Natural killer (NK) cells are innate lymphoid cells, and their presence within human tumors correlates with better prognosis. However, the mechanisms by which NK cells control tumors in vivo are ...unclear. Here, we used reflectance confocal microscopy (RCM) imaging in humans and in mice to visualize tumor architecture in vivo. We demonstrated that signaling via the NK cell receptor NKp46 (human) and Ncr1 (mouse) induced interferon-γ (IFN-γ) secretion from intratumoral NK cells. NKp46- and Ncr1-mediated IFN-γ production led to the increased expression of the extracellular matrix protein fibronectin 1 (FN1) in the tumors, which altered primary tumor architecture and resulted in decreased metastases formation. Injection of IFN-γ into tumor-bearing mice or transgenic overexpression of Ncr1 in NK cells in mice resulted in decreased metastasis formation. Thus, we have defined a mechanism of NK cell-mediated control of metastases in vivo that may help develop NK cell-dependent cancer therapies.
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•NKp46 expression on NK cells controls growth of melanoma and carcinoma metastases•In the absence of NKp46, tumor architectural properties indicate an aggressive phenotype•NK cell NKp46-mediated IFN-γ production controls tumor structure via FN1 induction•IFN-γ treatment or Ncr1 overexpression in tumor-bearing mice decreases tumor metastases
NK cells defend against various pathogens and tumors, but the mechanisms by which they control tumor metastases are not clear. Here, Glasner et al. show that NK cells prevent tumor metastases in vivo by editing tumor architecture via NKp46-mediated IFN-γ production that leads to upregulation of extracellular matrix protein FN1 in the tumor.
(Immunity 48, 107-119; January 16, 2018) In the version of this article originally published online on January 9, Figure 3 was printed twice, once correctly and once wrongly in place of Figure 4. The ...authors regret the error and the publisher apologies for the oversight.
Irradiation‐induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By ...combining scRNA‐seq analysis of whole skin‐derived irradiated cells with genetic ablation and molecular inhibition studies, we show that senescence‐associated IL‐6 and IL‐1 signaling, together with IL‐17 upregulation and CCR6+‐mediated immune cell migration, are crucial drivers of IRIAD. Bioinformatics analysis colocalized irradiation‐induced IL‐6 signaling with senescence pathway upregulation largely within epidermal hair follicles, basal keratinocytes, and dermal fibroblasts. Loss of cytokine signaling by genetic ablation in IL‐6−/− or IL‐1R−/− mice, or by molecular blockade, strongly ameliorated IRIAD, as did deficiency of CCL20/CCR6‐mediated immune cell migration in CCR6−/− mice. Moreover, IL‐6 deficiency strongly reduced IL‐17, IL‐22, CCL20, and CCR6 upregulation, whereas CCR6 deficiency reciprocally diminished IL‐6, IL‐17, CCL3, and MHC upregulation, suggesting that proximity‐dependent cellular cross talk promotes IRIAD. Therapeutically, topical application of Janus kinase blockers or inhibition of T‐cell activation by cyclosporine effectively reduced IRIAD, suggesting the potential of targeted approaches for the treatment of dermal side effects in radiotherapy patients.
Synopsis
Irradiation‐induced alopecia and dermatitis (IRIAD) represent two of the most prominent side effects of radiotherapy in the skin. This study utilized scRNA‐seq analysis to identify driving factors of IRIAD in order to facilitate development of targeted therapeutic approaches for its prevention.
IRIAD in mice is strongly associated with upregulation of senescence pathways involving IL‐6 and IL‐1 signaling, together with IL‐17 signaling.
Loss of IL‐6 and IL‐1 signaling, or of CCL20/CCR6‐mediated immune cell migration strongly ameliorated IRIAD, while simultaneously reducing irradiation‐induced cellular senescence.
IL‐6‐deficiency strongly reduced IL‐17, CCL20, and CCR6 upregulation, while loss of CCR6‐mediated immune cell migration reciprocally diminished IL‐6 and IL‐17 upregulation, and loss of immune privilege.
IRIAD is effectively ameliorated by treatment with Janus kinases blockers or cyclosporine A.
