Myeloid cell-derived LL-37 promotes lung cancer growth by activating Wnt/β-catenin signaling

Rationale: Antimicrobial peptides, such as cathelicidin LL-37/hCAP-18, are important effectors of the innate immune system with direct antibacterial activity. In addition, LL-37 is involved in the regulation of tumor cell growth. However, the molecular mechanisms underlying the functions of LL-37 in promoting lung cancer are not fully understood. Methods: The expression of LL-37 in the tissues and sera of patients with non-small cell lung cancer was determined through immunohistological, immunofluorescence analysis, and enzyme-linked immunosorbent assay. The animal model of wild-type and Cramp knockout mice was employed to evaluate the tumorigenic effect of LL-37 in non-small cell lung cancer. The mechanism of LL-37 involving in the promotion of lung tumor growth was evaluated via microarray analyses, recombinant protein treatment approaches in vitro, tumor immunohistochemical assays, and intervention studies in vivo. Results: LL-37 produced by myeloid cells was frequently upregulated in primary human lung cancer tissues. Moreover, its expression level correlated with poor clinical outcome. LL-37 activated Wnt/β-catenin signaling by inducing the phosphorylation of protein kinase B and subsequent phosphorylation of glycogen synthase kinase 3β mediated by the toll-like receptor-4 expressed in lung tumor cells. LL-37 treatment of tumor cells also decreased the levels of Axin2. In contrast, it elevated those of an RNA-binding protein (tristetraprolin), which may be involved in the mechanism through which LL-37 induces activation of Wnt/β-catenin. Conclusion: LL-37 may be a critical molecular link between tumor-supportive immune cells and tumors, facilitating the progression of lung cancer

Bronchoalveolar Lavage Fluid-Derived Exosomes: A Novel Role Contributing to Lung Cancer Growth

Exosomes are nanovesicles produced by a number of different cell types and regarded as important mediators of cell-to-cell communication. Although bronchoalveolar lavage fluid (BALF) has been shown to be involved in the development of tumors, its role in lung cancer (LC) remains unclear. In this article, we systemically studied BALF-derived exosomes in LC. C57BL/6 mice were injected with Lewis lung carcinoma cells and exposed to non-typeable Haemophilus influenza (NTHi) lysate. The analysis showed that the growth of lung tumors in these mice was significantly enhanced compared with the control cohort (only exposure to air). Characterization of the exosomes derived from mouse BALF demonstrated elevated levels of tumor necrosis factor alpha and interleukin-6 in mice exposed to NTHi lysates. Furthermore, abnormal BALF-derived exosomes facilitated the development of LC in vitro and in vivo. The internalization of the BALF-derived exosomes contributed to the development of LC tumors. Collectively, our data demonstrated that exosomes in BALF are a key factor involved in the growth and progression of lung cancer

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Investigation of the Influence of Multi-Walled Carbon Nanotubes on Laminate Composites During Progressive Tensile Damage Using Acoustic Emission

Progressive tensile damage for carbon fiber composites both containing and without multi-walled carbon nanotubes (MWCNTs) is discussed and this work is an extension of a previously published study. The composite specimens were subjected to progressive tensile experiments, and AE signals were collected during loading. The signals were post-processed using cluster analysis based on the Fuzzy C-Means algorithm. The results show that AE signals can be divided into three classes, corresponding to three damage modes: matrix cracking, fiber debonding, and fiber breakage. The AE peak frequency characteristics of each damage mode were found. Samples were also characterized using micro-computed tomography (Micro-CT) imaging and the observed damage shows good correlation with AE signal characterization for defect class prediction. Analyzing the data clusters it can be found that MWCNTs can delay and in some cases prevent both matrix cracking and fiber debonding in laminate composites. It was found that matrix cracking, debonding and fiber break AE signals for composites with CNTs correspond to a higher frequency range than that without CNTs. The results give guidance for composite design when considering MWCNTs and structure health monitoring of these composite materials.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s10921-021-00840-3. Copyright 2021 The Author(s). Posted with permission

