Preliminary analysis of the efficacy of Mohs micrographic surgery combined with photodynamic therapy in a case of noninvasive extramammary Paget's disease.

PURPOSE: To evaluate the efficacy of Mohs micrographic surgery (MMS) combined with photodynamic therapy (PDT) in treating non-invasive extramammary Paget's disease (EMPD). MATERIALS AND METHODS: A 77-year-old male patient with non-invasive EMPD was treated with MMS followed by PDT. Preoperative fluorescence localization using 5-aminolevulinic acid (ALA) was performed to determine the surgical scope. MMS was conducted under lumbar anesthesia with intraoperative frozen-section pathology. Postoperative PDT was administered weekly for three sessions. RESULTS: The patient achieved negative surgical margins after two rounds of intraoperative pathology. Postoperative follow-up over two years showed no recurrence, and the patient did not experience significant adverse reactions. CONCLUSION: The combination of MMS and PDT was effective in treating non-invasive EMPD, demonstrating favorable clinical outcomes and no recurrence over the two-year follow-up period.

Adipose-Derived Stem Cell Exosomes Antagonize the Inhibitory Effect of Dihydrotestosterone on Hair Follicle Growth by Activating Wnt/ß-Catenin Pathway.

The most prevalent type of alopecia is androgenetic alopecia (AGA), which has a high prevalence but no effective treatment. Elevated dihydrotestosterone (DHT) level in the balding area was usually thought to be critical in the pathophysiology of AGA. The canonical Wnt/ß-catenin signaling pathway plays a key role in promoting hair follicle development and sustaining the hair follicle cycle. Adipose-derived stem cell exosomes (ADSC-Exos) are widely used in the field of regenerative medicine due to the advantages of being cell free and immune privileged. Still, few studies have reported the therapeutic effect on hair disorders. As a result, we sought to understand how ADSC-Exos affected hair growth and explore the possibility that ADSC-Exos could counteract the hair-growth-inhibiting effects of DHT. This research using human hair follicle organs, in vitro dermal papilla cells, and in vivo animal models showed that ADSC-Exos not only encouraged healthy hair growth but also counteracted the inhibitory effects of DHT on hair growth. Additionally, we discovered that ADSC-Exos increased Ser9 phosphorylated glycogen synthase kinase-3ß levels and facilitated nuclear translocation of ß-catenin, which may have been blocked by the specific Wnt/ß-catenin signaling pathway inhibitor dickkopf-related protein 1. Our findings suggested that ADSC-Exos are essential for hair regeneration, which is anticipated to open up new therapeutic possibilities for clinical alopecia, particularly for the treatment of AGA.

Machine learning-based radiomics analysis for predicting local recurrence of primary dermatofibrosarcoma protuberans after surgical treatment.

BACKGROUND AND PURPOSE: Dermatofibrosarcoma protuberans (DFSP) is characterized by locally invasive growth patterns and high local recurrence rates. Accurately identifying patients with high local recurrence risk may benefit patients during follow-up and has potential value for making treatment decisions. This study aimed to investigate whether machine learning-based radiomics models could accurately predict the local recurrence of primary DFSP after surgical treatment. MATERIALS AND METHODS: This retrospective study included a total of 146 patients with DFSP who underwent MRI scans between 2010 and 2016 from two different institutions: institution 1 (n = 104) for the training set and institution 2 (n = 42) for the external test set. Three radiomics random survival forest (RSF) models were developed using MRI images. Additionally, the performance of the Ki67 index was compared with the three RSF models in the external validation set. RESULTS: The average concordance index (C-index) scores of the RSF models based on fat-saturation T2W (FS-T2W) images, fat-saturation T1W with gadolinium contrast (FS-T1W + C) images, and both FS-T2W and FS-T1W + C images from 10-fold cross-validation in the training set were 0.855 (95% CI: 0.629, 1.00), 0.873 (95% CI: 0.711, 1.00), and 0.875 (95% CI: 0.688, 1.00), respectively. In the external validation set, the C-indexes of the three trained RSF models were higher than that of the Ki67 index (0.838, 0.754, and 0.866 vs. 0.601, respectively). CONCLUSION: Random survival forest models developed using radiomics features derived from MRI images were proven helpful for accurate prediction of local recurrence of primary DFSP after surgical treatment and showed better predicting performance than the Ki67 index.

