Integrated single-cell and spatial transcriptomics reveals heterogeneity of fibroblast and pivotal genes in psoriasis.

Psoriasis, which is one of the most common skin diseases, involves an array of complex immune constituents including T cells, dendritic cells and monocytes. Particularly, the cytokine IL17A, primarily generated by TH17 cells, assumes a crucial function in the etiology of psoriasis. In this study, a comprehensive investigation utilizing bulk RNA analysis, single-cell RNA sequencing, and spatial transcriptomics was employed to elucidate the underlying mechanisms of psoriasis. Our study revealed that there is an overlap between the genes that are differentially expressed in psoriasis patients receiving three anti-IL17A monoclonal antibody drugs and the genes that are differentially expressed in lesion versus non-lesion samples in these patients. Further analysis using single-cell and spatial data from psoriasis samples confirmed the expression of hub genes that had low expressions in psoriasis tissue but were up-regulated after anti-IL17A treatments. These genes were found to be associated with the treatment effects of brodalumab and methotrexate, but not adalimumab, etanercept, and ustekinumab. Additionally, these genes were predominantly expressed in fibroblasts. In our study, fibroblasts were categorized into five clusters. Notably, hub genes exhibited predominant expression in cluster 3 fibroblasts, which were primarily engaged in the regulation of the extracellular matrix and were predominantly located in the reticular dermis. Subsequent analysis unveiled that cluster 3 fibroblasts also established communication with epithelial cells and monocytes via the ANGPTL-SDC4 ligand-receptor configuration, and their regulation was governed by the transcription factor TWIST1. Conversely, cluster 4 fibroblasts, responsible for vascular endothelial regulation, were predominantly distributed in the papillary dermis. Cluster 4 predominantly engaged in interactions with endothelial cells via MDK signals and was governed by the distinctive transcription factor, ERG. By means of an integrated analysis encompassing bulk transcriptomics, single-cell RNA sequencing, and spatial transcriptomics, we have discerned genes and clusters of fibroblasts that potentially contribute to the pathogenesis of psoriasis.

Development, efficacy and side effects of antibody­drug conjugates for cancer therapy (Review).

Antibody-drug conjugates (ADCs) are anticancer drugs that combine cytotoxic small-molecule drugs (payloads) with monoclonal antibodies through a chemical linker and that transfer toxic payloads to tumor cells expressing target antigens. All ADCs are based on human IgG. In 2009, the Food and Drug Administration (FDA) approved gemtuzumab ozogamicin as the initial first-generation ADC. Since then, at least 100 ADC-related projects have been initiated, and 14 ADCs are currently being tested in clinical trials. The limited success of gemtuzumab ozogamicin has led to the development of optimization strategies for the next generation of drugs. Subsequently, experts have improved the first-generation ADCs and have developed second-generation ADCs such as ado-trastuzumab emtansine. Second-generation ADCs have higher specific antigen levels, more stable linkers and longer half-lives and show great potential to transform cancer treatment models. Since the first two generations of ADCs have served as a good foundation, the development of ADCs is accelerating, and third-generation ADCs, represented by trastuzumab deruxtecan, are ready for wide application. Third-generation ADCs are characterized by strong pharmacokinetics and high pharmaceutical activity, and their drug-to-antibody ratio mainly ranges from 2 to 4. In the past decade, the research prospects of ADCs have broadened, and an increasing number of specific antigen targets and mechanisms of cytotoxic drug release have been discovered and studied. To date, seven ADCs have been approved by the FDA for lymphoma, and three have been approved to treat breast cancer. The present review explores the function and development of ADCs and their clinical use in cancer treatment.

Immunohistochemical Features of MMP-9 and pSTAT1 in Granuloma Annulare and Sarcoidosis: A Comparative Study of 62 Cases.

