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Abstract The rapid advancement of digital technology has not only affected the world of work but also students' learning. Digital learning competence (DLC) is one of the essential skills students need for effective learning in a digital environment. Despite the significant presence of secondary vocational school students in China, constituting one-third of the high school demographic, research on their digital learning needs remains sparse. Addressing this gap, this paper attempted to propose the elements and structural model of digital learning competence for secondary vocational school students (V-DLC). A corresponding questionnaire was compiled, and an analysis was carried out with 872 valid survey data of secondary vocational school students achieved by convenient sampling. A five-factor model for the V-DLC was established through exploratory and confirmatory factor analyses, cross-validity, and criterion validity tests. This paper suggests that evaluating students' digital learning competence in secondary vocational schools can be achieved by considering the dimensions of cognitive processing and reading, technology use, thinking skills, activity management, and will management, combined with students' learning experiences in school and other fields. Given the global focus on digital learning competence, this framework will pave the way for empirical research on digital learning and guide the enhancement of student learning ability in vocational settings, adapting to the digital era. Furthermore, transitioning to a digitalized vocational education system is essential for preparing students for a digitally-driven workforce, aligning with modern job market demands and global trends.

Abstract Background Facial infiltrating lipomatosis is characterized by excessive growth of adipose tissue. Its etiology is associated with somatic phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) variants, but the specific mechanisms are not yet fully understood. Methods We collected facial adipose tissue from both FIL patients and non-FIL individuals, isolated the stromal vascular fraction (SVF) and performed single-cell transcriptome sequencing on these samples. Results We mapped out the cellular landscape within the SVF, with a specific focus on a deeper analysis of fibro-adipogenic precursor cells (FAPs). Our analysis revealed that FAPs from FIL patients (FIL-FAPs) significantly overexpressed FK506 binding protein 51 (FKBP5) compared to FAPs from individuals without FIL. Further experiments indicated that FKBP5 is regulated by the PI3K-AKT signaling pathway. The overactivation of this pathway led to an increase in FKBP5 expression. In vitro experiments demonstrated that FKBP5 promoted adipogenic differentiation of FAPs, a process that could be hindered by FKBP5 knockdown or inhibition. Additionally, in vivo assessments confirmed FKBP5’s role in adipogenesis. Conclusions These insights into the pathogenesis of FIL underscore FKBP5 as a promising target for developing non-surgical interventions to manage the excessive adipose tissue growth in FIL.

Abstract Hemangioma of infancy is the most common vascular tumor during infancy and childhood. Despite the proven efficacy of propranolol treatment, certain patients still encounter resistance or face recurrence. The need for frequent daily medication also poses challenges to patient adherence. Bleomycin (BLM) has demonstrated effectiveness against vascular anomalies, yet its use is limited by dose-related complications. Addressing this, this study proposes a novel approach for treating hemangiomas using BLM-loaded hyaluronic acid (HA)-based microneedle (MN) patches. BLM is encapsulated during the synthesis of polylactic acid (PLA) microspheres (MPs). The successful preparation of PLA MPs and MN patches is confirmed through scanning electron microscopy (SEM) images. The HA microneedles dissolve rapidly upon skin insertion, releasing BLM@PLA MPs. These MPs gradually degrade within 28 days, providing a sustained release of BLM. Comprehensive safety assessments, including cell viability, hemolysis ratio, and intradermal reactions in rabbits, validate the safety of MN patches. The BLM@PLA-MNs exhibit an effective inhibitory efficiency against hemangioma formation in a murine hemangioma model. Of significant importance, RNA-seq analysis reveals that BLM@PLA-MNs exert their inhibitory effect on hemangiomas by regulating the P53 pathway. In summary, BLM@PLA-MNs emerge as a promising clinical candidate for the effective treatment of hemangiomas. Graphical Abstract

Congenital melanocytic nevi (CMN) are common skin tumors. Large and specially located nevi cannot be completely removed by surgery, posing the risks of both cosmetic deformities and potential malignancy. Nonsurgical treatments, such as laser therapy and physical dermabrasion, can overcome the limitations of surgery; however, the high rate of repigmentation remains an unresolved global challenge. We conducted a self-controlled observational study of a patient with a nevus on the chest. Two areas of the lesion were treated with an Er:YAG laser and 5% imiquimod cream was applied to one of these areas. After nearly 7-months of follow-up, we observed a significant difference in color between the two areas, suggesting that topical imiquimod may inhibit repigmentation and significantly enhance the effectiveness of laser treatment.