Photodynamic therapy combined with surgery versus Mohs micrographic surgery for the treatment of difficult-to-treat basal cell carcinoma: a retrospective clinical study.

BACKGROUND: Mohs micrographic surgery (MMS) is the preferable surgery for difficult -to-treat basal cell carcinoma (BCC) but is an expensive, labor-intensive, and time-consuming technique. The aim of this study is to compare the efficacy and safety of photodynamic therapy combined with surgery(S-PDT) versus Mohs micrographic surgery (MMS) for the treatment of difficult-to-treat BCC. METHODS: This was a retrospective, comparative study. A total of 32 patients, 16 patients with 48 lesions, were treated with S-PDT, and the other 16 patients with 17 lesions treated by MMS were enrolled in this study. Follow-up was at least 36 months posttreatment. RESULTS: The recurrence rate was no statistical difference between the S-PDT and MMS (p = 1.000, Fishers exact test). The median follow-up was 42.5 months (range 36-63 months). The mean healing time in the S-PDT [17.9 d (SD 9.8)] is longer than in MMS [7.5 d (SD 1.5)] during follow-up (p＜.001, Independent T-test). On the whole, the cosmetic outcome of patients in S-PDT was statistically no significant difference with that in MMS according to a 4-point scale (p = .719, chi-squared test). CONCLUSIONS: S-PDT is a safe, effective, and novel cosmetic treatment, which holds the potential to be an alternative treatment to MMS for some cases.

Adipose Mesenchymal Stromal Cell-Derived Exosomes Carrying MiR-122-5p Antagonize the Inhibitory Effect of Dihydrotestosterone on Hair Follicles by Targeting the TGF-ß1/SMAD3 Signaling Pathway.

Androgenic alopecia (AGA) is the most common type of hair loss, where local high concentrations of dihydrotestosterone (DHT) in the scalp cause progressive shrinkage of the hair follicles, eventually contributing to hair loss. Due to the limitations of existing methods to treat AGA, the use of multi-origin mesenchymal stromal cell-derived exosomes has been proposed. However, the functions and mechanisms of action of exosomes secreted by adipose mesenchymal stromal cells (ADSCs-Exos) in AGA are still unclear. Using Cell Counting Kit-8 (CCK8) analysis, immunofluorescence staining, scratch assays, and Western blotting, it was found that ADSC-Exos contributed to the proliferation, migration, and differentiation of dermal papilla cells (DPCs) and up-regulated the expression of cyclin, ß-catenin, versican, and BMP2. ADSC-Exos also mitigated the inhibitory effects of DHT on DPCs and down-regulated transforming growth factor-beta1 (TGF-ß1) and its downstream genes. Moreover, high-throughput miRNA sequencing and bioinformatics analysis identified 225 genes that were co-expressed in ADSC-Exos; of these, miR-122-5p was highly enriched and was found by luciferase assays to target SMAD3. ADSC-Exos carrying miR-122-5p antagonized DHT inhibition of hair follicles, up-regulated the expression of ß-catenin and versican in vivo and in vitro, restored hair bulb size and dermal thickness, and promoted the normal growth of hair follicles. So, ADSC-Exos enhanced the regeneration of hair follicles in AGA through the action of miR-122-5p and the inhibition of the TGF-ß/SMAD3 axis. These results suggest a novel treatment option for the treatment of AGA.