Background: Granuloma annulare (GA) and sarcoidosis are granulomatous inflammatory diseases that share similarities. Objective: To identify the histological and immunohistochemical (IHC) features of GA and sarcoidosis. Methods: A retrospective review of 36 patients with GA and 26 with sarcoidosis was performed. Results from hematoxylin and eosin (H&E) staining and IHC staining of MMP-9 and pSTAT1 within the skin lesions of GA and sarcoidosis were analyzed, and random forest was applied for developing a predictive model. Results: Significantly greater expressions of MMP-9 (especially in elastic fibers, EFs, P < 0.0001) and pSTAT1 (P = 0.0003) were observed in lesion samples of GA versus sarcoidosis patients. In GA patients, MMP-9 was significantly upregulated in the interstitial type (P = 0.0222), while staining of pSTAT1 was positively correlated with the area of mucinous collagen in palisading GA (R = 0.5356, P = 0.0484). In sarcoidosis patients, MMP-9 (R = -0.7127, P = 0.0009) and pSTAT1 (R = -0.5604, P = 0.0067) were found to show stronger expressions in lesions with less lymphocyte infiltration. The predictive model demonstrated an AUC of 0.9675. Conclusion: These results indicate that MMP-9 and pSTAT1 might exert roles in granulomatous inflammation in different modes, and the presence of more robust MMP-9 staining in EFs appears to be more suggestive of GA.

Artificial Intelligence in microbiomes analysis: A review of applications in dermatology.

Microorganisms are closely related to skin diseases, and microbiological imbalances or invasions of exogenous pathogens can be a source of various skin diseases. The development and prognosis of such skin diseases are also closely related to the type and composition ratio of microorganisms present. Therefore, through detection of the characteristics and changes in microorganisms, the possibility for diagnosis and prediction of skin diseases can be markedly improved. The abundance of microorganisms and an understanding of the vast amount of biological information associated with these microorganisms has been a formidable task. However, with advances in large-scale sequencing, artificial intelligence (AI)-related machine learning can serve as a means to analyze large-scales of data related to microorganisms along with determinations regarding the type and status of diseases. In this review, we describe some uses of this exciting, new emerging field. In specific, we described the recognition of fungi with convolutional neural networks (CNN), the combined application of microbial genome sequencing and machine learning and applications of AI in the diagnosis of skin diseases as related to the gut-skin axis.

Advances in machine learning-based bacteria analysis for forensic identification: identity, ethnicity, and site of occurrence.

When faced with an unidentified body, identifying the victim can be challenging, particularly if physical characteristics are obscured or masked. In recent years, microbiological analysis in forensic science has emerged as a cutting-edge technology. It not only exhibits individual specificity, distinguishing different human biotraces from various sites of occurrence (e.g., gastrointestinal, oral, skin, respiratory, and genitourinary tracts), each hosting distinct bacterial species, but also offers insights into the accident's location and the surrounding environment. The integration of machine learning with microbiomics provides a substantial improvement in classifying bacterial species compares to traditional sequencing techniques. This review discusses the use of machine learning algorithms such as RF, SVM, ANN, DNN, regression, and BN for the detection and identification of various bacteria, including Bacillus anthracis, Acetobacter aceti, Staphylococcus aureus, and Streptococcus, among others. Deep leaning techniques, such as Convolutional Neural Networks (CNN) models and derivatives, are also employed to predict the victim's age, gender, lifestyle, and racial characteristics. It is anticipated that big data analytics and artificial intelligence will play a pivotal role in advancing forensic microbiology in the future.

Advances in microbial metagenomics and artificial intelligence analysis in forensic identification.

Microorganisms, which are widely distributed in nature and human body, show unique application value in forensic identification. Recent advances in high-throughput sequencing technology and significant reductions in analysis costs have markedly promoted the development of forensic microbiology and metagenomics. The rapid progression of artificial intelligence (AI) methods and computational approaches has shown their unique application value in forensics and their potential to address relevant forensic questions. Here, we summarize the current status of microbial metagenomics and AI analysis in forensic microbiology, including postmortem interval inference, individual identification, geolocation, and tissue/fluid identification.