Abstract Background Lip infantile hemangiomas tend to show less volumetric regression and are more susceptible to visible sequelae in the involuted stage. Some of them still require surgical management after propranolol therapy. This study aimed to evaluate the efficacy and safety of the Stepwise, Multi-Incisional, and Single-Stage (SMISS) approach applied to lip reduction for those with involuted lip hemangiomas. Methods A retrospective review was performed to evaluate patients with lip hemangioma who received previous propranolol treatment and underwent the aforementioned procedure. Demographic characteristics, lesion morphology, and medical history were reviewed. The Visual Analog Scale was applied to assess the postoperative appearance. Complications within 12 months postoperatively were recorded. Results A total of 18 patients with lip hemangioma were eligible. All patients received oral propranolol therapy before surgery, with treatment duration ranging from 6.0 to 23.0 months. Their age at surgery ranged from 2.5 to 9.0 years. The median Visual Analog Scale scores were 8.0, ranging from 4.0 to 10.0. No severe complications were reported. Conclusions This modified technique based on the SMISS approach has proven reliable and effective in improving the aesthetic outcome for involuted lip infantile hemangiomas. Practical surgical techniques still play an important part in the propranolol era.

Summary: Facial infiltrating lipomatosis (FIL) is a congenital disorder. The pathogenesis of FIL is associated with PIK3CA mutations, but the underlying mechanisms remain undetermined. We found that the adipose tissue in FIL demonstrated adipocytes hypertrophy and increased lipid accumulation. All adipose-derived mesenchymal stem cells from FIL (FIL-ADSCs) harbored PIK3CA mutations. Moreover, FIL-ADSCs exhibited a greater capacity for adipogenesis. Knockdown of PIK3CA resulted in a reduction in the adipogenic potential of FIL-ADSCs. Furthermore, WX390, a dual-target PI3K/mTOR inhibitor, was found to impede PIK3CA-mediated adipogenesis both in vivo and in vitro. RNA sequencing (RNA-seq) revealed that the expression of transient receptor potential vanilloid subtype 1 (TRPV1) was upregulated after PI3K pathway inhibition, and overexpression or activation of TRPV1 both inhibited adipogenesis. Our study showed that PIK3CA mutations promoted adipogenesis in FIL-ADSCs and this effect was achieved by suppressing TPRV1. Pathogenesis experiments suggested that WX390 may serve as an agent for the treatment of FIL.

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Summary: Thymocyte development requires precise control of PI3K-Akt signaling to promote proliferation and prevent leukemia and autoimmune disorders. Here, we show that ablating individual clusters of the miR-17∼92 family has a negligible effect on thymocyte development, while deleting the entire family severely impairs thymocyte proliferation and reduces thymic cellularity, phenocopying genetic deletion of Dicer. Mechanistically, miR-17∼92 expression is induced by Myc-mediated pre-T cell receptor (TCR) signaling, and miR-17∼92 promotes thymocyte proliferation by suppressing the translation of Pten. Retroviral expression of miR-17∼92 restores the proliferation and differentiation of Myc-deficient thymocytes. Conversely, partial deletion of the miR-17∼92 family significantly delays Myc-driven leukemogenesis. Intriguingly, thymocyte-specific transgenic miR-17∼92 expression does not cause leukemia or lymphoma but instead aggravates skin inflammation, while ablation of the miR-17∼92 family ameliorates skin inflammation. This study reveals intricate roles of the miR-17∼92 family in balancing thymocyte development, leukemogenesis, and autoimmunity and identifies those microRNAs (miRNAs) as potential therapeutic targets for leukemia and autoimmune diseases.

