Tissue repair processes maintain proper organ function following mechanical or infection-related damage. In addition to antibacterial properties, mucosal associated invariant T (MAIT) cells express a ...tissue repair transcriptomic program and promote skin wound healing when expanded. Herein, we use a human-like mouse model of full-thickness skin excision to assess the underlying mechanisms of MAIT cell tissue repair function. Single-cell RNA sequencing analysis suggested that skin MAIT cells already express a repair program at steady state. Following skin excision, MAIT cells promoted keratinocyte proliferation, thereby accelerating healing. Using skin grafts, parabiosis, and adoptive transfer experiments, we show that MAIT cells migrated into the wound in a T cell receptor (TCR)-independent but CXCR6 chemokine receptor-dependent manner. Amphiregulin secreted by MAIT cells following excision promoted wound healing. Expression of the repair function was probably independent of sustained TCR stimulation. Overall, our study provides mechanistic insights into MAIT cell wound healing function in the skin.
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•MAIT cells accelerate wound closure in a human-like skin injury model•MAIT cells migrate into the inflamed skin via CXCR6/CXCL16 and independently of MR1•MAIT cell pro-repair function is independent of sustained TCR signaling•Amphiregulin production by MAIT cells accelerates wound closure
MAIT cells have tissue repair properties, but the underlying mechanisms are unclear. du Halgouet et al. demonstrate that MAIT cells accelerate wound closure by increasing epithelial proliferation. MAIT cells are recruited into the injured skin in a CXCL16/CXCR6-dependent MR1-independent manner, and their pro-repair effect is related to amphiregulin production.
Abstract
ReMap (http://remap.univ-amu.fr) aims to provide the largest catalogs of high-quality regulatory regions resulting from a large-scale integrative analysis of hundreds of transcription ...factors and regulators from DNA-binding experiments in Human and Arabidopsis (Arabidopsis thaliana). In this 2020 update of ReMap we have collected, analyzed and retained after quality control 2764 new human ChIP-seq and 208 ChIP-exo datasets available from public sources. The updated human atlas totalize 5798 datasets covering a total of 1135 transcriptional regulators (TRs) with a catalog of 165 million (M) peaks. This ReMap update comes with two unique Arabidopsis regulatory catalogs. First, a catalog of 372 Arabidopsis TRs across 2.6M peaks as a result of the integration of 509 ChIP-seq and DAP-seq datasets. Second, a catalog of 33 histone modifications and variants across 4.5M peaks from the integration of 286 ChIP-seq datasets. All catalogs are made available through track hubs at Ensembl and UCSC Genome Browsers. Additionally, this update comes with a new web framework providing an interactive user-interface, including improved search features. Finally, full programmatically access to the underlying data is available using a RESTful API together with a new R Shiny interface for a TRs binding enrichment analysis tool.
Mucosal-associated invariant T (MAIT) cells harbor evolutionarily conserved TCRs, suggesting important functions. As human and mouse MAIT functional programs appear distinct, the evolutionarily ...conserved MAIT functional features remain unidentified. Using species-specific tetramers coupled to single-cell RNA sequencing, we characterized MAIT cell development in six species spanning 110 million years of evolution. Cross-species analyses revealed conserved transcriptional events underlying MAIT cell maturation, marked by ZBTB16 induction in all species. MAIT cells in human, sheep, cattle, and opossum acquired a shared type-1/17 transcriptional program, reflecting ancestral features. This program was also acquired by human iNKT cells, indicating common differentiation for innate-like T cells. Distinct type-1 and type-17 MAIT subsets developed in rodents, including pet mice and genetically diverse mouse strains. However, MAIT cells further matured in mouse intestines to acquire a remarkably conserved program characterized by concomitant expression of type-1, type-17, cytotoxicity, and tissue-repair genes. Altogether, the study provides a unifying view of the transcriptional features of innate-like T cells across evolution.