Genomic alterations of dermatofibrosarcoma protuberans revealed by whole-genome sequencing.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare and marginal cutaneous sarcoma of intermediate-grade malignancy, for which the genomic landscape remains unclear. Understanding the landscape of DFSP will help to further classify the genomic pathway of malignant development in soft tissue. OBJECTIVES: To identify the comprehensive molecular pathogenesis of DFSP. METHODS: In this study, the comprehensive genomic features, with 53 tumour-normal pairs of DFSP, were revealed by whole-genome sequencing. RESULTS: The mutational signature 1 (C > T mutation at CpG dinucleotides) is featured in DFSP, resulting in higher mutations in DNA replication. Interestingly, the recurrence of DFSP is correlated with low tumour mutation burden. Novel mutation genes in DFSP were identified, including MUC4/6, KMT2C and BRCA1, and subsequently, three molecular subtypes of DFSP were classified on the basis of MUC4 and MUC6 mutations. Various structural aberrations including genomic rearrangements were identified in DSFPs, particularly in 17q and 22q, which cause oncogene amplification (AKT1, SPHK1, COL1A1, PDGFß) or tumour suppressor deletion (CDKN2A/B). In addition to gene fusion of COL1A1-PDGFß [t(17;22)], we identified gene fusion of SLC2A5-BTBD7 [t(1;14)] in DFSP through whole-genome sequencing, and verified it experimentally. Enrichment analysis of altered molecules revealed that DNA repair, cell cycle, phosphoinositide 3-kinase and Janus kinase pathways were primarily involved in DFSP. CONCLUSIONS: This is the first large-scale whole-genome sequencing for DFSP, and our findings describe the comprehensive genomic landscape, highlighting the molecular complexity and genomic aberrations of DFSP. Our findings also provide novel potential diagnostic and therapeutic targets for this disease. What is already known about this topic? Chromosomal translocation between chromosome 17 and chromosome 22 is the main feature in the pathogenesis of dermatofibrosarcoma protuberans (DFSP). What does this study add? We describe the comprehensive genomic landscape of DFSP, highlighting the molecular complexity and genomic aberrations. Our findings provide novel potential diagnostic and therapeutic targets for this disease. What is the translational message? Our study revealed novel molecular subtypes of DFSP based on genetic mutations, which benefits precision diagnosis. We also found oncogene amplification, including AKT1 and SPHK1, which provides novel potential target molecules for further DFSP treatment. In addition to gene fusion of COL1A1-PDGFß, we identified a novel gene fusion of SLC2A5-BTBD7 in DFSP, which is a novel potential diagnostic and therapeutic target for this disease.

Integrative molecular and clinical profiling of acral melanoma links focal amplification of 22q11.21 to metastasis.

Acral melanoma, the most common melanoma subtype among non-White individuals, is associated with poor prognosis. However, its key molecular drivers remain obscure. Here, we perform integrative genomic and clinical profiling of acral melanomas from 104 patients treated in North America (n = 37) or China (n = 67). We find that recurrent, late-arising focal amplifications of cytoband 22q11.21 are a leading determinant of inferior survival, strongly associated with metastasis, and linked to downregulation of immunomodulatory genes associated with response to immune checkpoint blockade. Unexpectedly, LZTR1 - a known tumor suppressor in other cancers - is a key candidate oncogene in this cytoband. Silencing of LZTR1 in melanoma cell lines causes apoptotic cell death independent of major hotspot mutations or melanoma subtypes. Conversely, overexpression of LZTR1 in normal human melanocytes initiates processes associated with metastasis, including anchorage-independent growth, formation of spheroids, and an increase in MAPK and SRC activities. Our results provide insights into the etiology of acral melanoma and implicate LZTR1 as a key tumor promoter and therapeutic target.

Curcumin protection against ultraviolet-induced photo-damage in Hacat cells by regulating nuclear factor erythroid 2-related factor 2.

Curcumin suppressed ultraviolet (UV) induced skin carcinogenesis and activated the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. However, whether curcumin protects skin injury caused by UV is still unknown. A vitro model was established and curcumin effects on Hacat cells were detected. Nrf2 was knocked down in Hacat cells to verify the Nrf2 role in the protective effect of curcumin. Results indicated that ultraviolet A (UVA) (or ultraviolet B (UVB)) irradiation would lead to decreased cell proliferation, increased cell apoptosis, decreased catalase, heme oxygenase 1, and superoxide dismutase expression, and increased levels of protein carbonylation and malondialdehyde (p < 0.05). These adverse events could be reversed by adding 5-µM curcumin. Meanwhile, we found that the application of curcumin effectively induced Nrf2 nuclear accumulation in Hacat cells. While in the Nrf2 knockdown cells, the protective effects of curcumin against UVA (or UVB) were attenuated. Conclusively, curcumin protects Hacat cells against UV exposure-induced photo-damage by regulating Nrf2 expression.

miRNA microarray profiling in patients with androgenic alopecia and the effects of miR-133b on hair growth.