Abstract Background Facial infiltrating lipomatosis (FIL) is a rare condition characterized by congenital facial enlargement. Beyond its impact on physical appearance, FIL can also impair essential facial functions such as swallowing, chewing, vision, and breathing, imposing a substantial physiological and psychological burden. Currently, fewer than 80 cases of FIL have been reported, and the characteristics and management strategies for FIL remain unclear. Methods We reviewed the clinical, surgical, and radiological records of 39 FIL patients who were treated at our center. Of these, genetic testing was performed for 21 patients. Results Aberrant overgrowth involves subcutaneous fat, bones, muscles, glands, tongue, lips, and teeth. Epidermal nevi could be observed in the dermatomes innervated by the three branches of the trigeminal nerve, with the highest frequency seen in the dermatome of the mandibular branch. Four patients exhibited concurrent hemimegalencephaly (HMEG), with one case presenting HMEG on the opposite side of the FIL. Nineteen patients were confirmed to harbor the PIK3CA mutation. Thirty-three patients underwent surgical procedures, with a post resection recurrence rate of approximately 25%. Conclusions A variety of maxillofacial structures may be involved in FIL. PIK3CA mutations are important pathogenic factors. Emerging targeted therapies could present an additional treatment avenue in the future. However, surgery currently remains the predominant treatment choice for FIL. The timing and modality of surgery should be individually customized, taking into account each patient's unique circumstances. Notably, there is a significant possibility of postoperative recurrence during childhood and adolescence, necessitating early strategic planning of disease management.

Abstract Background The excellent efficacy is mitigated by the limited safety profile of microfocused ultrasound procedures. Objective We sought to assess the safety and tightening efficacy of a novel microfocused ultrasound. Methods The randomized middle and lower face and submental region of the participants were treated with the novel device using the following transducers: M4.5, D4.5, M3.0, and D3.0. Improvement in paired comparison of pretreatment and posttreatment photographs, three-dimensional (3D) volumetric assessments, skin thickness measured by B-ultrasonography, and skin photoaging parameters were evaluated. Adverse events and patient satisfaction were also recorded. Results A total of 20 participants (20 female) were enrolled. Fourteen of 20 participants (70%) were judged to show clinically significant facial tightening during 3-month follow-up (P

Linear scars are scars formed after surgery or other trauma-healing procedures that typically exhibit a linear morphology. Optimal linear scars are characterized by narrowness, flatness, and a color closely resembling the adjacent tissue. Failure to meet these criteria can have detrimental effects on the physical and psychological well-being of patients. Thus, early intervention for linear scars can effectively improve functionality and aesthetics. This review aimed to consolidate the prevailing agreement on scar prevention therapies and provide clinical physicians with comprehensive and cutting-edge guidance.

Background The aim of this study was to evaluate the roles of interleukin (IL)-17A in risk stratification and prognosis of patients with sepsis-associated acute kidney injury (SAKI). Methods We enrolled 146 sepsis patients (84 non-SAKI and 62 SAKI patients) admitted to the emergency department from November 2020 to November 2021. Patients with SAKI were differentiated based on the severity of acute kidney injury. All clinical parameters were evaluated upon admission before administering antibiotic treatment. Inflammatory cytokines were assessed using flow cytometry and the Pylon 3D automated immunoassay system (ET Healthcare). In addition, a receiver operating characteristic (ROC) curve was utilized to determine the prognostic values of IL-17A in SAKI. Results The levels of creatinine, IL-2, IL-4, IL-6, IL-17A, tumor necrosis factor alpha, C-reactive protein, and procalcitonin (PCT) were significantly higher in the SAKI group than in the non-SAKI group (p < 0.05). The level of IL-17A revealed significant differences among stages 1, 2, and 3 in SAKI patients (p < 0.05). The mean levels of PCT, IL-4, and IL-17A were significantly higher in the non-survival group than in the survival group in SAKI patients (p < 0.05). In addition, the area under the ROC curve of IL-17A was 0.811. Moreover, the IL-17A cutoff for differentiating survivors from non-survivors was 4.7 pg/mL, of which the sensitivity and specificity were 77.4% and 71.0%, respectively. Conclusion Elevated levels of IL-17A could predict that SAKI patients are significantly prone to worsening kidney injury with higher mortality. The usefulness of IL-17A in treating SAKI requires further research.

Arteriovenous malformations (AVMs) are serious congenital vascular anomalies in which the arteries connect directly with veins without capillaries. This condition will continue to worsen without proper intervention and cause ulcers, repeated hemorrhages, and even cardiac insufficiency. Primary treatment options for AVMs include surgery and interventional treatment; however, they are associated with high risk and recurrence rates. Recent studies revealed that excessive activation of the Ras/MAPK pathway can induce the formation and development of peripheral AVM, whereas MEK inhibitors can effectively control nidus progression, making them a potential novel treatment for AVM. This review provides an up-to-date overview of correlated laboratory and clinical research to provide information for further research and clinical practice.

