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.].

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

Background: Despite the increasing use of preoperative ultrasound evaluation for melanoma, there is limited research on the use of this technique for Acral Melanoma (AM). Methods: This retrospective study analyzed the electronic medical records of patients who underwent preoperative evaluation for cutaneous melanoma maximum thickness using an 18 MHz probe and histopathological examination between December 2017 and March 2021 at the Department of Dermatology in Xiangya Hospital, Central South University. Results: A total of 105 patients were included in the study. The mean tumor thickness was 3.9 mm (s.d., 2.3), with 63% of the specimens showing ulceration and 44 patients showing lymph node metastasis. The results showed a good correlation between the high-frequency ultrasonography (HFUS) and histopathological thickness measurements, with a Spearman's correlation coefficient of 0.83 [(95% CI 0.73-0.90) (P < 0.001)]. The positive predictive value (PPV) of sonography in identifying tumor thickness was also found to be high. Conclusion: Our study suggests that high-frequency 18 MHz ultrasonography is an effective tool for the preoperative evaluation of AM thickness. The HFUS measurements correlated well with the histopathological thickness measurements, making it a valuable and reliable method for clinicians to assess the thickness of melanoma lesions preoperatively.

Inhibition of stress proteins TRIB3 and STC2 potentiates sorafenib sensitivity in hepatocellular carcinoma.

Sorafenib resistance is one of the main obstacles to the treatment of advanced hepatocellular carcinoma (HCC). Stress proteins TRIB3 and STC2 confer cell resistance to a variety of stresses, including hypoxia, nutritional deprivation, and other perturbations, which induce endoplasmic reticulum stress. However, the role of TRIB3 and STC2 in sorafenib sensitivity to HCC remains unclear. In this study, our results indicated that the common differentially expressed genes (DEGs) in sorafenib-treated HCC cells obtained from the NCBI-GEO database (Huh7 and Hep3B cells; GSE96796) included TRIB3, STC2, HOXD1, C2orf82, ADM2, RRM2, and UNC93A. The most significantly upregulated DEGs were TRIB3 and STC2, which were both stress protein genes. Bioinformatic analysis in NCBI public databases indicated that TRIB3 and STC2 were highly expressed in HCC tissues and closely associated with poor prognoses in HCC patients. Further investigation showed that inhibition of TRIB3 or STC2 with siRNA could enhance the anti-cancer effect of sorafenib in HCC cell lines. In conclusion, our study showed that stress proteins TRIB3 and STC2 are closely associated with sorafenib resistance in HCC. The combination of TRIB3 or STC2 inhibition and sorafenib may be a promising therapeutic strategy for HCC.

3D-Printed Integrated Ultrasonic Microneedle Array for Rapid Transdermal Drug Delivery.

Transdermal drug delivery (TDD) is an attractive alternative to oral and hypodermic injection drug administration, and is poised to increase its impact on medicine and pharmaceutical design. Microneedles (MNs) are a new minimally invasive TDD method widely used in medicine and cosmetology. MNs create a microscale channel from the stratum corneum to the dermis and enable drug delivery of hydrophilic and macromolecular into the skin. Although MNs allow different drugs to penetrate the stratum corneum, they cannot provide an extra driving force for drug transport in tissue. To overcome this limitation and achieve fast, controllable drug delivery, an integrated 3D-printed ultrasonic MN array (USMA) device consisting of hollow MNs and an ultrasonic transducer is proposed. The hollow MNs enable drug to penetrate the stratum corneum, and the ultrasound transmitted through the MNs provides the driving force for drug transportation in tissue. Using methylene blue and bovine serum albumin as model drugs, we tested the drug delivery performance of USMA on porcine skin; the results show that USMA significantly enhanced the delivery efficiency of model drugs. Besides, USMA obviously reduced MNs insertion force and tissue damage, which were well-tolerated and gentle. This study suggests that the integrated ultrasonic MN array has great potential for clinical drug delivery with high efficiency and lessening the suffering of patients.

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.

Dermabrasion combined with photodynamic therapy: a new option for the treatment of non-melanoma skin cancer.

