Reflectance confocal microscopy for plaque psoriasis therapeutic follow-up during an anti-interleukin-17A monoclonal antibody: an observational study.

Interleukin-17A therapeutic inhibitors are among the most effective treatment methods for moderate-to-severe plaque psoriasis (PP). Reflectance confocal microscopy is a non-invasive imaging technique already documented to be beneficial in evaluating the follow-up of PP under treatment with topical actives and phototherapy. This study aimed to assess the epidermal and dermal changes associated with psoriasis and its treatment with RCM during systemic secukinumab treatment in patients with moderate-to-severe PP. A pilot study was conducted to evaluate RCM as a non-invasive tool for monitoring secukinumab treatment in patients with PP. For patients receiving secukinumab treatment, lesional skin was selected for RCM imaging, which were recorded at all scheduled times. The RCM evaluation criteria were established based on the histopathological diagnostic criteria for psoriasis. The clinical severity of psoriasis was assessed utilizing the psoriasis area severity index. A total of 23 patients with PP were included in the study. Each patient received 300 mg of subcutaneous secukinumab as induction therapy at baseline and weeks 1-4, followed by maintenance therapy every four weeks. Microscopic confocal changes were observed during the treatment. The results identified early microscopic evidence of the anti-inflammatory activity of secukinumab, which was not detected during the clinical examination. RCM findings correlating with the PASI were used to observe the patient's response to treatment and were identified as follows: acanthosis and parakeratosis, presence of epidermal and dermal inflammatory cells, presence of non-edge dermal papillae, and vascularization in the papillary dermis. This study is the first to demonstrate the use of RCM as an effective tool for non-invasive monitoring of secukinumab therapeutic response at a cellular level in a clinical or research setting. Early detection of RCM parameters associated with secukinumab activity may facilitate the identification of an early treatment response. RCM appears to be capable of providing practical and helpful information regarding follow-up in patients with PP undergoing secukinumab treatment. RCM may also provide novel perspectives on the subclinical evaluation of PP's response to biological therapy.

ALA-PDT promotes the death and contractile capacity of hypertrophic scar fibroblasts through inhibiting the TGF-ß1/Smad2/3/4 signaling pathway.

BACKGROUND: Hypertrophic scars, an abnormal wound-healing response to burn injuries, are characterized by massive fibroblast proliferation and excessive deposition of extracellular matrix and collagen. 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT) is a promising therapy for hypertrophic scar, details of the mechanisms remain to be elucidated. In this study, we aimed to investigate the molecular mechanisms involved in ALA-PDT against hypertrophic scar fibroblasts. METHODS: The morphologies of hypertrophic scar fibroblasts (HSFs) treated with ALA-PDT were observed under a light microscopy. The viability of HSFs was detected using the CCK-8 assay. HSFs-populated collagen gel contraction assays were conducted to examine the fibroblast contractility and the cytotoxicity of HSFs in 3D collagen tissues were observed using confocal microscopy. The effect of ALA-PDT on TGF-ß1/Smad2/3/4 signaling pathway activation and effector gene expression were verified by immunoprecipitation, western blot and real-time quantitative PCR analysis. RESULTS: We observed significant changes in cell morphology after ALA-PDT treatment of HSFs. As ALA concentration and light dose increased, the viability of HSFs significantly decreased. ALA-PDT can significantly alleviate the contractile capacity and promote the death of HSFs induced by TGF-ß1 treatment in a three-dimensional collagen culture model. TGF-ß1 treatment of HSFs can significantly induce phosphorylation of Smad2/3 (p-Smad2/3) in whole cells, as well as p-Smad2/3 and Smad4 proteins into the nucleus and increase the mRNA levels of collagen 1/3 and α-SMA. ALA-PDT hampers the TGF-ß1-Smad2/3/4 signaling pathway activation by inducing K48-linked ubiquitination and degradation of Smad4. CONCLUSIONS: Our results provide evidence that ALA-PDT can inhibit fibroblast contraction and promote cell death by inhibiting the activation of the TGF-ß1 signaling pathway that mediates hypertrophic scar formation, which may be the basis for the efficacy of ALA-PDT in the treatment of hypertrophic scars.