Arteriovenous malformations (AVMs) are aggressive congenital high-flow vascular anomalies, in which the feeding artery and draining vein are connected through fistulas without normal capillary networks. In severe cases, the condition may cause swelling, ulceration, bleeding, and even heart failure. Various treatment options are available for AVMs, including laser, surgical resection, embolization, and targeted drug therapy. With the development of endovascular treatment technology, absolute ethanol embolization of AVMs has become one of the first-line therapies owing to its sustained efficacy and low recurrence rate. However, administration of this therapy is challenging and may lead to serious complications if inappropriately managed. In this article, we reviewed and summarized previous clinical articles, literature reviews, and clinical trial data to comprehensively describe clinical manifestations of AVMs, the mechanism of ethanol embolotherapy, key points in treatment and management of complications, and issues that need to be addressed. We expect to provide a reliable information reference source for clinical physicians and researchers.

Abstract Background Facial infiltrating lipomatosis (FIL) is a rare congenital disorder characterized by unilateral facial swelling, for which surgery is the prevailing therapeutic option. Several studies have shown that the development of FIL is closely associated with PIK3CA mutations. This study aimed to further identify rare clinical features and underlying molecular variants in patients with FIL. Results Eighteen patients were included in this study, and all patients presented with infiltrating adipose tissues confirmed by magnetic resonance imaging. Macrodactyly, polydactyly, hemimegalencephaly and hemihyperplasia were also observed in patients with FIL. In total, eight different PIK3CA mutations were detected in tissues obtained from sixteen patients, including the missense mutations p.His1047Arg (n = 4), p.Cys420Arg (n = 2), p.Glu453Lys (n = 2), p.Glu542Lys (n = 2), p.Glu418Lys (n = 1), p.Glu545Lys (n = 1), and p.His1047Tyr (n = 1) and the deletion mutation p.Glu110del (n = 3). Furthermore, the GNAQ mutation p.Arg183Gln was detected in the epidermal nevus tissue of one patient. Imaging revealed that several patients carrying hotspot mutations had more severe adipose infiltration and skeletal deformities. Conclusions The abundant clinical presentations and genetic profiles of FIL make it difficult to treat. PIK3CA mutations drive the pathogenesis of FIL, and PIK3CA hotspot mutations may lead to more extensive infiltration of lipomatosis. Understanding the molecular variant profile of FIL will facilitate the application of novel PI3K-targeted inhibitors.

Abstract Background Surgery is a common treatment strategy for patients with neurofibromatosis type 1 (NF1)-related plexiform neurofibroma (PN) and has limited efficacy. FCN-159 is a novel anti-tumorigenic drug via selective inhibition of MEK1/2. This study assesses the safety and efficacy of FCN-159 in patients with NF1-related PN. Methods This is a multicenter, open-label, single-arm, phase I dose-escalation study. Patients with NF1-related PN that was non-resectable or unsuitable for surgery were enrolled; they received FCN-159 monotherapy daily in 28-day cycles. Results Nineteen adults were enrolled in the study, 3 in 4 mg, 4 in 6 mg, 8 in 8 mg, and 4 in 12 mg. Among patients included in dose-limiting toxicity (DLT) analysis, DLTs (grade 3 folliculitis) were reported in 1 of 8 patients (16.7%) receiving 8 mg and 3 of 3 (100%) patients receiving 12 mg. The maximum tolerated dose was determined to be 8 mg. FCN-159-related treatment-emergent adverse events (TEAEs) were observed in 19 patients (100%); most of which were grade 1 or 2. Nine (47.4%) patients reported grade 3 study-drug–related TEAEs across all dose levels, including four experiencing paronychia and five experiencing folliculitis. Of the 16 patients analyzed, all (100%) had reduced tumor size and six (37.5%) achieved partial responses; the largest reduction in tumor size was 84.2%. The pharmacokinetic profile was approximately linear between 4 and 12 mg, and the half-life supported once daily dosing. Conclusions FCN-159 was well tolerated up to 8 mg daily with manageable adverse events and showed promising anti-tumorigenic activity in patients with NF1-related PN, warranting further investigation in this indication. Trial registration ClinicalTrials.gov, NCT04954001. Registered 08 July 2021.

