Integrated multiomics revealed adenosine signaling predict immunotherapy response and regulate tumor ecosystem of melanoma.

Extracellular adenosine is extensively involved in regulating the tumor microenvironment. Given the disappointing results of adenosine-targeted therapy trials, personalized treatment might be necessary, tailored to the microenvironment status of individual patients. Here, we introduce the adenosine signaling score (ADO-score) model using non-negative matrix fraction identified patient subtypes using publicly available melanoma dataset, which aimed to profile adenosine signaling-related genes and construct a model to predict prognosis. We analyzed 580 malignant melanoma samples and demonstrated its robust value for prognosis. Further investigation in immune checkpoint inhibitor dataset suggests its potential as a stratified factor of immune checkpoint inhibitor efficacy. We validated the power of the ADO-score at the protein level immunofluorescence in a melanoma cohort from Xiangya Hospital. More importantly, single-cell and spatial transcriptomic data highlighted the cell-specific expression patterns of adenosine signaling-related genes and the existence of adenosine signaling-mediated crosstalk between tumor cells and immune cells in melanoma. Our study reveals a robust connection between adenosine signaling and clinical benefits in melanoma patients and proposes a universally applicable adenosine signaling model, the ADO-score, in gene expression profiles and histological sections. This model enables us to more precisely and conveniently select patients who are likely to benefit from immunotherapy.

Cavitation-on-a-Chip Enabled Size-Specific Liposomal Drugs for Selective Pharmacokinetics and Pharmacodynamics.

The size of liposomal drugs has been demonstrated to strongly correlate with their pharmacokinetics and pharmacodynamics. While the microfluidic method successfully achieves the production of liposomes with well-controlled sizes across various buffer/lipid flow rate ratio (FRR) settings, any adjustments to the FRR inevitably influence the concentration, encapsulation efficiency (EE), and stability of liposomal drugs. Here we describe a controllable cavitation-on-a-chip (CCC) strategy that facilitates the precise regulation of liposomal drug size at any desired FRR. The CCC-enabled size-specific liposomes exhibited striking differences in uptake and biodistribution behaviors, thereby demonstrating distinct antitumor efficacy in both tumor-bearing animal and melanoma patient-derived organoid (PDO) models. Intriguingly, as the liposome size decreased to approximately 80 nm, the preferential accumulation of liposomal drugs in the liver transitioned to a predominant enrichment in the kidneys. These findings underscore the considerable potential of our CCC approach in influencing the pharmacokinetics and pharmacodynamics of liposomal nanomedicines.

One-Step Formation of Targeted Liposomes in a Versatile Microfluidic Mixing Device.

Targeted liposomes, as a promising carrier, have received tremendous attention in COVID-19 vaccines, molecular imaging, and cancer treatment, due to their enhanced cellular uptake and payload accumulation at target sites. However, the conventional methods for preparing targeted liposomes still suffer from limitations, including complex operation, time-consuming, and poor reproducibility. Herein, a facile and scalable strategy is developed for one-step construction of targeted liposomes using a versatile microfluidic mixing device (MMD). The engineered MMD provides an advanced synthesis platform for multifunctional liposome with high production rate and controllability. To validate the method, a programmed death-ligand 1 (PD-L1)-targeting aptamer modified indocyanine green (ICG)-liposome (Apt-ICG@Lip) is successfully constructed via the MMD. ICG and the PD-L1-targeting aptamer are used as model drug and targeting moiety, respectively. The Apt-ICG@Lip has high encapsulation efficiency (89.9 ± 1.4%) and small mean diameter (129.16 ± 5.48 nm). In vivo studies (PD-L1-expressing tumor models) show that Apt-ICG@Lip can realize PD-L1 targeted photoacoustic imaging, fluorescence imaging, and photothermal therapy. To verify the versatility of this approach, various targeted liposomes with different functions are further prepared and investigated. These experimental results demonstrate that this method is concise, efficient, and scalable to prepare multifunctional targeted liposomal nanoplatforms for molecular imaging and disease theranostics.

Wider indications and more efficient drug delivery: A bibliometric analysis and visualization of photodynamic therapy in skin cancer.