A randomized, prospective pilot study for comparison of a triple combination of 2940 nm Er:YAG Laser and triamcinolone acetonide solution with either 308 nm excimer laser or 0.1% tacrolimus in treatment of stable segmental vitiligo.

This study aimed to assess and compare the clinical efficacy and safety of a triple combination treatment using 2940 nm Er:YAG laser, triamcinolone acetonide solution combined with either 308 nm excimer laser or 0.1% tacrolimus for the treatment of stable segmental vitiligo. Patients with stable segmental vitiligo were randomly divided into two groups and received a 5-month treatment with 2940 nm Er:YAG laser followed by triamcinolone acetonide and, either 308 nm excimer laser (Group A, N = 8) or 0.1% tacrolimus (Group B, N = 13). General information and imaging data were collected before and at 1 month after treatments. Marked repigmentation and overall repigmentation rates were analyzed and any adverse skin reactions were recorded. Both treatments significantly reduced the percent of skin lesions per total body surface area (p < 0.05) and no significant differences in repigmentation were observed between the two groups (p > 0.05). The marked repigmentation rate of Group A was 42.11% and overall repigmentation rate was 94.74%, while for Group B these rates were 51.16% and 100%, respectively. There were no significant differences in the number of fingertip units at each time point (p > 0.05). While there was a significant effect for time on the number of fingertip units without considering other factors (p < 0.05), the time x treatment interaction was not significant (p > 0.05). One Group A patient developed adverse reactions consisting of erythema, burning sensation and blisters and one Group B patient developed mild erythema and burning sensations. Both treatments demonstrated a high level of efficacy and safety in the treatment of stable segmental vitiligo.

Computer Image Analysis Reveals C-Myc as a Potential Biomarker for Discriminating between Keratoacanthoma and Cutaneous Squamous Cell Carcinoma.

The distinction between Keratoacanthoma (KA) and Cutaneous Squamous Cell Carcinoma (cSCC) is critical yet usually challenging to discriminate clinically and histopathologically. One approach to differentiate KA from cSCC is through assessing the immunohistochemical staining patterns of the three indicators, ß-catenin, C-Myc, and CyclinD1, which are critical molecules that play important roles in the Wnt/ß-catenin signaling pathway. Ki-67, as a proliferation biomarker for human tumor cells, was also assessed as an additional potential marker for differentiating KA from cSCC. In this report, these four indicators were analyzed in 42 KA and 30 cSCC cases with the use of the computer automated image analysis system. Computer automated image analysis is a time-based and cost-effective method of determining IHC staining in KA and cSCC samples. We found that C-Myc staining was predominantly localized in the nuclei of basal cells within KA patients, whereas cSCC staining was predominantly localized in the nuclei of diffuse cells. This C-Myc staining pattern has a sensitivity of 78.6% and a specificity of 66.7% for identifying KA. Moreover, positive rates of distinct expression patterns of C-Myc and Ki-67 may also serve as a means to clinically distinguish KA from cSCC. Taken together, our results suggest that these markers, in particular C-Myc, may be useful in differentiating KA from cSCC.

Clinical guideline for the diagnosis and treatment of cutaneous warts (2022).

AIM: Cutaneous warts caused by human papillomavirus are benign proliferative lesions that occur at any ages in human lives. Updated, comprehensive and systematic evidence-based guidelines to guide clinical practice are urgently needed. METHODS: We collaborated with multidisciplinary experts to formulate this guideline based on evidences of already published literature, focusing on 13 clinical questions elected by a panel of experts. We adopted Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to form classification of recommendations as well as the improved Delphi method to retain respective recommendations with a consensus degree of over 80%. RESULTS: Our guideline covered aspects of the diagnosis and treatment of cutaneous warts such as diagnostic gold standard, transmission routes, laboratory tests, treatment principle, clinical cure criterion, definitions, and treatments of common warts, flat warts, plantar warts, condyloma acuminatum, and epidermodysplasia verruciformis. Recommendations about special population such as children and pregnant women are also listed. In total, 49 recommendations have been obtained. CONCLUSIONS: It is a comprehensive and systematic evidence-based guideline and we hope this guideline could systematically and effectively guide the clinical practice of cutaneous warts and improve the overall levels of medical services.