Non-melanoma skin cancer (NMSC) is the most common malignancy. Photodynamic therapy (PDT) is effective for the treatment of certain NMSCs. However, the clinical response rates of some NMSCs to single PDT are still far from ideal. The reason may be that PDT has shown limited efficacy in managing thicker NMSCs. To explore the efficacy and safety of dermabrasion combined with PDT (D-PDT) for the treatment of NMSCs. This was a retrospective, single-arm, multi-centre study. In total, 172 tumours from 40 patients were treated with D-PDT during the study period. The mean follow-up period was 40 months (range 15-110 months). D-PDT was performed with 633-nm red light at 80 m W/cm2 after lesion dermabrasion and 4 h of photosensitizer exposure. Six nodular basal cell carcinomas (nBCCs) from 6 patients, 9 squamous cell carcinomas (SCCs) from 9 patients, 17 Bowen diseases (BDs) from 10 patients and 140 actinic keratoses (AKs) from 15 patients treated with D-PDT were examined in this study. Only two patients with three AKs experienced recurrence over 12 months. The mean final follow-up periods of patients with AKs, BDs, nBCCs and SCCs were 30, 33, 45 and 60 months, respectively. Thirty-four of the 40 patients treated with D-PDT reported excellent or good cosmetic results. The mean Dermatology Life Quality Index (DLQI) scores of the patients improved significantly after treatment (estimated MD 9.72 [95% CI 8.69 to 10.75]; p < 0.001). D-PDT is a safe, cosmetic and effective treatment that could be a new candidate therapeutic for NMSC.

ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing of diabetic foot ulcers.

BACKGROUND: Adipose-derived mesenchymal stem cells (ADSCs) are an important focus in regenerative medicine. However, the biological function of ADSCs in the wound repair of diabetic foot ulcers (DFUs) remains unclear. This study aimed to determine the underlying mechanisms of ADSCs involved in the wound healing of DFUs. METHODS: The cell surface markers cluster of differentiation 34 (CD34), stromal cell antigen 1 (Stro-1), cluster of differentiation 90 (CD90) and cluster of differentiation 105 (CD105) on ADSCs were identified by flow cytometry. Oil Red O staining and Alizarin Red S staining were performed to identify the multipotential differentiation of ADSCs into adipocytes and bone. The levels of Methyltransferase-like 3 (METTL3), vascular endothelial growth factor C (VEGF-C) and insulin-like growth factor 2 binding protein 2 (IGF2BP2) were assessed by RT-qPCR. CCK-8, Transwell and tubule formation assays were conducted to assess lymphatic endothelial cell (LEC) viability, migration and tubule formation ability, respectively. RIP and RNA pulldown assays were conducted to assess the interaction between IGF2BP2 and VEGF-C. The levels of VEGF-C, VEGFR3, LYVE-1 and IGF2BP2 proteins were assessed by Western blotting. The levels of VEGF-C in LECs were measured by ELISA. RESULTS: Our findings illustrated that ADSCs accelerate LEC proliferation, migration and lymphangiogenesis via the METTL3 pathway and regulate VEGF-C expression via the METTL3/IGF2BP2-m6A pathway VEGF-C-mediated lymphangiogenesis via the METTL3/IGF2BP2-m6A pathway in DFU mice. CONCLUSION: ADSCs enhance VEGFR3-mediated lymphangiogenesis via METTL3-mediated VEGF-C m6A modification to improve wound healing in DFUs, indicating that ADSCs may be regarded as a promising therapeutic strategy to promote wound healing in DFUs.

Ultrasound-Mediated Microbubble Destruction Inhibits Skin Melanoma Growth by Affecting YAP1 Translation Using Ribosome Imprinting Sequencing.

Cutaneous melanoma (CMM) is a skin tumor with a high degree of malignancy. BRAF resistance imposes great difficulty to the treatment of CMM, and partially contributes to the poor prognosis of CMM. YAP is involved in the growth and drug resistance of a variety of tumors, and mechanical signals may affect the activation of YAP1. As a novel ultrasound treatment technology, ultrasound-mediated microbubble destruction (UMMD) has been reported to have a killing effect on isolated CMM cells. In this study, the tumor tissue samples were collected from 64 CMM patients. We found that YAP1 mRNA expression was irrelevant to the clinicopathological characteristics and prognostic survival of the CMM patients. The drug-resistant cell line was constructed and subcutaneously implanted into nude mice, which were further separately treated with UMMD, ultrasound (US), and microbubbles (MB). The result showed that UMMD significantly inhibited the growth of tumor tissues. Ribosome imprinting sequencing (Ribo-seq) is a genetic technology for studying protein translation at genetic level. Ribo-seq, RNA-seq, and RT-qPCR were applied to detect YAP1 expression in CMM mouse tumor tissues. Ribo-seq data revealed that UMMD greatly up-regulated the expression of YAP1, interestingly, the up-regulated YAP1 was found to be negatively correlated with the weight of tumor tissues, while no significant change in YAP1 expression was detected by RNA-seq or RT-qPCR assay. These results indicated that UMMD could inhibit the tumor growth of drug-resistant CMM by affecting the translation efficiency of YAP1, providing a strong basis for the clinical treatment of UMMD in CMM.