OBJECTIVE: Androgenetic alopecia (AGA), a common alopecia, is often accompanied by abnormal expression of multiple miRNAs. This study aims to investigate abnormally expressed miRNAs in patients with AGA and their specific molecular mechanism. METHODS: miRNA microarray profiling and qRT-PCR validation were used to screen and verify abnormally expressed miRNAs in patients with AGA. Human hair follicles (HFs) were treated with different concentrations of dihydrotestosterone (DHT, 10-5, 10-6, 10-7 and 10-8 mol/L) for 10 days. The effects of DHT on HF growth, proliferation, and miRNA expression in cultured HFs were investigated using immunofluorescence staining and qRT-PCR. Moreover, human dermal papilla cells (HDPCs) were treated/transfected with a Wnt/ß-catenin pathway activator and/or miR-133b mimic, and then the CCK-8 assay was used to evaluate HDPC proliferation. qRT-PCR and Western blotting were used to measure the expression of Versican, ALP and ß-catenin RESULTS: miRNA microarray profiling identified 43 miRNAs that were significantly differentially expressed in AGA patients, and qRT-PCR verified that 8 miRNAs were significantly differentially expressed. The expression of miR-133b was abnormally high in AGA patients. DHT (10-5 mol/L) inhibited human HF growth and upregulated miR-133b expression, and DHT (10-7 mol/L) induced human HF growth and downregulated miR-133b expression. HDPC proliferation was inhibited, and the expression of ß-catenin was downregulated in the miR-133b mimic-transfected group compared with the control group (P < 0.05). Wnt/ß-catenin pathway activator treatment significantly promoted HDPC proliferation and upregulated the expression of ß-catenin (P < 0.05). In addition, the proliferation of HDPCs was not significantly different between the group cotreated with a Wnt/ß-catenin pathway activator and miR-133b mimic, and the control group (P > 0.05), but the expression of Versican and ALP was suppressed in the cotreatment group (P < 0.05) CONCLUSION: Our data indicated that patients with androgenic alopecia have specific miRNA expression profiles and that the abnormal expression of miR-133b may inactivate the Wnt/ß-catenin pathway and ultimately regulate hair growth.

Assistant Diagnosis of Basal Cell Carcinoma and Seborrheic Keratosis in Chinese Population Using Convolutional Neural Network.

Objectives: To evaluate CNN models' performance of identifying the clinical images of basal cell carcinoma (BCC) and seborrheic keratosis (SK) and to compare their performance with that of dermatologists. Methods: We constructed a Chinese skin diseases dataset which includes 1456 BCC and 1843 SK clinical images and the corresponding medical history. We evaluated the performance using four mainstream CNN structures and transfer learning techniques. We explored the interpretability of the CNN model and compared its performance with that of 21 dermatologists. Results: The fine-tuned InceptionResNetV2 achieved the best performance, with an accuracy and area under the curve of 0.855 and 0.919, respectively. Further experimental results suggested that the CNN model was not only interpretable but also had a performance comparable to that of dermatologists. Conclusions: This study is the first on the assistant diagnosis of BCC and SK based on the proposed dataset. The promising results suggested that CNN model's performance was comparable to that of expert dermatologists.

Dihydrotestosterone Regulates Hair Growth Through the Wnt/ß-Catenin Pathway in C57BL/6 Mice and In Vitro Organ Culture.