In-depth study of Wood's lamp examination combined with reflective confocal laser scanning microscopy for the guidance of vitiligo staging and treatment.

BACKGROUND: Both Wood's lamp and reflective confidential laser scanning microcopy are helpful for the diagnosis and treatment of vitiligo. However, there is few research that contains large samples and consistent observations. AIMS: To analyze the characteristics of Wood's lamp images and reflectance confocal microscopy (RCM) images of vitiligo lesions and to evaluate their significance in vitiligo staging. METHODS: We analyzed the characteristics of RCM images, Wood's lamp images, the vitiligo disease activity (VIDA) score, and clinical features to guide vitiligo staging and treatment. RESULTS: The expert consensus based on the clinical features, VIDA score, Wood's lamp findings, and isomorphic response was consistent with the Wood's lamp findings (χ2 = 3.63, p > 0.05) and RCM findings (χ2 = 3.60, p > 0.05) in diagnosing vitiligo and assessing the disease stage. There was a correlation between the three lesion grades based on the Wood's lamp findings and the stage of vitiligo (p < 0.01). Lesions that appeared porcelain white under the Wood's lamp were in the slowly progressive stage; lesions that appeared gray-white or trichromatic under the Wood's lamp were in the rapidly progressive stage; lesions with clear borders under the Wood's lamp needed further analysis by RCM for the stage to be determined; lesions with blurred borders under the Wood's lamp were in the rapidly progressive stage; lesions that were visible under the naked eye and under the Wood's lamp were in the rapidly progressive stage. CONCLUSION: The study demonstrates a reliable correlation between the findings of RCM (a sophisticated expensive tool) and Wood's lamp examination (a simple, readily available, inexpensive tool) in the assessment of the disease activity of vitiligo lesions.

Grape seed proanthocyanidins regulate mitophagy of endothelial cells and promote wound healing in mice through p-JNK/FOXO3a/ROS signal pathway.

Skin wound healing is a dynamic and complex process that involves multiple physiological and cellular events. Grape seed proanthocyanidins (GSP) have strong anti-oxidation and elimination of oxygen free radicals, and have been shown to significantly promote wound healing, but the underlying mechanism remains unclear. Studies have indicated that reactive oxygen species (ROS) acts as an upstream signal to induce mitophagy, suggesting that GSP can regulate mitophagy through the signal pathway. This study aimed to investigate whether GSP regulates mitophagy by down-regulating oxidative stress to promote wound healing. In vivo, GSP treatment accelerated wound healing, granulation tissue formation, collagen deposition, and angiogenesis in mice. Moreover, GSP down-regulated ROS levels and promoted the expression of antioxidant proteins by up-regulating the expression of p-JNK/FOXO3a protein, thereby regulating the expression of mitophagy-related proteins. In vitro, 4 µg/mL GSP showed no apparent toxic effects on cells and effectively reduce the oxidative stress damage of cells induced by H2O2. Western blot and superoxide anion fluorescence probe further confirmed that GSP effectively reduced Dihydroethidium content and up-regulated the expression of antioxidant proteins by activation of p-JNK/FOXO3a protein expression, thereby regulating mitophagy. Taken together, the findings from in vitro and in vivo experiments provide new insights into the promotion of wound healing by GSP.

The Eotaxin-1/CCR3 Axis and Matrix Metalloproteinase-9 Are Critical in Anti-NC16A IgE-Induced Bullous Pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune bullous skin disease of humans and is characterized by eosinophilic inflammation and circulating and tissue-bound IgG and IgE autoantibodies directed against two hemidesmosomal proteins: BP180 and BP230. The noncollagenous 16A domain (NC16A) of BP180 has been found to contain major epitopes recognized by autoantibodies in BP. We recently established the pathogenicity of anti-NC16A IgE through passive transfer of patient-derived autoantibodies to double-humanized mice that express the human high-affinity IgE receptor, FcεRI, and human NC16A domain (FcεRI/NC16A). In this model, anti-NC16A IgEs recruit eosinophils to mediate tissue injury and clinical disease in FcεRI/NC16A mice. The objective of this study was to characterize the molecular and cellular events that underlie eosinophil recruitment and eosinophil-dependent tissue injury in anti-NC16A IgE-induced BP. We show that anti-NC16A IgEs significantly increase levels of key eosinophil chemoattractants, eotaxin-1 and eotaxin-2, as well as the proteolytic enzyme matrix metalloproteinase-9 (MMP-9) in the lesional skin of FcεRI/NC16A mice. Importantly, neutralization of eotaxin-1, but not eotaxin-2, and blockade of the main eotaxin receptor, CCR3, drastically reduce anti-NC16A IgE-induced disease activity. We further show that anti-NC16A IgE/NC16A immune complexes induce the release of MMP-9 from eosinophils, and that MMP-9-deficient mice are resistant to anti-NC16A IgE-induced BP. Lastly, we find significantly increased levels of eotaxin-1, eotaxin-2, and MMP-9 in blister fluids of BP patients. Taken together, this study establishes the eotaxin-1/CCR3 axis and MMP-9 as key players in anti-NC16A IgE-induced BP and candidate therapeutic targets for future drug development and testing.