Long noncoding RNA-antisense noncoding RNA in the INK4 locus accelerates wound healing in diabetes by promoting lymphangiogenesis via regulating miR-181a/Prox1 axis.

BACKGROUND: Slow lymphangiogenesis is one crucial reason for the impaired wound healing process in diabetes. Accumulative evidence showed that long noncoding RNA-antisense noncoding RNA in the INK4 locus (ANRIL) could influence lymphangiogenesis. Besides, miR-181a has been reported to regulate Prox1 that is essential for lymphangiogenesis. However, the relationship between ANRIL and miR-181a as well as the definitive function of ANRIL in lymphangiogenesis is not clear. METHODS: The diabetic mouse model was set up to assess the wound healing rate in vivo. Quantitative real-time polymerase chain reaction was performed to measure the expressions of ANRIL, miR-181a, and Prox1. Western blot analysis was used to assess the expressions of vascular endothelial growth factor receptor-3, lymphatic vessel hyaluronan receptor-1, Prox1, and epithelial-mesenchymal transition (EMT)-related proteins. Flow cytometry was used to assess the cell apoptosis. Wound healing assay was used to determine the effect of ANRIL on cell migration. Tube-formation assay and immunofluorescence staining were performed to determine tube-formation capacity of human dermal lymphatic endothelial cells (LECs). RESULTS: ANRIL and Prox1 were downregulated, whereas miR-181a was upregulated in the diabetic wound healing mouse model and high glucose (HG)-induced LECs. The wound healing rate and EMT were inhibited during the diabetic wound healing process. Dual-luciferase assay proved that miR-181a could bind Prox1 to repress its expression, whereas ANRIL could sponge miR-181a to recover Prox1 expression. Overexpression of ANRIL or inhibition of miR-181a rescued the impairments of survival, migration, EMT formation, and tube formation of LECs caused by HG. CONCLUSION: ANRIL could promote lymphangiogenesis during the diabetic wound healing process via sponging miR-181a to enhance Prox1 expression, which might help design new therapy to improve the wound healing efficacy for diabetes.

Salubrinal protects against cigarette smoke extract-induced HBEpC apoptosis likely via regulating the activity of PERK-eIF2α signaling pathway.

BACKGROUND AND AIMS: Endoplasmic reticulum (ER) stress plays an important role in cigarette smoke extract (CSE)-induced apoptotic cell death, which is an important pathogenic factor of chronic obstructive pulmonary disease (COPD). The aim of this study was to explore the role of the PERK-eIF2 pathway in CSE-induced human bronchial epithelial (HBE) cell apoptosis and to evaluate the protective effects and possible mechanism of salubrinal (Sal) on CSE-induced HBE cell apoptosis. METHODS: Normal human bronchial epithelial cells (HBEpC) were cultured and then treated with CSE alone or together with Sal or preincubated with or without PERK siRNA. Expressions of p-PERK/PERK, p-eIF2α/eIF2α, and caspase 3 and 4 were detected with PCR, Western blot, and immunofluorescence. Apoptosis was detected using AnnexinV-PI flow cytometry. RESULTS: CSE induced apoptotic cell death and caused a dynamic change in PERK-eIF2α pathway activity following the course of CSE exposure. The knockdown of PERK suppressed the expression of both PERK and p-eIF2a and caused a great increase in cell apoptosis. Sal could eliminate the effects of PERK knockdown, protecting the cells against the CSE insult, and this protection was accomplished through maintaining the homeostasis of PERK- eIF2α pathway. CONCLUSIONS: PERK-eIF2α pathway mediates the CSE-induced HBE cell apoptosis. The intactness of PERK-eIF2α pathway is crucial for HBE cell survival under CSE insult. Sal can protect against CSE-induced HBE cell apoptosis, and this effect is likely achieved through maintaining the homeostasis of PERK- eIF2α pathway.