Dihydrotestosterone (DHT) is the most potent androgen that regulates hair cycling. Hair cycling involves cross-talk between the androgen and Wnt/ß-catenin pathways. However, how DHT regulates hair follicle (HF) growth through the Wnt/ß-catenin pathway has not been well investigated. This study aimed to investigate the roles of DHT in hair growth in vivo and in vitro. Human scalp HFs were treated with different concentrations of DHT (10-5, 10-6, 10-7, 10-8, and 10-9 mol/L) for 10 days. The effects of DHT on hair shaft elongation, the proliferation of hair matrix cells, and the levels of ß-catenin, GSK-3ß, and phosphorylated GSK-3ß (ser9) were evaluated in the cultured HFs. The effects of DHT were further investigated in C57BL/6 mice. Moreover, the growth of cultured human HFs was observed after interfering with the ß-catenin pathway through inhibitors or activators in the presence or absence of DHT. We found that different concentrations of DHT had different effects on human HFs in vitro and C57BL/6 mice. At 10-6 mol/L, DHT inhibited HF growth and ß-catenin/p-GSK-3ß expression, whereas 10-7 mol/L DHT induced HF growth and ß-catenin/p-GSK-3ß expression. In addition, a ß-catenin inhibitor (21H7) inhibited HF growth in vitro, while a ß-catenin activator (IM12) promoted HF growth in vitro and antagonized the inhibition of HFs by high levels of DHT. These results suggest that DHT plays a pivotal role in region-specific hair growth, which may be related to the Wnt/ß-catenin pathway.

Activation of Wnt/ß-catenin signaling is involved in hair growth-promoting effect of 655-nm red light and LED in in vitro culture model.

Activation of the Wnt/ß-catenin signaling pathway plays an important role in hair follicle morphogenesis and hair growth. Recently, low-level laser therapy (LLLT) was evaluated for stimulating hair growth in numerous clinical studies, in which 655-nm red light was found to be most effective and practical for stimulating hair growth. We evaluated whether 655-nm red light + light-emitting diode (LED) could promote human hair growth by activating Wnt/ß-catenin signaling. An in vitro culture of human hair follicles (HFs) was irradiated with different intensities of 655-nm red light + LED, 21 h7 (an inhibitor of ß-catenin), or both. Immunofluorescence staining was performed to assess the expression of ß-catenin, GSK3ß, p-GSK3ß, and Lef1 in the Wnt/ß-catenin signaling. The 655-nm red light + LED not only enhanced hair shaft elongation, but also reduced catagen transition in human hair follicle organ culture, with the greatest effectiveness observed at 5 min (0.839 J/cm2). Additionally, 655-nm red light + LED enhanced the expression of ß-catenin, p-GSK3ß, and Lef1, signaling molecules of the Wnt/ß-catenin pathway, in the hair matrix. Activation of Wnt/ß-catenin signaling is involved in hair growth-promoting effect of 655-nm red light and LED in vitro and therefore may serve as an alternative therapeutic option for alopecia.

Clinical Benefits of Preoperative Conventional Fluorescence Diagnosis in Surgical Treatment of Extramammary Paget Disease.

BACKGROUND: In extramammary Paget disease (EMPD), initial margins of surgical excision are difficult to determine preoperatively. Fluorescence diagnosis (FD) may have utility as a noninvasive method for delineating tumor boundaries. OBJECTIVE: The relationship between FD-delineated borders and results of multiple scouting biopsies (MSBs) in EMPD was investigated, evaluating the potential clinical role of FD. MATERIALS AND METHODS: A cohort of 21 patients was studied, looking for consistencies between FD and MSB results. Initial surgical margins were determined by FD or FD plus MSB. All margins were subjected to frozen section analysis. RESULTS: Paget cells were identified in 88 of 117 (71.8%) biopsies obtained from FD borders. When used preoperatively with MSB in 9 patients, 96.4% of margins proved negative at initial resection stage. Using a 6-mm margin beyond FD borders in another 9 patients, 86.7% of margins were negative at initial stage. The maximum distance of excision beyond FD border was 12 mm. CONCLUSION: Fluorescence diagnosis borders (identified visually) correlated well with MSB histopathology. Fluorescence diagnosis is a useful method to delineate initial margins for surgical resection of EMPD.

Functionalization of composite bacterial cellulose with C60 nanoparticles for wound dressing and cancer therapy.

