clinical impact of WGS. Methods Our cohort consisted of 42 glioblastoma tumor tissue and matched whole-blood samples, which were whole-genome sequenced as part of the CPCT-02 study. Somatic single-nucleotide variants, small insertions/deletions, multi-nucleotide variants, copy-number alterations (CNAs) and structural variants were analyzed. These aberrations were harnessed to investigate driver genes, enrichments in CNAs, mutational signatures, fusion genes and potential targeted therapies. Results Tumor mutational burden (TMB) was similar to other WGS efforts (1-342 mutations per megabase pair). Mutational analysis in low TMB samples showed that the age-related CpG demethylation signature was dominant, while hyper- and ultramutated tumors had additional defective DNA mismatch repair signatures and showed microsatellite instability in their genomes. We detected chromothripsis in 24% of our cohort, recurrently on chromosomes 1 and 12. Recurrent non-coding regions only resulted in TERT promoter variants. Finally, we found biomarkers and potentially druggable changes in all but one of our tumor samples. Conclusions With high quality WGS data and comprehensive methods, we identified the landscape of driver gene events and druggable targets in glioblastoma patients.

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Summary We present an R-based open-source software termed ProteoDisco that allows for flexible incorporation of genomic variants, fusion-genes and (aberrant) transcriptomic variants from standardized formats into protein variant sequences. ProteoDisco allows for a flexible step-by-step workflow allowing for in-depth customization to suit a myriad of research approaches in the field of proteogenomics, on all organisms for which a reference genome and transcript annotations are available. Availability ProteoDisco (R package version ≥ 1.0.0) is available on Bioconductor at https://doi.org/doi:10.18129/B9.bioc.ProteoDisco and from https://github.com/ErasmusMC-CCBC/ProteoDisco/. Supplementary information Supplementary table, figures and data files are available at Bioinformatics online.

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Methods: Expression profile analysis was performed in 26 HCV-induced HCC patients and 14 healthy controls. Huh7 cell lines were cultured. Total RNA was extracted using Trizol. miR-873, miR-181a and miR-17-5p were measured using q-RT-PCR and normalized to RNU6B while PD-L1 and CD155 were normalized to b-2-microglobulin.Results: miR-17-5p, miR-181a and miR-873 were found to be significantly upregulated in PBMCs and sera of HCV-induced HCC patients and cell lines compared to healthy controls. Furthermore, their level of expression was directly associated with a-fetoprotein (AFP) level. On the other hand, HCC patients showed a paradoxical expression of immune checkpoints where HCC patients showed high levels of PD-L1 and low expression level of CD155. PD-L1 expression level was inversely correlated with miR-873, miR-17-5p and AFP.Conclusions: This study sheds the lights onto novel non-invasive oncoimmunological biomarkers among HCC patients. miR-873, miR181a, miR-17-5p are potential diagnostic and prognostic markers for HCV induced HCC patients that is highly correlated with PD-L1 and alpha-fetoprotein levels.Legal entity responsible for the study: The authors.