Activating anaplastic lymphoma kinase (ALK) mutations were recently detected in most familial and 10% of sporadic neuroblastomas. However, the role of mutated ALK in tumorigenesis remains elusive. We ...demonstrate that targeted expression of the most frequent and aggressive variant, ALK(F1174L), is tumorigenic in mice. Tumors resembled human neuroblastomas in morphology, metastasis pattern, gene expression, and the presence of neurosecretory vesicles as well as synaptic structures. This ALK-driven neuroblastoma mouse model precisely recapitulated the genetic spectrum of the disease. Chromosomal aberrations were syntenic to those in human neuroblastoma, including 17q gain and MYCN oncogene amplification. Targeted ALK(F1174L) and MYCN coexpression revealed a strong synergism in inducing neuroblastoma with minimal chromosomal aberrations, suggesting that fewer secondary hits are required for tumor induction if both oncoproteins are targeted. Treatment of ALK(F1174L) transgenic mice with the ALK inhibitor TAE-684 induced complete tumor regression, indicating that tumor cells were addicted to ALK(F1174L) activity. We conclude that an activating mutation within the ALK kinase domain is sufficient to induce neuroblastoma development, and ALK inhibitors show promise for treating human neuroblastomas harboring ALK mutations.
Major depressive disorder (MDD) is a prevalent disorder involving disturbances in mood. There is still much to understand regarding precisely how emotions are disrupted in individuals with MDD. In ...this study, we used a network approach to examine the emotional disturbances underlying MDD. We hypothesized that compared with healthy control individuals, individuals diagnosed with MDD would be characterized by a denser emotion network, thereby indicating that their emotion system is more resistant to change. Indeed, results from a 7-day experience sampling study revealed that individuals with MDD had a denser overall emotion network than did healthy control individuals. Moreover, this difference was driven primarily by a denser negative, but not positive, network in MDD participants. These findings suggest that the disruption in emotions that characterizes depressed individuals stems from a negative emotion system that is resistant to change.
Purpose
To investigate the feasibility of lymph drainage mapping (LDM) using SPECT/CT to help select head and neck cancer (HNSCC) patients for unilateral elective neck irradiation (ENI). Patients ...with lateralized HNSCC treated with radiotherapy routinely undergo bilateral ENI, despite the incidence of contralateral regional failure being relatively low even after unilateral ENI. We hypothesized that patients with a lateralized tumor without visible lymph drainage to the contralateral neck have an extremely low risk of contralateral involved nodes. Excluding the contralateral neck from elective irradiation will reduce radiation-induced toxicity and improve quality-of-life.
Methods
Fifty-five patients with lateralized cT1-3N0-2bM0 HNSCC not crossing the midline underwent LDM. Radiolabeled
99m
Tc-nanocolloid was injected in 4–5 depots around and in the primary tumor. Lymph drainage patterns were visualized using planar scintigraphy and SPECT/CT after 4 h. We report on the incidence of contralateral drainage, the location of draining areas, and the size of underlying nodes.
Results
Lymphatic drainage was successfully visualized in 54 patients (98%). In 11 patients (20%) with visible contralateral drainage, 14 draining areas (16 nodes; median volume 0.50 cc, diameter 8.0 mm) were identified. Neck levels with contralateral drainage were level II (88%), III (25%), and IV (13%). Contralateral drainage was significantly higher in T3 compared to T1–2 tumors (45 and 14%, respectively,
P
= 0.035).
Conclusion
SPECT/CT-guided LDM is feasible and can be used to guide unilateral ENI in HNSCC patients in prospective studies. In addition, the anatomical confidence in visualization of contralateral drainage indicates a potential for ENI limited to draining levels alone.
