Impaired wound healing complicates a wide range of diseases and represents a major cost to healthcare systems. Here we describe the use of discarded wound dressings as a novel, cost effective, ...accessible, and non-invasive method of isolating viable human cells present at the site of skin wounds. By analyzing 133 discarded wound dressings from 51 patients with the inherited skin-blistering disease epidermolysis bullosa (EB), we show that large numbers of cells, often in excess of 100 million per day, continually infiltrate wound dressings. We show, that the method is able to differentiate chronic from acute wounds, identifying significant increases in granulocytes in chronic wounds, and we show that patients with the junctional form of EB have significantly more cells infiltrating their wounds compared with patients with recessive dystrophic EB. Finally, we identify subsets of granulocytes and T lymphocytes present in all wounds paving the way for single cell profiling of innate and adaptive immune cells with relevance to wound pathologies. In summary, our study delineates findings in EB that have potential relevance for all chronic wounds, and presents a method of cellular isolation that has wide reaching clinical application.
Somatic mutations in cancer are more frequent in heterochromatic and late-replicating regions of the genome. We report that regional disparities in mutation density are virtually abolished within ...transcriptionally silent genomic regions of cutaneous squamous cell carcinomas (cSCCs) arising in an XPC−/− background. XPC−/− cells lack global genome nucleotide excision repair (GG-NER), thus establishing differential access of DNA repair machinery within chromatin-rich regions of the genome as the primary cause for the regional disparity. Strikingly, we find that increasing levels of transcription reduce mutation prevalence on both strands of gene bodies embedded within H3K9me3-dense regions, and only to those levels observed in H3K9me3-sparse regions, also in an XPC-dependent manner. Therefore, transcription appears to reduce mutation prevalence specifically by relieving the constraints imposed by chromatin structure on DNA repair. We model this relationship among transcription, chromatin state, and DNA repair, revealing a new, personalized determinant of cancer risk.
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•Regional genomic mutational rates reflect differential access to DNA repair•Transcription restores DNA repair access to tightly packaged chromatin•We model gene mutation rate based on transcription level and chromatin state
Zheng et al. report that variable mutation densities within cancer genomes result from differential access of DNA repair machinery, imposed by chromatin state. By showing that transcription restores DNA repair to tightly packaged DNA, their study reveals natural differences in expression level as a potentially important modulator of oncogene mutation rate.
Loss of ZNF750 in ocular and cutaneous sebaceous carcinoma North, Jeffrey P.; Solomon, David A.; Golovato, Justin ...
Journal of cutaneous pathology,
October 2019, 2019-Oct, 2019-10-00, 20191001, Letnik:
46, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Background
Sebaceous carcinoma (SeC) is an uncommon malignancy arising from sebaceous glands of the conjunctiva and skin. Recurrent mutations in the ZNF750 were recently identified in ocular SeC. We ...assessed whether ZNF750 loss is a specific feature of ocular SeC or a general feature of sebaceous tumors.
Methods
Immunostaining for ZNF750 expression was performed in 54 benign and malignant sebocytic proliferations. Staining for ZNF750 was scored on a three‐tier scale: positive (>75%), partially positive (5%‐74%), and negative (<5%).
Results
ZNF750 expression was negative in 4/11 ocular SeC, and partially positive in 4/11 ocular SeC and 6/13 cutaneous SeC. No extraocular tumors were negative. No loss was found in sebaceous adenoma or sebaceous hyperplasia. In nine previously sequenced ocular SeCs, two lacked detectable somatic mutations in ZNF750, but showed complete loss of staining, indicating non‐mutational inactivation of ZNF750.
Conclusion
We show complete loss of the ZNF750 epidermal differentiation regulator in about half of ocular SeC, highlighting the most common genetic defect in this cancer type. Loss of ZNF750 expression is seen even in tumors without truncating mutations and reduced in many of the remaining ocular and cutaneous SeC. In contrast, no ZNF750 loss was detected in benign sebaceous proliferations.