Potential Role of Lysine Acetylation and Autophagy in Brown Film Formation and Postripening of Lentinula edodes Mycelium

ABSTRACT Lentinula edodes is one of the most widely cultivated edible mushrooms in the world. When cultivated in sawdust, the surface mycelium of L. edodes needs a long postripening stage wherein it forms a brown film (BF) by secreting and accumulating pigments. BF formation is critical for the high quality and yield of fruiting bodies. Protein lysine acetylation (KAC) is an important post-translational modification that regulates growth and development. Previous studies have shown that deacetylase levels are significantly increased during BF formation in the postripening stage of L. edodes. The aim of this study was to assess the role of protein acetylation during BF formation. To this end, we compared the acetylome of L. edodes mycelia before and after BF formation using anti-acetyl antibody-based label-free quantitative proteomics. We identified 5,613 acetylation sites in 1,991 proteins, and quantitative information was available for 4,848 of these sites in 1,815 proteins. Comparative acetylome analysis showed that the modification of 699 sites increased and that of 562 sites decreased during BF formation. Bioinformatics analysis of the differentially acetylated proteins showed significant enrichment in the tricarboxylic acid (TCA) cycle and proteasome pathways. Furthermore, functional assays showed that BF formation is associated with significant changes in the activities of proteasome, citrate synthase, and isocitrate dehydrogenase. Consistent with this hypothesis, the lysine deacetylase inhibitor trichostatin (TSA) delayed autophagy and BF formation in L. edodes. Taken together, KAC and autophagy play important roles in the mycelial BF formation and postripening stage of L. edodes. IMPORTANCE Mycelial BF formation and postripening of L. edodes affects the quality and quantity of its edible fruiting bodies. In this study, we explored the role of protein KAC in this biological process, with the aim of optimizing the cultivation and yield of L. edodes

A Transgenic Drosophila Model for Arsenic Methylation Suggests a Metabolic Rationale for Differential Dose-Dependent Toxicity Endpoints

The mechanisms by which exposure to arsenic induces its myriad pathological effects are undoubtedly complex, while individual susceptibility to their type and severity is likely to be strongly influenced by genetic factors. Human metabolism of arsenic into methylated derivatives, once presumed to result in detoxification, may actually produce species with significantly greater pathological potential. We introduce a transgenic Drosophila model of arsenic methylation, allowing its consequences to be studied in a higher eukaryote exhibiting conservation of many genes and pathways with those of human cells while providing an important opportunity to uncover mechanistic details via the sophisticated genetic analysis for which the system is particularly well suited. The gene for the human enzyme, arsenic (+3 oxidation state) methyltransferase, was introduced into nonmethylating Drosophila under inducible control. Transgenic flies were characterized for enzyme inducibility, production of methylated arsenic species, and the dose-dependent consequences for chromosomal integrity and organismal longevity. Upon enzyme induction, transgenic flies processed arsenite into mono and dimethylated derivatives identical to those found in human urine. When induced flies were exposed to 9 ppm arsenite, chromosomal stability was clearly reduced, whereas at much higher doses, adult life span was significantly increased, a seemingly paradoxical pair of outcomes. Measurement of arsenic body burden in the presence or absence of methylation suggested that enhanced clearance of methylated species might explain this greater longevity under acutely toxic conditions. Our study clearly demonstrates both the hazards and the benefits of arsenic methylation in vivo and suggests a resolution based on evolutionary grounds

Xylan alleviates dietary fiber deprivation-induced dysbiosis by selectively promoting Bifidobacterium pseudocatenulatum in pigs

Using growing pigs as model, we profiled the temporal response of swine gut microbiota to dietary fiber deprivation. Then swine gut microbiome response to resistant starch, beta-glucan and xylan throughout the gastrointestinal tract was investigated