Corrigendum: Detection algorithm for pigmented skin disease based on classifier-level and feature-level fusion.

[This corrects the article DOI: 10.3389/fpubh.2022.1034772.].

Fingerstick blood assay maps real-world NAD+ disparity across gender and age.

Nicotinamide adenine dinucleotide (NAD+ ) level has been associated with various age-related diseases and its pharmacological modulation emerges as a potential approach for aging intervention. But human NAD+ landscape exhibits large heterogeneity. The lack of rapid, low-cost assays limits the establishment of whole-blood NAD+ baseline and the development of personalized therapies, especially for those with poor responses towards conventional NAD+ supplementations. Here, we developed an automated NAD+ analyzer for the rapid measurement of NAD+ with 5 µL of capillary blood using recombinant bioluminescent sensor protein and automated optical reader. The minimal invasiveness of the assay allowed a frequent and decentralized mapping of real-world NAD+ dynamics. We showed that aerobic sport and NMN supplementation increased whole-blood NAD+ and that male on average has higher NAD+ than female before the age of 50. We further revealed the long-term stability of human NAD+ baseline over 100 days and identified major real-world NAD+ -modulating behaviors.

[Clinical Analysis of Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm].

OBJECTIVE: To explore the clinical characteristics, treatment, and prognosis of patients with blastic plasmacytoid dendritic cell neoplasm(BPDCN). METHODS: Clinical data of 5 patients diagnosed with BPDCN in Wuhan First Hospital and Wuhan Tongji Hospital from June 2016 to November 2021 were retrospectively analyzed. RESULTS: Among the 5 patients, 3 were male and 2 were female, with a median age of 28(10-52) years old. Four patients showed obvious skin damage at the initial diagnosis; the other one showed clinical manifestations of acute leukemia rather than obvious skin damage at the initial diagnosis, but infiltrated skin when the disease relapsed after treatment. Other infiltration sites of lesions included bone marrow (2/5), peripheral blood (2/5), lymph nodes (3/5), liver and spleen (2/5). All patients had no clinical manifestation of central nervous system infiltration. Tumor cell specific immune markers CD4, CD56, CD123 were all positive, and the median Ki-67 index was 70%. TET2, ASXL1 and NRAS gene mutations were found respectively in 3 patients by next-generation sequencing technique (NGS). ALL-like, AML-like and invasive NK/T cell lymphoma-like first-line induction chemotherapy regimens were used for the patients. One patient died of severe complications during the early stage of chemotherapy, 3 patients were evaluated as CR, and 1 patient was evaluated as PR. 2 patients were recurred and progressed after induction of chemotherapy, and one of them was evaluated as CR after re-treatment. One patient received autologous hematopoietic stem cell transplantation (auto-HSCT) and got long-term survival (OS 87 months). 3 patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT), of which one died of transplantation related complications, and 2 cases survived. The median follow-up time of 4 patients with evaluable efficacy was 28.5(9-84) months, the median OS time was 31.5(10-87) months. CONCLUSION: BPDCN is a highly heterogeneous malignant tumor with a poor prognosis. HSCT, especially allo-HSCT can significantly improve the prognosis of BPDCN patients.

Hemoporfin-mediated photodynamic therapy with general anesthesia showed superior efficacy in the treatment of port-wine stains: a retrospective evaluation.

