Cell-intrinsic differences between human airway epithelial cells from children and adults

Summary The airway epithelium is a protective barrier that is maintained by the self-renewal and differentiation of basal stem cells. Increasing age is a principle risk factor for chronic lung diseases, but few studies have explored age-related molecular or functional changes in the airway epithelium. We retrieved epithelial biopsies from histologically normal tracheobronchial sites from pediatric and adult donors and compared their cellular composition and gene expression profile (in laser capture-microdissected whole epithelium, fluorescence-activated cell-sorted basal cells and basal cells in cell culture). Histologically, pediatric and adult tracheobronchial epithelium were similar in composition. We observed age-associated changes in RNA sequencing studies, including higher interferon-associated gene expression in pediatric epithelium. In cell culture, pediatric cells had higher colony-formation ability, sustained in vitro growth and out-competed adult cells in a direct competitive proliferation assay. Our results demonstrate cell-intrinsic differences between airway epithelial cells from children and adults in both homeostatic and proliferative states

Immune Surveillance in Clinical Regression of Preinvasive Squamous Cell Lung Cancer

This is the author accepted manuscript. the final version is available from the American Association for Cancer Research via the DOI in this recordData Availability: All raw data used in this study is publicly available. Previously published CIS gene expression and methylation data is stored on GEO under accession number GSE108124; matched stromal gene expression data is stored under accession number GSE133690. Previously published CIS whole genome sequencing data is available from the European Genome Phenome Archive (https://www.ebi.ac.uk/ega/) under accession number EGAD00001003883. Annotated H&E images of all samples used for lymphocyte quantification were deposited to the Image Data Resource (https://idr.openmicroscopy.org) under accession number idr0082.Code Availability: All code used in our analysis will be made available at http://github.com/ucl446 respiratory/cis_immunology on publication. All software information, and parameters used in our analysis can be found here.Before squamous cell lung cancer develops, precancerous lesions can be found in the airways. From longitudinal monitoring, we know that only half of such lesions become cancer, whereas a third spontaneously regress. Although recent studies have described the presence of an active immune response in high-grade lesions, the mechanisms underpinning clinical regression of precancerous lesions remain unknown. Here, we show that host immune surveillance is strongly implicated in lesion regression. Using bronchoscopic biopsies from human subjects, we find that regressive carcinoma in situ lesions harbor more infiltrating immune cells than those that progress to cancer. Moreover, molecular profiling of these lesions identifies potential immune escape mechanisms specifically in those that progress to cancer: antigen presentation is impaired by genomic and epigenetic changes, CCL27-CCR10 signaling is upregulated, and the immunomodulator TNFSF9 is downregulated. Changes appear intrinsic to the carcinoma in situ lesions, as the adjacent stroma of progressive and regressive lesions are transcriptomically similar. SIGNIFICANCE: Immune evasion is a hallmark of cancer. For the first time, this study identifies mechanisms by which precancerous lesions evade immune detection during the earliest stages of carcinogenesis and forms a basis for new therapeutic strategies that treat or prevent early-stage lung cancer.See related commentary by Krysan et al., p. 1442.This article is highlighted in the In This Issue feature, p. 1426

Engineered Models of Metastasis with Application to Study Cancer Biomechanics

Three-dimensional complex biomechanical interactions occur from the initial steps of tumor formation to the later phases of cancer metastasis. Conventional monolayer cultures cannot recapitulate the complex microenvironment and chemical and mechanical cues that tumor cells experience during their metastatic journey, nor the complexity of their interactions with other, noncancerous cells. As alternative approaches, various engineered models have been developed to recapitulate specific features of each step of metastasis with tunable microenvironments to test a variety of mechanistic hypotheses. Here the main recent advances in the technologies that provide deeper insight into the process of cancer dissemination are discussed, with an emphasis on three-dimensional and mechanical factors as well as interactions between multiple cell types

Interface Trap Generation and Hole Trapping Under NBTI and PBTI in Advanced CMOS Technology With a 2-nm Gate Oxide

International audienceThis paper gives an insight into the degradation mechanisms during negative and positive bias temperature instabilities in advanced CMOS technology with a 2-nm gate oxide. We focus on generated interface traps and oxide traps to distinguish their dependencies and effects on usual transistor parameters. negative bias temperature instability (NBTI) and positive bias temperature instability in both NMOS and PMOS have been compared and a possible explanation for all configurations has been suggested. Recovery and temperature effect under NBTI were also investigated showing different behaviors of the two components

A thorough investigation of MOSFETs NBTI degradation

International audienceAn overview of evolution of transistor parameters under negative bias temperature instability stress conditions commonly observed in p-MOSFETs in recent technologies is presented. The physical mechanisms of the degradation as well as the different defects involved have been discussed according to a systematic set of experiments with different stress conditions. According to our findings, a physical model is proposed which could be used to more accurately predict the transistor degradation. Finally, the influence of different process splits as the gate oxide nitridation, the nitrogen content, the source/drain implant and poly doping level on the NBTI degradation is investigated and discussed with our present understanding

Two HLA-B27 alleles differently associated with spondylarthritis, B*2709 and B*2705, display similar intracellular trafficking and oligomer formation

To examine whether and to what extent the intracellular trafficking features of HLA-B*2705, which is associated with the development of spondylarthritis (SpA), differ from those of HLA-B*2709 and HLA-B*0702, which are not associated with SpA. METHODS: HeLa cells were transfected with complementary DNA encoding for HLA-B proteins fused to Renilla luciferase or yellow fluorescent protein. The subcellular distribution of properly folded and unfolded/misfolded HLA-B proteins was examined by flow cytometry and confocal microscopy of cells labeled with ME1 and HC-10 antibodies, respectively. HLA-B/HLA-B interactions were monitored in endoplasmic reticulum (ER)- and plasma membrane-enriched subcellular fractions, by bioluminescence resonance energy transfer (BRET). RESULTS: All 3 HLA-B alleles displayed a similar distribution pattern (properly folded heavy chain at the cell surface, unfolded/misfolded proteins only in the cytoplasm). By means of BRET, we provided evidence that both HLA-B*2705 and HLA-B*2709 formed more oligomers in the ER and the plasma membrane than did HLA-B*0702. The propensity of HLA-B*2705 to form oligomers in the ER was partly attributable to residue Cys(67) of the molecule. For all 3 alleles, increased expression of HLA-B proteins was associated with intracytoplasmic accumulation of unfolded/misfolded proteins and intracellular vesicles, probably corresponding to expanded ER-Golgi intermediate compartments, in which these proteins accumulated together with the stress sensor BiP. CONCLUSION: Our results suggest that the difference in disease susceptibility conferred by HLA-B*2705 and HLA-B*2709 cannot be explained by their different propensity to form dimers or misfolded proteins, thus presumably implicating other, still unknown factors