BACKGROUND: Photodynamic therapy (PDT) has been widely accepted in keratocyte carcinoma and an increasing number of literatures concerning PDT in skin cancer is published. But a detailed examination of publication patterns of PDT in skin cancer has not yet been carried out. METHODS: Bibliographies were retrieved from Web of Science Core Collection restricted the publication date from January 1, 1985 to December 31, 2021. The search terms were photodynamic therapy and skin cancer. Visualization analysis and statistical analysis were performed by VOSviewer (Version 1.6.13), R software (Version 4.1.2) and Scimago Graphica (Version 1.0.15). RESULTS: 3248 documents were selected for analysis. The results showed that the number of annual publications related to PDT in skin cancer was gradually increased and would continue to increase in the future. The results illustrated that "melanoma", "nanoparticles", "drug-delivery", "mechanism", "delivery" and "in-vitro" are newly occurred topics. The most prolific country was the United States and the most productive institution was the University of Sao Paulo in Brazil. German researcher Szeimies RM published the most papers related to PDT in skin cancer. British Journal of Dermatology was the most popular journal in this field. CONCLUSION: The topic that PDT in skin cancer is a heated issue. Our study revealed the bibliometric result of the field, which might provide the prospects for further research. We recommend future investigations focusing on PDT in treating melanoma, innovation of photosensitizer, improvement of drug delivery and the mechanism of PDT in skin cancer.

Artificial Intelligence-Based Psoriasis Severity Assessment: Real-world Study and Application.

BACKGROUND: Psoriasis is one of the most frequent inflammatory skin conditions and could be treated via tele-dermatology, provided that the current lack of reliable tools for objective severity assessments is overcome. Psoriasis Area and Severity Index (PASI) has a prominent level of subjectivity and is rarely used in real practice, although it is the most widely accepted metric for measuring psoriasis severity currently. OBJECTIVE: This study aimed to develop an image-artificial intelligence (AI)-based validated system for severity assessment with the explicit intention of facilitating long-term management of patients with psoriasis. METHODS: A deep learning system was trained to estimate the PASI score by using 14,096 images from 2367 patients with psoriasis. We used 1962 patients from January 2015 to April 2021 to train the model and the other 405 patients from May 2021 to July 2021 to validate it. A multiview feature enhancement block was designed to combine vision features from different perspectives to better simulate the visual diagnostic method in clinical practice. A classification header along with a regression header was simultaneously applied to generate PASI scores, and an extra cross-teacher header after these 2 headers was designed to revise their output. The mean average error (MAE) was used as the metric to evaluate the accuracy of the predicted PASI score. By making the model minimize the MAE value, the model becomes closer to the target value. Then, the proposed model was compared with 43 experienced dermatologists. Finally, the proposed model was deployed into an app named SkinTeller on the WeChat platform. RESULTS: The proposed image-AI-based PASI-estimating model outperformed the average performance of 43 experienced dermatologists with a 33.2% performance gain in the overall PASI score. The model achieved the smallest MAE of 2.05 at 3 input images by the ablation experiment. In other words, for the task of psoriasis severity assessment, the severity score predicted by our model was close to the PASI score diagnosed by experienced dermatologists. The SkinTeller app has been used 3369 times for PASI scoring in 1497 patients from 18 hospitals, and its excellent performance was confirmed by a feedback survey of 43 dermatologist users. CONCLUSIONS: An image-AI-based psoriasis severity assessment model has been proposed to automatically calculate PASI scores in an efficient, objective, and accurate manner. The SkinTeller app may be a promising alternative for dermatologists' accurate assessment in the real world and chronic disease self-management in patients with psoriasis.

Preoperative Ultrasound-Guided Incisional Biopsy Enhances the Pathological Accuracy of Incisional Biopsy of Cutaneous Melanoma: A Prospective Clinical Trial in Chinese Patients.