Life satisfaction is an essential component of subjective well-being and provides a fundamental resource for optimal everyday functioning. The goal of the present study was to examine how life ...satisfaction influences self-referential processing of emotionally valenced stimuli. Nineteen individuals with high life satisfaction (HLS) and 21 individuals with low life satisfaction (LLS) were scanned using functional MRI while performing a face-word relevance rating task, which consisted of 3 types of face stimuli (self, public other, and unfamiliar other) and 3 types of word stimuli (positive, negative, and neutral). We found a significant group x word valence interaction effect, most strikingly in the dorsal medial prefrontal cortex. In the positive word condition dorsal medial prefrontal cortex activity was significantly higher in the LLS group, whereas in the negative word condition it was significantly higher in the HLS group. The two groups showed distinct functional connectivity of the dorsal medial prefrontal cortex with emotional processing-related regions. The findings suggest that, in response to emotional stimuli, individuals with HLS may successfully recruit emotion regulation-related regions in contrast to individuals with LLS. The difference in functional connectivity during self-referential processing may lead to an influence of life satisfaction on responses to emotion-eliciting stimuli.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
DNA methylation and histone acetylation contribute to the transcriptional regulation of genes involved in apoptosis. We have demonstrated that docosahexaenoic acid (DHA, 22:6 n-3) and butyrate ...enhance colonocyte apoptosis. To determine if DHA and/or butyrate elevate apoptosis through epigenetic mechanisms thereby restoring the transcription of apoptosis-related genes, we examined global methylation; gene-specific promoter methylation of 24 apoptosis-related genes; transcription levels of Cideb, Dapk1, and Tnfrsf25; and global histone acetylation in the HCT-116 colon cancer cell line. Cells were treated with combinations of (50 µM) DHA or linoleic acid (18:2 n-6), (5 mM) butyrate or an inhibitor of DNA methyltransferases, and 5-aza-2'-deoxycytidine (5-Aza-dC, 2 µM). Among highly methylated genes, the combination of DHA and butyrate significantly reduced methylation of the proapoptotic Bcl2l11, Cideb, Dapk1, Ltbr, and Tnfrsf25 genes compared to untreated control cells. DHA treatment reduced the methylation of Cideb, Dapk1, and Tnfrsf25. These data suggest that the induction of apoptosis by DHA and butyrate is mediated, in part, through changes in the methylation state of apoptosis-related genes.
Inflammatory response heterogeneity has impeded high-resolution dissection of diverse immune cell populations during activation. We characterize mouse cutaneous immune cells by single-cell RNA ...sequencing, after inducing inflammation using imiquimod and oxazolone dermatitis models. We identify 13 CD45+ subpopulations, which broadly represent most functionally characterized immune cell types. Oxazolone pervasively upregulates Jak2/Stat3 expression across T cells and antigen-presenting cells (APCs). Oxazolone also induces Il4/Il13 expression in newly infiltrating basophils, and Il4ra and Ccl24, most prominently in APCs. In contrast, imiquimod broadly upregulates Il17/Il22 and Ccl4/Ccl5. A comparative analysis of single-cell inflammatory transcriptional responses reveals that APC response to oxazolone is tightly restricted by cell identity, whereas imiquimod enforces shared programs on multiple APC populations in parallel. These global molecular patterns not only contrast immune responses on a systems level but also suggest that the mechanisms of new sources of inflammation can eventually be deduced by comparison to known signatures.
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•Oxazolone pervasively upregulates Jak2/Stat3 expression across T cells and APCs•Il4/Il13 induction in skin by oxazolone is dominated by infiltrating basophils•Imiquimod broadly increases Il17/Il22 and Ccl4/Ccl5, extending to non-T cells•Oxazolone induces more highly compartmentalized immune cell responses than imiquimod
Immunology; Systems Biology
Tumors acquire many chromosomal amplifications, and those acquired early in the lifespan of the tumor may be not only important for tumor growth but also can be used for diagnostic purposes. Many ...methods infer the order of the accumulation of abnormalities based on their occurrence in a large cohort of patients. Recently, Durinck et al. (2011) and Greenman et al. (2012) developed methods to order a single tumor's chromosomal amplifications based on the patterns of mutations accumulated within those regions. This method offers an unprecedented opportunity to assess the etiology of a single tumor sample, but has not been widely evaluated.
We show that the model for timing chromosomal amplifications is limited in scope, particularly for regions with high levels of amplification. We also show that the estimation of the order of events can be sensitive for events that occur early in the progression of the tumor and that the partial maximum likelihood method of Greenman et al. (2012) can give biased estimates, particularly for moderate read coverage or normal contamination. We propose a maximum-likelihood estimation procedure that fully accounts for sequencing variability and show that it outperforms the partial maximum-likelihood estimation method. We also propose a Bayesian estimation procedure that stabilizes the estimates in certain settings. We implement these methods on a small number of ovarian tumors, and the results suggest possible differences in how the tumors acquired amplifications.
