Insulin-Like Growth Factor-Binding Protein 7 Regulates Keratinocyte Proliferation, Differentiation and Apoptosis

Insulin-like growth factor (IGF)-binding protein 7 (IGFBP7) belongs to the IGFBP superfamily, which is involved in the regulation of IGF and insulin signaling. Recently, a global gene expression study revealed that IGFBP7 is downregulated in the psoriatic epidermis, with UVB phototherapy restoring its expression to normal. In the present study, we confirmed that IGFBP7 expression is decreased in psoriatic lesions. Given the previous data suggesting a role for IGFBP7 in the control of cancer cell growth, we investigated its involvement in the regulation of keratinocyte (KC) proliferation and differentiation, which are abnormal in psoriasis. To model IGFBP7 downregulation in vitro, we used IGFBP7-specific small interfering RNA or small hairpin RNA-expressing lentiviral vectors in HaCaT cells or primary human KCs. Downregulation of IGFBP7 was found to markedly enhance KC proliferation in both systems, was associated with a significant decrease in KC susceptibility to tumor necrosis factor-α-induced apoptosis, but did not affect senescence. Downregulation of IGFBP7 was also shown to block expression of genes associated with calcium-induced differentiation of human KCs. Finally, recombinant IGFBP7 was found to inhibit KC proliferation and enhanced their apoptosis. These data position IGFBP7 as a regulator of KC proliferation and differentiation, suggesting a potential role for this protein in the pathophysiology and treatment of hyperproliferative dermatoses such as psoriasis

Vector and reservoir control for preventing leishmaniasis

Background Leishmaniasis is caused by the Leishmania parasite, and transmitted by infected phlebotomine sandflies. Of the two distinct clinical syndromes, cutaneous leishmaniasis (CL) affects the skin and mucous membranes, and visceral leishmaniasis (VL) affects internal organs. Approaches to prevent transmission include vector control by reducing human contact with infected sandflies, and reservoir control, by reducing the number of infected animals. Objectives To assess the effects of vector and reservoir control interventions for cutaneous and for visceral leishmaniasis. Search methods We searched the following databases to 13 January 2015: Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS and WHOLIS, Web of Science, and RePORTER. We also searched trials registers for ongoing trials. Selection criteria Randomized controlled trials (RCTs) evaluating the effects of vector and reservoir control interventions in leishmaniasis-endemic regions. Data collection and analysis Two review authors independently searched for trials and extracted data from included RCTs. We resolved any disagreements by discussion with a third review author. We assessed the quality of the evidence using the GRADE approach. Main results We included 14 RCTs that evaluated a range of interventions across different settings. The study methods were generally poorly described, and consequently all included trials were judged to be at high or unclear risk of selection and reporting bias. Only seven trials reported clinical outcome data which limits our ability to make broad generalizations to different epidemiological settings and cultures. Cutaneous leishmaniasis One four-arm RCT from Afghanistan compared indoor residual spraying (IRS), insecticide-treated bednets (ITNs), and insecticide-treated bedsheets, with no intervention. Over 15 months follow-up, all three insecticide-based interventions had a lower incidence of CL than the control area (IRS: risk ratio (RR) 0.61, 95% confidence interval (CI) 0.38 to 0.97, 2892 participants, moderate quality evidence; ITNs: RR 0.32, 95% CI 0.18 to 0.56, 2954 participants, low quality evidence; ITS: RR 0.34, 95% CI 0.20 to 0.57, 2784 participants, low quality evidence). No difference was detected between the three interventions (low quality evidence). One additional trial of ITNs from Iran was underpowered to show a difference. Insecticide treated curtains were compared with no intervention in one RCT from Venezuela, where there were no CL episodes in the intervention areas over 12 months follow-up compared to 142 in control areas (RR 0.00, 95% CI 0.00 to 0.49, one trial, 2938 participants, low quality evidence). Personal protection using insecticide treated clothing was evaluated by two RCTs in soldiers, but the trials were underpowered to reliably detect effects on the incidence of CL (RR 0.40, 95% CI 0.13 to 1.20, two trials, 558 participants, low quality evidence). Visceral leishmaniasis In a single RCT of ITNs versus no intervention from India and Nepal, the incidence of VL was low in both groups and no difference was detected (RR 0.99, 95% CI 0.46 to 2.15, one trial, 19,810 participants, moderate quality evidence). Two trials from Brazil evaluated the effects of culling infected dogs compared to no intervention or IRS. Although they report a reduction in seroconversion over 18 months follow-up, they did not measure or report effects on clinical disease. Authors' conclusions Using insecticides to reduce phlebotomine sandfly numbers may be effective at reducing the incidence of CL, but there is insufficient evidence from trials to know whether it is better to spray the internal walls of houses or to treat bednets, curtains, bedsheets or clothing

Single‐cell transcriptomics reveals a senescence‐associated IL‐6/CCR6 axis driving radiodermatitis

Abstract 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

RIN2 Deficiency Results in Macrocephaly, Alopecia, Cutis Laxa, and Scoliosis: MACS Syndrome

Inherited disorders of elastic tissue represent a complex and heterogeneous group of diseases, characterized often by sagging skin and occasionally by life-threatening visceral complications. In the present study, we report on an autosomal-recessive disorder that we have termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis). The disorder was mapped to chromosome 20p11.21-p11.23, and a homozygous frameshift mutation in RIN2 was found to segregate with the disease phenotype in a large consanguineous kindred. The mutation identified results in decreased expression of RIN2, a ubiquitously expressed protein that interacts with Rab5 and is involved in the regulation of endocytic trafficking. RIN2 deficiency was found to be associated with paucity of dermal microfibrils and deficiency of fibulin-5, which may underlie the abnormal skin phenotype displayed by the patients