OBJECTIVES: To assess the feasibility of preoperative ultrasound (US)-guided incisional biopsy through a prospective controlled clinical trial. METHODS: This was a prospective, double-arm, single-center study of Chinese patients. Thirty patients were enrolled in the study. Fourteen patients received incisional biopsies for which the choice of biopsy area relied on a clinical evaluation, and 16 patients received incisional biopsies for which the choice of biopsy area relied on a US-guided evaluation. The following procedure was used in the US-guided incisional biopsy group: 1) clinical and dermoscopic evaluation of skin lesions; 2) US examination; 3) incisional biopsy; 4) surgical excision; and 5) histopathological examination. The same procedure was used in the non-US-guided group except without US examination. RESULTS: In the non-US-guided group, the mean tumor thicknesses obtained from incisional biopsy and postoperative histopathological examination were 2.1 and 4.1 mm, respectively. Seven melanomas were underestimated by incisional biopsy, resulting in margins narrower than currently recommended. In the US-guided group, the mean tumor thicknesses obtained from US, incisional biopsy, and postoperative histopathological examination were 3.4, 2.9, and 2.7 mm, respectively. In only 3 melanomas was the tumor thickness of the incisional biopsy less than that of the postoperative histopathological examination, demonstrating that US-guided biopsy obtains the maximum thickness area. CONCLUSIONS: Preoperative US-guided incisional biopsy can enhance the pathological accuracy of incisional biopsy, which may allow us to better perform surgical excision with safe peripheral surgical margins.

Research Trends in Immune Checkpoint Blockade for Melanoma: Visualization and Bibliometric Analysis.

BACKGROUND: Melanoma is one of the most life-threatening skin cancers; immune checkpoint blockade is widely used in the treatment of melanoma because of its remarkable efficacy. OBJECTIVE: This study aimed to conduct a comprehensive bibliometric analysis of research conducted in recent decades on immune checkpoint blockade for melanoma, while exploring research trends and public interest in this topic. METHODS: We summarized the articles in the Web of Science Core Collection on immune checkpoint blockade for melanoma in each year from 1999 to 2020. The R package bibliometrix was used for data extraction and visualization of the distribution of publication year and the top 10 core authors. Keyword citation burst analysis and cocitation networks were calculated with CiteSpace. A Gunn online world map was used to evaluate distribution by country and region. Ranking was performed using the Standard Competition Ranking method. Coauthorship analysis and co-occurrence were analyzed and visualized with VOSviewer. RESULTS: After removing duplicates, a total of 9169 publications were included. The distribution of publications by year showed that the number of publications rose sharply from 2015 onwards and either reached a peak in 2020 or has yet to reach a peak. The geographical distribution indicated that there was a large gap between the number of publications in the United States and other countries. The coauthorship analysis showed that the 149 top institutions were grouped into 8 clusters, each covering approximately a single country, suggesting that international cooperation among institutions should be strengthened. The core author extraction revealed changes in the most prolific authors. The keyword analysis revealed clustering and top citation bursts. The cocitation analysis of references from 2010 to 2020 revealed the number of citations and the centrality of the top articles. CONCLUSIONS: This study revealed trends in research and public interest in immune checkpoint blockade for melanoma. Our findings suggest that the field is growing rapidly, has several core authors, and that the United States is taking the lead position. Moreover, cooperation between countries should be strengthened, and future research hot spots might focus on deeper exploration of drug mechanisms, prediction of treatment efficacy, prediction of adverse events, and new modes of administration, such as combination therapy, which may pave the way for further research.

The Classification of Six Common Skin Diseases Based on Xiangya-Derm: Development of a Chinese Database for Artificial Intelligence.

BACKGROUND: Skin and subcutaneous disease is the fourth-leading cause of the nonfatal disease burden worldwide and constitutes one of the most common burdens in primary care. However, there is a severe lack of dermatologists, particularly in rural Chinese areas. Furthermore, although artificial intelligence (AI) tools can assist in diagnosing skin disorders from images, the database for the Chinese population is limited. OBJECTIVE: This study aims to establish a database for AI based on the Chinese population and presents an initial study on six common skin diseases. METHODS: Each image was captured with either a digital camera or a smartphone, verified by at least three experienced dermatologists and corresponding pathology information, and finally added to the Xiangya-Derm database. Based on this database, we conducted AI-assisted classification research on six common skin diseases and then proposed a network called Xy-SkinNet. Xy-SkinNet applies a two-step strategy to identify skin diseases. First, given an input image, we segmented the regions of the skin lesion. Second, we introduced an information fusion block to combine the output of all segmented regions. We compared the performance with 31 dermatologists of varied experiences. RESULTS: Xiangya-Derm, as a new database that consists of over 150,000 clinical images of 571 different skin diseases in the Chinese population, is the largest and most diverse dermatological data set of the Chinese population. The AI-based six-category classification achieved a top 3 accuracy of 84.77%, which exceeded the average accuracy of dermatologists (78.15%). CONCLUSIONS: Xiangya-Derm, the largest database for the Chinese population, was created. The classification of six common skin conditions was conducted based on Xiangya-Derm to lay a foundation for product research.