We provide implementation of these methods in an R package cancerTiming, which is available from the Comprehensive R Archive Network (CRAN) at http://CRAN.R-project.org/.
Aggressive squamous cell carcinomas (SCCs) present frequently in the context of chronic skin injury occurring in patients with the congenital blistering disease recessive dystrophic epidermolysis ...bullosa. Recently, these cancers were shown to harbor mutation signatures associated with endogenous deaminases of the active polynucleotide cytosine deaminase family, collectively termed APOBEC, and clock-like COSMIC Catalogue of Somatic Mutations in Cancer signatures, which are associated with normal aging and might result from cumulative DNA replication errors. We present a case of a nasal septal SCC arising in the context of recurrent injury, but also modest past tobacco use. Our genetic analysis of this tumor reveals unusually high APOBEC and clock-like but low tobacco-related COSMIC signatures, suggesting that chronic injury may have played a primary role in somatic mutation. This case report demonstrates how signature-based analyses may implicate key roles for certain mutagenic forces in individual malignancies such as head-and-neck SCC, with multiple etiological origins.
We report the case of a 43-year-old male former smoker who presented with congestion and swelling following a traumatic nasal fracture. During surgery, the mucosa surrounding the right nasal valve appeared abnormal, and biopsies revealed invasive keratinizing SCC. Frozen section biopsies revealed multiple areas to be positive for SCC. Gene sequencing showed loss of PTEN (exons 2-8), CDKN2A/B and TP53 (exons 8-9), MYC amplification, and BLM S338*. Exome sequencing data also revealed that 36% of mutations matched an APOBEC mutational signature (COSMIC signatures 2 and 13) and 53% of mutations matched the clock-like mutation signature (COSMIC signature 5). These proportions place this tumor in the 90th percentile bearing each signature, independently, in a reference data set combining cutaneous and The Cancer Genome Atlas (TCGA) head and neck SCC data. In contrast, few mutations harbored a tobacco-related COSMIC signature 4, representing about the 10th percentile in our reference SCC data set. The patient was treated with partial rhinectomy with local flap reconstruction, bilateral neck dissection, and adjuvant radiation therapy; the patient remains disease-free to date.
Based on comparative mutational signature analysis, we propose that the history of tobacco use and traumatic injury may have collaborated in activating APOBEC enzymes and the clock-like mutational process, ultimately leading to cancer formation. Clinical awareness of the relationship between epithelial injury and tumorigenesis should enhance earlier detection of this particularly aggressive type of cancer.
BACKGROUNDDespite tremendous progress in understanding the unmet needs of cancer survivors, our understanding of oncology nursesʼ perspectives and practices in the delivery of survivorship care is ...inadequate.
OBJECTIVESThe aims of this study were to assess oncology nursesʼ perceptions about their responsibility and frequency of delivery of survivorship care to cancer patients and to examine the factors influencing such care.
METHODSA cross-sectional survey was administered to 81 nurses working in the oncology unit of hospitals in Hong Kong. Participants completed an investigator-developed questionnaire designed to assess oncology nursesʼ perceptions of responsibility, practices, and barriers regarding the provision of survivorship care for cancer patients.
RESULTSResults revealed discrepancies between oncology nursesʼ perceptions of responsibility and practices, with high levels of perceptions of various survivorship care as their responsibility but low levels in delivery of such care. Despite that discussing and managing pain was agreed by most oncology nurses as their responsibility (95.1%), 34.6% of them have never managed survivorsʼ pain. Besides, 33.3% of nurses have never discussed and managed survivorsʼ sexuality issues. Lack of time (79.0%), inadequate educational resources for family members (59.3%), and lack of knowledge and skills (54.4%) were major factors that impeded survivorship care provision.
CONCLUSIONSThis study provides further evidence for inadequacies of oncology nurses in delivering survivorship care and their perceived barriers. Further studies are required to enhance our understanding of the strategies for improving the quality of cancer survivorship care.
IMPLICATIONS FOR PRACTICEResults underscore the need to develop educational resources and enhance training in survivorship care for oncology nurses.
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