Sporothrix schenckii regulates macrophage inflammatory responses via the c-JUN-induced Dab2 transcription.

Macrophages, which serve as a bridge between innate and adaptive immunity, play an important role in sporotrichosis. Sporothrix schenckii infections can produce immune responses such as macrophage polarization and inflammatory factor secretion. In the early stages of inflammation, the expression of DAB2 in macrophages is increased, which controls the secretion of inflammatory factors and affects the polarization of macrophages. However, the expressions and mechanisms of DAB2 in sporotrichosis are not clear. In this study, we examined the expression of DAB2 and its regulation of inflammatory factors under conditions of Sporothrix schenckii infection. Our results indicated that the Sporothrix schenckii infection increased the expression of DAB2 and revealed a mixed M1/M2-like type of gene expression in BMDMs with the inhibited Il-6, Il1-ß and Arg-1 and induced Tnf-α, Il-10 and Mgl-1. The deficiency of Dab2 gene suspended the changes of cytokines. In addition, JNK activity in BMDMs was inhibited by Sporothrix schenckii infection, leading to an increase in c-JUN. We also identified c-JUN as a transcription factor for Dab2 through chromatin immunoprecipitation and luciferase reporter assays. In an in vivo mouse model, sporotrichosis-induced skin lesions were accompanied with an upregulation of c-JUN and inhibition of JNK activity, which were in accord with findings from in vitro experiments. Taken together, these findings indicate that in the early stages of Sporothrix schenckii infection there is a promotion of DAB2 expression through the JNK/c-JUN pathway, effects that can then control the expression of inflammatory factors.

A multi center real world observation to evaluate the efficacy of cryotherapy versus local hyperthermia for the treatment of plane warts.

Most plane warts are recalcitrant to treatment. Both cryotherapy and local hyperthermia have been applied to treat plane warts. However, no direct comparative study on their respective efficacy and safety has ever been performed. To assess the efficacy and safety of local hyperthermia at 43 ± 1°C versus liquid nitrogen cryotherapy for plane warts. Sequential patients with plane warts entered the study, either receiving cryotherapy or local hyperthermia therapy at the discretion of the patients and the recommendations of consultants. Cryotherapy with liquid nitrogen was delivered in two sessions 2 weeks apart, while local hyperthermia was delivered on three consecutive days, plus two similar treatments 10 ± 3 days later. The temperature over the treated skin surface was set at 43 ± 1°C for 30 min in each session. The primary outcome was the clearance rates of the lesions 6 months after treatment. Among the 194 participants enrolled, 183 were included in the analysis at 6 months. Local hyperthermia and cryotherapy achieved clearance rates of 35.56% (48/135) and 31.25% (15/48), respectively (p = 0.724); recurrence rates of 16.67% (8/48) and 53.33% (8/15) (p = 0.01); and adverse events rates of 20.74% (28/135) and 83.33% (40/48), respectively (p < 0.001). Cryotherapy had a higher pain score (p < 0.001) and a longer healing time (p < 0.001). Local hyperthermia at 43°C and cryotherapy had similar efficacy for plane warts. Local hyperthermia had a safer profile than cryotherapy but it required more treatment visits during a treatment course. More patients preferred local hyperthermia due to its treatment friendly nature.

Local Hyperthermia Versus Cryotherapy for Treatment of Plantar Warts: A Prospective Multi-centre Non-randomized Concurrent Controlled Clinical Trial.