Small non-coding RNAs, in particular microRNAs(miRNAs), regulate fine-tuning of gene expression and can act as oncogenes or tumor suppressor genes. Differential miRNA expression has been reported to ...be of functional relevance for tumor biology. Using next-generation sequencing, the unbiased and absolute quantification of the small RNA transcriptome is now feasible. Neuroblastoma(NB) is an embryonal tumor with highly variable clinical course. We analyzed the small RNA transcriptomes of five favorable and five unfavorable NBs using SOLiD next-generation sequencing, generating a total of >188 000 000 reads. MiRNA expression profiles obtained by deep sequencing correlated well with real-time PCR data. Cluster analysis differentiated between favorable and unfavorable NBs, and the miRNA transcriptomes of these two groups were significantly different. Oncogenic miRNAs of the miR17-92 cluster and the miR-181 family were overexpressed in unfavorable NBs. In contrast, the putative tumor suppressive microRNAs, miR-542-5p and miR-628, were expressed in favorable NBs and virtually absent in unfavorable NBs. In-depth sequence analysis revealed extensive post-transcriptional miRNA editing. Of 13 identified novel miRNAs, three were further analyzed, and expression could be confirmed in a cohort of 70 NBs.
BACKGROUND: Diagnostic hysteroscopy is not widely performed in the office setting, one of the reasons being the discomfort produced by the procedure. This randomized controlled trial was performed to ...evaluate the effects of instrument diameter, patient parity and surgeon experience on the pain suffered and success rate of the procedure. METHODS: Patients were randomly assigned to undergo office diagnostic hysteroscopy either with 5.0 mm conventional instruments (n=240) or with 3.5 mm mini-instruments (n=240). Procedures were stratified according to patient parity and surgeon's previous experience. The pain experienced during the procedure (0–10), the quality of visualization of the uterine cavity (0–3) and the complications were recorded. The examination was considered successful when the pain score was <4, visualization score was >1 and no complication occurred. RESULTS: Less pain, better visualization and higher success rates were observed with mini-hysteroscopy (P < 0.0001, P < 0.0001 and P < 0.0001, respectively), in patients with vaginal deliveries (P < 0.0001, P < 0.0001 and P < 0.0001, respectively) and in procedures performed by experienced surgeons (P = 0.02, P = NS and P = NS, respectively). The effects of patient parity and surgeon experience were no longer important when mini-hysteroscopy was used. CONCLUSIONS: Our data demonstrate the advantages of mini-hysteroscopy and the importance of patient parity and surgeon experience, suggesting that mini-hysteroscopy should always be used, especially for inexperienced surgeons and when difficult access to the uterine cavity is anticipated. They indicate that mini-hysteroscopy can be offered as a first line office diagnostic procedure.
Previous studies have evaluated the role of miRNAs in cancer initiation and progression. MiR‐34a was found to be downregulated in several tumors, including medulloblastomas. Here we employed targeted ...transgenesis to analyze the function of miR‐34a in vivo. We generated mice with a constitutive deletion of the miR‐34a gene. These mice were devoid of mir‐34a expression in all analyzed tissues, but were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters revealed no apparent phenotype. Analysis of miR‐34a expression in human medulloblastomas and medulloblastoma cell lines revealed significantly lower levels than in normal human cerebellum. Re‐expression of miR‐34a in human medulloblastoma cells reduced cell viability and proliferation, induced apoptosis and downregulated the miR‐34a target genes, MYCN and SIRT1. Activation of the Shh pathway by targeting SmoA1 transgene overexpression causes medulloblastoma in mice, which is dependent on the presence and upregulation of Mycn. Analysis of miR‐34a in medulloblastomas derived from ND2:SmoA1(tg) mice revealed significant suppression of miR‐34a compared to normal cerebellum. Tumor incidence was significantly increased and tumor formation was significantly accelerated in mice transgenic for SmoA1 and lacking miR‐34a. Interestingly, Mycn and Sirt1 were strongly expressed in medulloblastomas derived from these mice. We here demonstrate that miR‐34a is dispensable for normal development, but that its loss accelerates medulloblastomagenesis. Strategies aiming to re‐express miR‐34a in tumors could, therefore, represent an efficient therapeutic option.
What's new?
MicroRNAs (miRNAs) play an important role in cancer initiation and progression. An miRNA called “miR‐34a” is downregulated in a variety of human cancers. In this study, the authors found that miR‐34a acts as a tumor suppressor in genetically engineered mice, and that it appears to regulate medulloblastoma formation in vivo. Restoring expression of miR‐34a in medulloblastomas or other human cancers with deregulated miR‐34a might, therefore, be a promising therapeutic strategy.
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