Intestinal Colonization of IL-2 Deficient Mice with Non-Colitogenic B. vulgatus Prevents DC Maturation and T-Cell Polarization

BACKGROUND: IL-2 deficient (IL-2(-/-)) mice mono-colonized with E. coli mpk develop colitis whereas IL-2(-/-)-mice mono-colonized with B. vulgatus mpk do not and are even protected from E. coli mpk induced colitis. METHODOLOGY/PRINCIPAL FINDINGS: We investigated if mono-colonization with E. coli mpk or B. vulgatus mpk differentially modulates distribution, activation and maturation of intestinal lamina propria (LP) dendritic cells (DC). LP DC in mice mono-colonized with protective B. vulgatus mpk or co-colonized with E. coli mpk/B. vulgatus mpk featured a semi-mature LP DC phenotype (CD40(lo)CD80(lo)MHC-II(hi)) whereas mono-colonization with colitogenic E. coli mpk induced LP DC activation and maturation prior to onset of colitis. Accordingly, chemokine receptor (CCR) 7 surface expression was more strikingly enhanced in mesenteric lymph node DC from E. coli mpk than B. vulgatus mpk mono- or co-colonized mice. Mature but not semi-mature LP DC promoted Th1 polarization. As B. vulgatus mpk promotes differentiation of semi-mature DC presumably by IL-6, mRNA and protein expression of IL-6 was investigated in LP DC. The data demonstrated that IL-6 mRNA and protein was increased in LP DC of B. vulgatus mpk as compared to E. coli mpk mono-colonized IL-2(-/-)-mice. The B. vulgatus mpk mediated suppression of CCR7 expression and DC migration was abolished in IL-6(-/-)-DC in vitro. CONCLUSIONS/SIGNIFICANCE: From this data we conclude that the B. vulgatus triggered IL-6 secretion by LP DC in absence of proinflammatory cytokines such as IL-12 or TNF-alpha induces a semi-mature LP DC phenotype, which might prevent T-cell activation and thereby the induction of colitis in IL-2(-/-)-mice. The data provide new evidence that IL-6 might act as an immune regulatory cytokine in the mucosa by targeting intestinal DC

Prognostic value of indoleamine 2,3 dioxygenase in patients with higher‐risk myelodysplastic syndromes treated with azacytidine

Hypomethylating agents (HMAs) are widely used in patients with higher‐risk myelodysplastic syndromes (MDS) not eligible for stem cell transplantation; however, the response rate is <50%. Reliable predictors of response are still missing, and it is a major challenge to develop new treatment strategies. One current approach is the combination of azacytidine (AZA) with checkpoint inhibitors; however, the potential benefit of targeting the immunomodulator indoleamine‐2,3‐dioxygenase (IDO‐1) has not yet been evaluated. We observed moderate to strong IDO‐1 expression in 37% of patients with high‐risk MDS. IDO‐1 positivity was predictive of treatment failure and shorter overall survival. Moreover, IDO‐1 positivity correlated inversely with the number of infiltrating CD8+ T cells, and IDO‐1+ patients failed to show an increase in CD8+ T cells under AZA treatment. In vitro experiments confirmed tryptophan catabolism and depletion of CD8+ T cells in IDO‐1+ MDS, suggesting that IDO‐1 expression induces an immunosuppressive microenvironment in MDS, thereby leading to treatment failure under AZA treatment. In conclusion, IDO‐1 is expressed in more than one‐third of patients with higher‐risk MDS, and is predictive of treatment failure and shorter overall survival. Therefore, IDO‐1 is emerging as a promising predictor and therapeutic target, especially for combination therapies with HMAs or checkpoint inhibitors

Traditionelle Westschweizer Spezialitäten aus regional erzeugtem Schweinefleisch

Boutefas und Jambon de la borne sind Fleischprodukte aus den Regionen Waadt und Freiburg mit einer lebendigen Tradition. Ob sich für diese Spezialtäten eine spezifische Grundlage und damit die Voraussetzung für eine geschützte Ursprungsbezeichnungen (AOP) ergibt, wenn das Fleisch von Schweinen einer definierten Genetik stammt und diese ausschliesslich mit Futter aus regionalen Komponenten gemästet werden, war Gegenstand dieser Untersuchung. Dazu wurden 170 Schweine, die von Ebern der Rassen Duroc, Piétrain oder der Edelschwein-Vaterlinie abstammten und die entweder auf Zuwachs oder auf Fleischqualität selektiert waren, balanciert in zwei Gruppen verteilt und mit einem üblichen Ergänzungsfutter (Kontrolle) zu Schotte oder einem Ergänzungsfutter ohne Sojaschrot und mit abgesenktem Protein- und Lysingehalt gemästet. Mit diesem regionalen Futter wuchsen die Tiere etwas langsamer und der Fettansatz war etwas höher. Daneben ergab sich ein tieferer Anteil an mehrfach ungesättigten Fettsäuren im Fettgewebe und ein vorteilhafteres Omega- 6/Omega-3 Verhältnis, was auch in den Fleischprodukten deutlich nachzuweisen war. In sensorischen Analysen unterschieden sich die Boutefas aus der Kontrolle und der regionalen Fütterung deutlich. Die Piétrain Kreuzungen zeigten mit der regionalen Fütterung erheblich geringere Zunahmen und in den Jambon de la borne eine erhöhte Frequenz von Farbabweichungen. Mit der regionalen Fütterung und ausgewählten Genetik ergab sich eine spezifische Fleisch- und Fettqualität, die sich auch in den Produkten widerspiegelte

Regulation and function of the atypical cadherin FAT1 in hepatocellular carcinoma