A series of novel bacterial cellulose/C60 (BCC60) composites was prepared using a original dehydration-rehydration method. The composites were characterized to demonstrate their potential in multifunctional wound dressings for skin cancer treatment using photodynamic therapy. Raman spectroscopy revealed that the C60 nanoparticles were successfully incorporated into the bacterial cellulose (BC) network. Scanning electron microscopy was used to examine the morphology and distribution of the C60 particles as photosensitizers in the bacterial cellulose network, and the C60 particles were uniformly distributed in the hyperfine three-dimensional BC network with diameters less than 100 nm. Reactive oxygen species (ROS) measurements indicated that the BCC60 composites possessed a high ROS generation ability when exposed to light. The antibacterial assessment of the BCC60 composites revealed their ability to inhibit the growth of E. coli and S. aureus and their relationship with light irradiation. In vitro cell experiments also confirmed that the BCC60 composites had low cytotoxicity in the dark, while they exhibited significant cancer cell damage activity under visible light.

ß-Catenin is involved in oleanolic acid-dependent promotion of proliferation in human hair matrix cells in an in vitro organ culture model.

Oleanolic acid (OA), a pentacyclic triterpenoid compound which can be found in >1600 plants, has been shown to promote hair growth. To study the mechanisms of OA on hair growth, we investigated hair follicle (HF) growth on four different concentration OA using human hair follicle organ culture model. We found that HFs treated with 1 or 10µg/mL OA showed statistically enhanced elongation of the hair shaft and anagen-like stage. Moreover, higher positive rate of Ki-67, a matrix cellular marker of proliferation, was detected in the same groups treated with 1 or 10µg/mL than those treated with vehicle. We further demonstrated that ß-catenin, a key Wnt signaling transducer, was highly expressed in the OA treated groups using immunofluorescence stain assay. These results suggest that OA may promote human hair growth by stimulating hair matrix cell proliferation through the Wnt/ß-catenin pathway.

Skin Erythema, Pigmentation and Hydration Kinetics after Ultraviolet Radiation-induced Photodamage in Southern Chinese Women.

Although there have been some studies about changes of skin erythema and pigmentation following ultraviolet radiation in other races, the relevant data in Chinese have never been achieved. Thus, we evaluated the long-time course of skin erythema, pigmentation and hydration changes after different doses of solar-simulated ultraviolet (SSUV) irradiation in 26 Chinese women for 168 days. The erythema index increased abruptly and peaked during 3 days of SSUV exposure, then slowly returned to the baseline level starting at day 7 and completely recovered during 168-day course of this study only in one minimal erythema doses (MED) SSUV irradiation. The melanin index started to slowly increase at day 3 of SSUV exposure, peaking at day 14 and gradually returned to the baseline level thereafter, but did not return to the baseline level during 168-day course in all doses. Skin hydration slowly declined at day 3 of exposure, hitting the lowest point at day 7, then slowly recovered starting at day 14 and completely returned to the baseline level at day 28 only in 1.5MED. These results will serve as baseline data on Chinese skin and provide useful references for the treatment of serious skin photodamage in Chinese.

Attitudes, Beliefs, and Measures Taken by Parents to Protect Their Children from the Sun in Guangzhou City, China.

Excessive sun exposure can cause sunburn, suntan, skin photoaging, and even skin cancer. Skin photoaging conflicts with the human pursuit of a young and beautiful appearance. Some research data indicate that the incidence of skin cancer in the Chinese has been increasing, although it remains lower than in whites. To estimate the prevalence of sun protection used on Chinese children aged 3-13 years and identify its predictors, a population-based cross-sectional questionnaire was given to 3684 parents/guardians of children in Guangzhou, China, of which 3083 questionnaires were returned. Of those returned, 35.5% of parents/guardians reported regularly using sun protection on their children and the primary reason cited was to prevent sunburn. Hats and handheld umbrellas were the most frequently used measures; sunscreen was less common, and when used, 48.8% of parents/guardians still reapplied sunscreen on their children every 2.0-3.0 h. Parental age, parents using sun protection measures themselves when outdoors, and the child's sex were factors associated with regular use of sun protection on children. These results suggest that sun protection campaigns targeted toward parents and children need to be conducted in Guangzhou, or throughout China, to strengthen awareness about sun protection and address any inadequate protocols of sun protection.