Background: Hemoporfin-mediated photodynamic therapy (PDT) is an effective treatment for port-wine stains (PWS), and pain is the main adverse effect of this therapy. General anesthesia is commonly used for pain management during PDT, but the effect of general anesthetics on the subsequent treatment efficacy of PDT in PWS has not been reported. Objectives: To assess the use of general anesthesia combined with PDT compared with PDT alone in 207 PWS patients, and to provide further safety and efficacy data on this combined therapy. Methods: Propensity score matching (PSM) was used at a 2:1 ratio to create a general anesthetic group (n = 138) and a highly comparable nonanesthetic group (n = 69). The clinical outcomes were evaluated, and the treatment reactions and adverse effects were recorded after one treatment with PDT. Results: After matching, there was no significant difference in the demographic data of the patients in the two groups (p > 0.05), while the treatment efficacy was significantly higher in the general anesthetic group than in the nonanesthetic group (76.81 vs. 56.52%, p < 0.05). Moreover, logistic regression analysis confirmed that patients receiving general anesthesia showed an association with a good response to PDT (OR = 3.06; 95% CI, 1.57-6.00; p = 0.0011). Purpura lasted longer in the general anesthetic group, but the other treatment reactions and adverse effects were similar in the two groups (p > 0.05). No serious systemic adverse reactions were observed. Conclusion: We recommend this combined therapy, which is associated with painless, as a high efficacy treatment option for PWS patients, especially for patients with a poor response to multiple PDT alone treatments.

Ratiometric NAD+ Sensors Reveal Subcellular NAD+ Modulators.

Mapping NAD+ dynamics in live cells and human is essential for translating NAD+ interventions into effective therapies. Yet, genetically encoded NAD+ sensors with better specificity and pH resistance are still needed for the cost-effective monitoring of NAD+ in both subcellular compartments and clinical samples. Here, we introduce multicolor, resonance energy transfer-based NAD+ sensors covering nano- to millimolar concentration ranges for clinical NAD+ measurement and subcellular NAD+ visualization. The sensors captured the blood NAD+ increase induced by NMN supplementation and revealed the distinct subcellular effects of NAD+ precursors and modulators. The sensors then enabled high-throughput screenings for mitochondrial and nuclear NAD+ modulators and identified α-GPC, a cognition-related metabolite that induces NAD+ redistribution from mitochondria to the nucleus relative to the total adenine nucleotides, which was further confirmed by NAD+ FRET microscopy.

Clinical and dermoscopic variation of basal cell carcinoma according to age of onset and anatomic location: a multicenter, retrospective study.

Basal cell carcinoma (BCC) is rare in young individuals and reported to possess different pathogenetic, clinical and histological features from late-onset BCC. However, the dermoscopic variability of BCC according to age of onset has not been investigated. Anatomic location was revealed to be associated with dermoscopic variation of BCC in Western population, but whether it applies to Asian population remains unknown. We evaluated the clinical and dermoscopic features of 448 BCCs and compared each feature by age of onset (age < 50/ > 50 years) and anatomic location. Early-onset BCCs occurred more frequently on non-sun-exposed sites (OR 3.28, P = 0.001) and were less pigmented than late-onset BCCs (P = 0.003). Blue-gray globules (OR 1.74, P = 0.037) and no vessels (OR 2.04, P = 0.021) were independently associated with early-onset BCCs, whereas arborizing telangiectasia (OR 0.30, P < 0.001), large blue-gray ovoid nests (OR 0.38, P < 0.001) and ulceration (OR 0.33, P < 0.001) were less common in early-onset BCCs. Scalp BCCs were significantly more pigmented than BCCs located elsewhere (P = 0.022). Superficial subtype (OR 5.90, P < 0.001), spoke-wheel areas (OR 4.78, P = 0.034), superficial erosions (OR 4.69, P = 0.003) and polymorph vessels (OR 6.86, P = 0.001) were independently associated with trunk BCCs, whereas nodular subtype (OR 5.48, P < 0.001) and arborizing telangiectasias (OR 3.64, P < 0.001) with BCCs on face and neck. Our findings suggest that age of onset and anatomic location are independent factors affecting the dermoscopic appearance of BCC.