Cryotherapy is one of the most common treatments for warts; however, pain during treatment and relatively high recurrence rates limit its use. Local hyperthermia has also been used successfully in the treatment of plantar warts. The aim of this study was to compare the clinical effectiveness of local hyperthermia vs cryotherapy for the treatment of plantar warts. This multi- centre, open, 2-arm, non-randomized concurrent controlled trial included 1,027 patients, who received either cryotherapy or local hyperthermia treatment. Three months after treatment, local hyperthermia and cryotherapy achieved complete clearance rates of 50.9% and 54.3%, respectively. Recurrence rates were 0.8% and 12%, respectively. Pain scores during local hyperthermia were significantly lower than for cryotherapy. Both local hyperthermia and cryotherapy demonstrated similar efficacy for clearance of plantar warts; while local hyperthermia had a lower recurrence rate and lower pain sensation during treatment.

A multicenter retrospective analysis of the clinical and pathological characteristics of 1188 cases of actinic keratosis in different ultraviolet radiation intensity areas of China.

BACKGROUND: Actinic keratosis (AK) is a precancerous disease, caused by ultraviolet radiation (UV). OBJECTIVE: To analyze the clinical and pathological characteristics of AK in four areas with different ultraviolet radiation intensities. METHODS: 1188 diagnosed AK patients, from January 2000 to July 2015, in dermatology department of four hospitals were collected. The UV intensity of hospital located cities from high to low is Kunming, Yinchuan, Shenyang and Nanjing. The information comes from medical records, and the pathological types and Keratinocyte Intraepithelial Neoplasia (KIN) grades were checked by two experienced pathologists. All information was conducted a retrospective multicenter research. RESULTS: The patients were mainly middle-aged and elderly female, which was in direct contrast to the majority of men in European. The age of onset in Kunming group was lower than that in Yinchuan Group (p = 0.013) and Nanjing Group (p < 0.01). The course of disease in Kunming group was significantly shorter than that in Nanjing Group (p < 0.001). The lesions were almost located in the exposed area. The proportion of unexposed areas in Shenyang group was significantly higher than that in other groups (p < 0.001). There were statistical differences in pathological morphological classification among the four groups. These differences were not affected by age and gender. The number of KIN III grade patients in Shenyang group was significantly higher than that in other three groups (p < 0.05). CONCLUSION: The Asian patients were mainly female. The clinical characteristics of AK are closely related to UV intensity, and environmental pollution, lifestyle, religious beliefs and other factors are also related.

Efficacy and safety of Resveratrol combined with Ablative Fractional CO2 laser system in the treatment of skin photoaging.

OBJECTIVE: To evaluate the efficacy and safety of resveratrol combined with ablative fractional CO2  laser system (AFL) treating skin photoaging. METHODS: Thirty-two subjects were assigned to the treatment group (TG) or the control group (CG), respectively, applied test product (resveratrol essence) or control product twice daily for 6 months. Each subject was given an AFL treatment or no laser treatment on left or right side of the face randomly. Subjective evaluations by investigators and subjects themselves were conducted after treatment. Melanin index, erythema index, and cuticle moisture content were conducted at baseline and after treatments. Adverse events (AEs) were evaluated during the study period. RESULTS: All subjects in TG achieved improvements of their photoaging signs compared to pre-treatment both the laser side and the non-laser side at 6 months (p < 0.05). On the laser side, TG produced a better improvement than CG at 6 months (p < 0.05). On the laser side, the difference values of MI in TG at the 2 months after enrollment (M2), M3, and M4 were more obvious than those in CG (p < 0.05). On the non-laser side, the difference values of MI in TG at M3, M4, M5, and M6 were more obvious than those of CG (p < 0.05). Subjects in TG were more likely to have tingling and had a faster subsidence of erythema mild edema, and pigmentation induced by AFL compared to CG. CONCLUSION: The resveratrol can improve photoaging alone and add an efficacy to the AFL treatment and subside the AEs induced by AFL.