Topical antimitotic treatments for plantar warts are more beneficial: A Bayesian network meta-analysis of randomized controlled trials.

BACKGROUND: Plantar warts are common infectious cutaneous growths causing severe physiological and psychological discomforts in patients and heaving global financial burdens. However, paucity of clear-cut guidelines for plantar warts, selecting appropriate treatments for plantar warts remains challenging. The objective of the study is to evaluate the efficacy and safety of common treatments for plantar warts. METHODS: PubMed, EMbase, and The Cochrane Library were searched from inception to March 1, 2023 for randomized controlled trials (RCTs) of plantar warts. The primary outcome (complete response) and secondary outcome (recurrence and pain) were extracted and combined using Bayesian network meta-analysis (NMA) with random-effect and fixed-effect models. RESULTS: Totally, 33 RCTs were included in the systematic review and quantitative NMA. In NMA of complete response, topical application of 1% cantharidin, 20% podophylotoxin, 30% salicylic acid (CPS), microneedles plus bleomycin (MNB), and intralesional bleomycin injection (INB) were the only three treatments significantly superior to no treatment (NT) and CPS was of the highest possibility to be the top-ranked treatment (SUCRA = 0.9363). However, traditional warts treatments, salicylic acid (SA) and cryotherapy were not superior to NT. CONCLUSIONS: The NMA has produced evidence for using CPS, MNB, and INB, which are all topical antimitotic treatments, to improve the management of plantar warts. The classic treatment modalities for plantar warts, including SA and cryotherapy, may play a less important role in the clinical practice of plantar warts.

Corrigendum: The utility of high-frequency 18 MHz ultrasonography for preoperative evaluation of acral melanoma thickness in Chinese patients.

[This corrects the article DOI: 10.3389/fonc.2023.1185389.].

Liposomes Loaded with 5-Fluorouracil Can Improve the Efficacy in Pathological Scars.

Introduction: Pathological scars, such as hypertrophic scars and keloids, are characterized by the proliferation of fibroblasts and the deposition of collagen that often cause pruritus, pain, and disfigurement. Due to their high incidence and deformity, pathological scars have resulted in severe physical and psychological trauma for patients. Intralesional injection of 5-fluorouracil (5-Fu) is a recommended option for treating pathological scars. However, the efficacy of 5-Fu injection was limited and unstable due to limited drug penetration and short retention time. Methods: Liposomes are promising carriers that have advantages, such as high biocompatibility, controlled release property, and enhanced clinical efficacy. Here, we constructed a transdermal 5-Fu-loaded liposome (5-Fu-Lip) to provide a more effective and safer modality to scar treatment. Results: Compared to 5-Fu, 5-Fu-Lip showed superior ability in inhibiting primary keloid fibroblasts proliferation, migration, and collagen deposition, and also significantly inhibited human umbilical vein endothelial cells (HUVECs) proliferation and microvessel construction. In vivo experiments demonstrated that 5-Fu-Lip can significantly reduce the severity of hypertrophic scars in a rabbit ear wounding model. Discussion: 5-Fu-Lip provides a promising strategy to improve drug efficacy, which has great potential in the treatment of pathological scars.

Low-Frequency Ultrasound Sensitive Piezo1 Channels Regulate Keloid-Related Characteristics of Fibroblasts.