Giant cadherin FAT1 is increased in HCC and is a protumorigenic factors in HCC cell

Transient hypoglycemia as a rare cause of recurring transient loss of consciousness: a case report

Background Syncopes and transient loss of consciousness affect a large number of patients. Determining the underlying mechanism of a syncope is key to effectively treating and preventing future events. However, given the broad differential diagnosis of transient loss of consciousness, it can be challenging to determine the exact etiology. Case presentation This case presents a 42-year-old Caucasian female patient with recurrent transient loss of consciousness due to a hitherto undiagnosed impaired glucose tolerance and hyperinsulinism. The patient had been thoroughly tested for all typical causes of syncope without finding any causal explanation. An oral glucose tolerance test confirmed rapidly dropping blood glucose levels associated with rapidly fading consciousness as the underlying cause of transient loss of consciousness. Further diagnostic workup revealed that the patient suffered from impaired glucose tolerance and subsequent hyperinsulinism without overt diabetes mellitus. Nutritional counseling including reduction of glucose intake and frequently eating smaller meal portions led to a significant reduction in the frequency of transient loss of consciousness and overall improvement in quality of life. Conclusions The current European Society of Cardiology (ESC) guideline on syncope does not list hypoglycemia as a cause of transient loss of consciousness. However, this case report stresses that metabolic dysregulation can indeed lead to self-limited transient loss of consciousness. Thus, in the case of recurrent syncope with an unclear underlying mechanism, physicians should consider transient hypoglycemia and metabolic workup as a possible differential diagnosis

A molecular insight into algal-oomycete warfare : cDNA analysis of Ectocarpus siliculosus infected with the basal oomycete Eurychasma dicksonii

Peer reviewedPublisher PD

Network reconstruction for trans acting genetic loci using multi-omics data and prior information

BACKGROUND: Molecular measurements of the genome, the transcriptome, and the epigenome, often termed multi-omics data, provide an in-depth view on biological systems and their integration is crucial for gaining insights in complex regulatory processes. These data can be used to explain disease related genetic variants by linking them to intermediate molecular traits (quantitative trait loci, QTL). Molecular networks regulating cellular processes leave footprints in QTL results as so-called trans-QTL hotspots. Reconstructing these networks is a complex endeavor and use of biological prior information can improve network inference. However, previous efforts were limited in the types of priors used or have only been applied to model systems. In this study, we reconstruct the regulatory networks underlying trans-QTL hotspots using human cohort data and data-driven prior information. METHODS: We devised a new strategy to integrate QTL with human population scale multi-omics data. State-of-the art network inference methods including BDgraph and glasso were applied to these data. Comprehensive prior information to guide network inference was manually curated from large-scale biological databases. The inference approach was extensively benchmarked using simulated data and cross-cohort replication analyses. Best performing methods were subsequently applied to real-world human cohort data. RESULTS: Our benchmarks showed that prior-based strategies outperform methods without prior information in simulated data and show better replication across datasets. Application of our approach to human cohort data highlighted two novel regulatory networks related to schizophrenia and lean body mass for which we generated novel functional hypotheses. CONCLUSIONS: We demonstrate that existing biological knowledge can improve the integrative analysis of networks underlying trans associations and generate novel hypotheses about regulatory mechanisms

Autophagy suppresses the formation of hepatocyte-derived cancer-initiating ductular progenitor cells in the liver

Hepatocellular carcinoma (HCC) is driven by repeated rounds of inflammation, leading to fibrosis, cirrhosis, and, ultimately, cancer. A critical step in HCC formation is the transition from fibrosis to cirrhosis, which is associated with a change in the liver parenchyma called ductular reaction. Here, we report a genetically engineered mouse model of HCC driven by loss of macroautophagy and hemizygosity of phosphatase and tensin homolog, which develops HCC involving ductular reaction. We show through lineage tracing that, following loss of autophagy, mature hepatocytes dedifferentiate into biliary-like liver progenitor cells (ductular reaction), giving rise to HCC. Furthermore, this change is associated with deregulation of yes-associated protein and transcriptional coactivator with PDZ-binding motif transcription factors, and the combined, but not individual, deletion of these factors completely reverses the dedifferentiation capacity and tumorigenesis. These findings therefore increase our understanding of the cell of origin of HCC development and highlight new potential points for therapeutic intervention

Comprehensive genomic analysis of refractory multiple myeloma reveals a complex mutational landscape associated with drug resistance and novel therapeutic vulnerabilities

The outcomes of patients with multiple myeloma (MM) refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) remain poor. In this study, we performed whole genome and transcriptome sequencing of 39 heavily pretreated relapsed/refractory MM (RRMM) patients to identify mechanisms of resistance and potential therapeutic targets. We observed a high mutational load and indications of increased genomic instability. Recurrently mutated genes in RRMM, which had not been previously reported or only observed at a lower frequency in newly diagnosed MM, included NRAS, BRAF, TP53, SLC4A7, MLLT4, EWSR1, HCFC2, and COPS3. We found multiple genomic regions with bi-allelic events affecting tumor suppressor genes and demonstrated a significant adverse impact of bi-allelic TP53 alterations on survival. With regard to potentially resistance conferring mutations, recurrently mutated gene networks included genes with relevance for PI and IMiD activity; the latter particularly affecting members of the Cereblon and the COP9 signalosome complex. We observed a major impact of signatures associated with exposure to melphalan or impaired DNA double-strand break homologous recombination repair in RRMM. The latter coincided with mutations in genes associated with PARP inhibitor sensitivity in 49% of RRMM patients; a finding with potential therapeutic implications. In conclusion, this comprehensive genomic characterization revealed a complex mutational and structural landscape in RRMM and highlights potential implications for therapeutic strategies