Exogenous Local Hyperthermia at 41℃ Is Effective to Eliminate Mouse Model of Sporotrichosis, Independent of Neutrophil Extracellular Traps Formation.

BACKGROUND: Local hyperthermia is recommended for the treatment of patients with fixed cutaneous sporotrichosis, though the effectiveness and mechanisms of action remain elusive. While neutrophils represent the main inflammatory cells associated with sporotrichosis lesions, the issue of whether hyperthermia is involved with interactions between neutrophils and Sporothrix globosa remains unclear. OBJECTIVE: To evaluate the effect of local hyperthermia on sporotrichosis and determine whether local hyperthermia involves effects of neutrophils against Sporothrix. METHODS: For the in vivo study, mice were infected with yeast cells of S. globosa followed by treatment with local hyperthermia. In vitro, an isolated Sporothrix strain was co-cultured with or without neutrophils and subjected under different temperatures. Immunofluorescence was used to assess the formation of neutrophil extracellular trap (NETs) were formed under these different culture conditions and the number of fungi colony forming units were compared. RESULTS: Hyperthermia was significantly more effective in clearing the lesions in the mouse model, as compared to sham treatment. Neutrophils failed to exert any fungicidal effects against S. globosa in response to hyperthermia. Moreover, NETs were formed after interaction with S. globosa, and the percentage of NETs formed was not significantly different at 41℃ or 37℃. CONCLUSION: While hyperthermia could serve as an effective therapy for fixed cutaneous sporotrichosis, this ability does not involve the formation of NETs.

Distinct miRNA Gene Expression Profiles Among the Nodule Tissues of Lung Sarcoidosis, Tuberculous Lymphadenitis and Normal Healthy Control Individuals.

Background: Sarcoidosis and tuberculosis share similarities in clinical manifestations and histopathological features. We aimed to identify the microRNA (miRNA) profiles of the lymph nodes of individuals with sarcoidosis and of those with tuberculous lymphadenitis to investigate the value of miRNAs in the differential diagnosis of sarcoidosis and tuberculous lymphadenitis. Methods: The miRNA profiles of the lymph nodes of individuals with sarcoidosis, those with tuberculous lymphadenitis (TBLN) and controls were detected by miRNA microarray analysis in the age- and sex-matched development group of the controls (n = 3), patients with TBLN (n = 3) and patients with sarcoidosis (n = 3), and the results were validated by quantitative real-time polymerase chain reaction in the validation group of the controls (n = 30), TBLN (n = 30) and patients with sarcoidosis (n = 31). The relationship between miRNA expression and the clinical parameters of sarcoidosis was analyzed. Results: miR-145, miR-185-5p, miR-301, miR-425-5P, miR-449b and miR-885-5P were differentially expressed between individuals with sarcoidosis and controls (P < 0.0001, P < 0.0001, P = 0.0008, P = 0.0002, P = 0.0018, and P < 0.0001, respectively), and the same six miRNAs were differentially expressed between individuals with tuberculous lymphadenitis and controls (P = 0.0002, P = 0.0004, P = 0.0238, P = 0.0006, P = 0.0149, and P = 0.0045, respectively). miR-185-5p was differentially expressed between individuals with tuberculous lymphadenitis and those with sarcoidosis (P = 0.0101). The area under the receiver operating characteristic curve calculated for miR-185-5p was 0.6860, and the sensitivity and specificity of miR-185-5p for the differential diagnosis of sarcoidosis from TBLN were 61 and 80%, respectively. The levels of miR-145, miR-301, miR-425-5P, and miR-885-5P were positively correlated with CD4+/CD8+ T lymphocytes in bronchoalveolar lavage fluid. Conclusions: miRNAs in lymph nodes show similar expression patterns between individuals with sarcoidosis and those with tuberculous lymphadenitis, which were experimentally selected. miR-185-5p in the lymph nodes can be used as an auxiliary marker for the differential diagnosis of sarcoidosis and tuberculous lymphadenitis.