Irradiation‐induced alopecia and dermatitis (IRIAD) represent two of the most prominent side effects of radiotherapy in the skin. In this study, Paldor et al applied scRNA‐seq analysis to identify driving factors of IRIAD in order to facilitate the development of targeted therapeutic approaches for its prevention.
Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis ...and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.
Summary
Background
Actinic cheilitis (AC) is a common, chronic premalignant condition resulting from protracted sun exposure affecting the vermilion border of the lower lip. Treatment of AC aims at ...terminating the progression to squamous cell carcinoma by obliterating the primary lesion, and includes ablative methods; nonablative modalities such as cryotherapy, electrodessication, chemical peeling, topical imiquimod and 5‐fluorouracil; and photodynamic therapy (PDT). Daylight‐activated PDT, in which natural daylight serves as the light source, showed promising results in the treatment of actinic keratoses with substantially less pain than conventional PDT.
Purpose
To determine the safety and efficacy of daylight PDT in a series of patients with AC.
Methods
Eleven patients with AC were treated with daylight PDT. All patients underwent repeated treatment sessions until clinical and histological remission were achieved.
Results
Cure rate was 91% (10 of 11 patients, three females/eight males; mean age 59.2 ± 14.4 years). Mean number of treatments to attain cure was 2.7. Patients experienced mild erythema and minimal to no pain during treatment.
Conclusions
Daylight PDT is a promising modality for the treatment of AC, with impressive cosmetic results and few side effects.
Actinic cheilitis is a common premalignant condition of the lower lip that requires treatment to prevent its progression to squamous cell carcinoma. We describe our therapeutic experience using a daylight photodynamic therapy. Treatment sessions continued until achieving clinical and histological remission. Symptoms were resolved in 10 of 11 patients (91%) after a median of two (range 1‐6) treatments, with only few adverse effects. Daylight photodynamic therapy is a promising modality for the treatment of actinic cheilitis.
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The percutaneous passage of poorly skin absorbed molecules can be improved using nanocarriers, particularly biodegradable polymeric nanospheres (NSs) or nanocapsules (NCs). However, ...penetration of the encapsulated molecules may be affected by other factors than the nanocarrier properties. To gain insight information on the skin absorption of two fluorescent cargos, DiIC18(5) and coumarin-6 were incorporated in NSs or NCs and topically applied on various human and porcine skin samples. 3D imaging techniques suggest that NSs and NCs enhanced deep dermal penetration of both probes similarly, when applied on excised human skin irrespective of the nature of the cargo. However, when ex vivo pig skin was utilized, the cutaneous absorption of DiIC18(5) was more pronounced by means of PLGA NCs than NSs. In contrast, PLGA NSs noticeably improved the porcine skin penetration of coumarin-6, as compared to the NCs. Furthermore, the porcine skin results were reproducible when triplicated whereas from various human skin samples, as expected, the results were not sufficiently reproducible and large deviations were observed. The overall findings from this comprehensive comparison emphasize the potential of PLGA NCs or NSs to promote cutaneous bioavailability of encapsulated drugs, exhibiting different physicochemical properties but depending on the nature of the skin.
Two focused libraries based on two types of compounds, that is, thiazolidinediones and dioxazaborocanes were designed. Structural resemblances can be found between thiazolidinediones and well-known ...furanone type quorum sensing (QS) inhibitors such as N-acylaminofuranones, and/or acyl-homoserine lactone signaling molecules, while dioxazaborocanes structurally resemble previously reported oxazaborolidine derivatives which antagonized autoinducer 2 (AI-2) binding to its receptor. Because of this, we hypothesized that these compounds could affect AI-2 QS in Vibrio harveyi. Although all compounds blocked QS, the thiazolidinediones were the most active AI-2 QS inhibitors, with EC50 values in the low micromolar range. Their mechanism of inhibition was elucidated by measuring the effect on bioluminescence in a series of V. harveyi QS mutants and by DNA-binding assays with purified LuxR protein. The active compounds neither affected bioluminescence as such nor the production of AI-2. Instead, our results indicate that the thiazolidinediones blocked AI-2 QS in V. harveyi by decreasing the DNA-binding ability of LuxR. In addition, several dioxazaborocanes were found to block AI-2 QS by targeting LuxPQ.
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