Keloids are benign fibroproliferative tumors that severely diminish the quality of life due to discomfort, dysfunction, and disfigurement. Recently, ultrasound technology as a noninvasive adjuvant therapy is developed to optimize treatment protocols. However, the biophysical mechanisms have not yet been fully elucidated. Here, it is proposed that piezo-type mechanosensitive ion channel component 1 (Piezo1) plays an important role in low-frequency sonophoresis (LFS) induced mechanical transduction pathways that trigger downstream cellular signaling processes. It is demonstrated that patient-derived primary keloid fibroblasts (PKF), NIH 3T3, and HFF-1 cell migration are inhibited, and PKF apoptosis is significantly increased by LFS stimulation. And the effects of LFS is diminished by the application of GsMTx-4, the selective inhibitor of Piezo1, and the knockdown of Piezo1. More importantly, the effects of LFS can be imitated by Yoda1, an agonist of Piezo1 channels. Establishing a patient-derived xenograft keloid implantation mouse model further verified these results, as LFS significantly decreased the volume and weight of the keloids. Moreover, blocking the Piezo1 channel impaired the effectiveness of LFS treatment. These results suggest that LFS inhibits the malignant characteristics of keloids by activating the Piezo1 channel, thus providing a theoretical basis for improving the clinical treatment of keloids.

A piezoelectric-driven microneedle platform for skin disease therapy.

With over a million cases detected each year, skin disease is a global public health problem that diminishes the quality of life due to its difficulty to eradicate, propensity for recurrence, and potential for post-treatment scarring. Photodynamic therapy (PDT) is a treatment with minimal invasiveness or scarring and few side effects, making it well tolerated by patients. However, this treatment requires further research and development to improve its effective clinical use. Here, a piezoelectric-driven microneedle (PDMN) platform that achieves high efficiency, safety, and non-invasiveness for enhanced PDT is proposed. This platform induces deep tissue cavitation, increasing the level of protoporphyrin IX and significantly enhancing drug penetration. A clinical trial involving 25 patients with skin disease was conducted to investigate the timeliness and efficacy of PDMN-assisted PDT (PDMN-PDT). Our findings suggested that PDMN-PDT boosted treatment effectiveness and reduced the required incubation time and drug concentration by 25% and 50%, respectively, without any anesthesia compared to traditional PDT. These findings suggest that PDMN-PDT is a safe and minimally invasive approach for skin disease treatment, which may improve the therapeutic efficacy of topical medications and enable translation for future clinical applications.

A real-time augmented reality system integrated with artificial intelligence for skin tumor surgery: experimental study and case series.

BACKGROUND: Skin tumors affect many people worldwide, and surgery is the first treatment choice. Achieving precise preoperative planning and navigation of intraoperative sampling remains a problem and is excessively reliant on the experience of surgeons, especially for Mohs surgery for malignant tumors. MATERIALS AND METHODS: To achieve precise preoperative planning and navigation of intraoperative sampling, we developed a real-time augmented reality (AR) surgical system integrated with artificial intelligence (AI) to enhance three functions: AI-assisted tumor boundary segmentation, surgical margin design, and navigation in intraoperative tissue sampling. Non-randomized controlled trials were conducted on manikin, tumor-simulated rabbits, and human volunteers in Hunan Engineering Research Center of Skin Health and Disease Laboratory to evaluate the surgical system. RESULTS: The results showed that the accuracy of the benign and malignant tumor segmentation was 0.9556 and 0.9548, respectively, and the average AR navigation mapping error was 0.644 mm. The proposed surgical system was applied in 106 skin tumor surgeries, including intraoperative navigation of sampling in 16 Mohs surgery cases. Surgeons who have used this system highly recognize it. CONCLUSIONS: The surgical system highlighted the potential to achieve accurate treatment of skin tumors and to fill the gap in global research on skin tumor surgery systems.

Superficial shaving combined with photodynamic therapy for treating verrucous epidermal nevi: A case report.

Verrucous epidermal nevi is a refractory skin disease. Photodynamic therapy is considered a third-line treatment for verrucous epidermal nevi due to its unstable efficacy and high recurrence rate, mainly because of its limited depth of penetration. In this case, we conducted a successful treatment using superficial shaving combined with photodynamic therapy to treat verrucous epidermal nevi and gained a satisfactory efficacy. Before photodynamic therapy treatment, the epidermis in situ of each lesion in the tissue is removed with superficial shaving. Removal of the epidermal layer by intentional in situ injury improves the diffusion and absorption of topically applied photosensitizers and enhances the efficacy of photodynamic therapy. Our results show that photodynamic therapy combined with superficial shaving maybe is a safe and effective treatment for verrucous epidermal nevi.