Infantile hemangiomas (IHs) are the most common benign soft-tissue tumors in infancy; about 10%–15% of them may result in various complications that require active management. The current first-line treatment for IH is oral propranolol; however, some studies recommend intralesional corticosteroid injections for small, limited, deep, or prominent tumors because of concern regarding serious systemic complications related to propranolol. This review summarizes and analyzes the current clinical studies on corticosteroid injections in IHs, discusses treatment norms, and explores future research directions.

Port-wine stain (PWS) is a congenital capillary malformation that occurs in 0.3%–0.5% of newborns. The pulsed dye laser is the current gold standard treatment for PWS; however, its efficacy is poor. Photosensitizer photodynamic therapy (PDT) is considered a promising treatment for PWS. Here we provide a comprehensive overview of PDT.

ABSTRACT: In China, fresh food has always been a top priority and live poultry has been a staple in the diet for thousands of years. As a result, the live poultry market (LPM) remains a popular and important source for purchasing live poultry among the public. However, LPMs also play a crucial role in spreading and retaining highly pathogenic avian influenza (HPAI) due to the high poultry movement and trade volume. Therefore, the preventive behavior of LPM vendors is essential in blocking the transmission of HPAI and reducing occupational exposure. Based on the health belief model, this study utilized structural equation modeling to examine the effect of risk perceptions on preventive behavior among vendors in the live poultry wholesale market (wLPM) and the live poultry retail market (rLPM) in Guangdong Province. The results indicated that perceived severity and perceived benefits positively influenced the wLPM vendors’ ability to adopt preventive behavior (i.e., self-efficacy) while perceived barriers negatively affected self-efficacy in both wLPM and rLPM. Moreover, cues to action positively mediated the relationship between perceived severity, perceived benefits, and self-efficacy of wLPM and rLPM vendors. Cues to action also positively mediated the effect of perceived susceptibility among wLPM vendors. To promote preventive behavior among vendors, the market management companies and the government must provide timely and effective HPAI information through various channels and develop differentiated health campaigns according to the market types to raise vendors’ awareness about HPAI.

Facial infiltrating lipomatosis (FIL) is a congenital asymmetrical deformity of the maxillofacial region that can significantly affect a patient’s facial appearance and function. With the development of sequencing technologies, PIK3CA mutations are considered among the potential etiologies of FIL. The management and treatment of FIL involves plastic surgery; more recently, an improved understanding of its pathogenesis has given rise to new treatment options, including targeted therapy. Here we report the clinical data of two patients diagnosed with FIL and present current curative concepts.

Sumoylation is a reversible post-translational modification that regulates certain significant biochemical functions in proteins. The protein alterations caused by sumoylation are associated with the incidence of some human diseases. Therefore, identifying the sites of sumoylation in proteins may provide a direction for mechanistic research and drug development. Here, we propose a new computational approach for identifying sumoylation sites using an encoding method based on topological data analysis. The features of our model captured the key physical and biological properties of proteins at multiple scales. In a 10-fold cross validation, the outcomes of our model showed 96.45% of sensitivity (Sn), 94.65% of accuracy (Acc), 0.8946 of Matthew’s correlation coefficient (MCC), and 0.99 of area under curve (AUC). The proposed predictor with only topological features achieves the best MCC and AUC in comparison to the other released methods. Our results suggest that topological information is an additional parameter that can assist in the prediction of sumoylation sites and provide a novel perspective for further research in protein sumoylation.

ObjectiveInfantile hemangioma (IH), the most common infantile vascular neoplasm, is uniquely characterized by rapid proliferation followed by slow spontaneous involution lasting for years. In IH lesions, perivascular cells are the most dynamic cell subset during the transition from the proliferation phase to the involution phase, and we aimed to systematically study this kind of cell.Methods and resultsCD146-selective microbeads were used to isolate IH-derived mural-like cells (HemMCs). Mesenchymal markers of HemMCs were detected by flow cytometry, and the multilineage differentiation potential of HemMCs was detected by specific staining after conditioned culture. CD146-selected nonendothelial cells from IH samples showed characteristics of mesenchymal stem cells with distinct angiogenesis-promoting effects detected by transcriptome sequencing. HemMCs spontaneously differentiated into adipocytes 2 weeks after implantation into immunodeficient mice, and almost all HemMCs had differentiated into adipocytes within 4 weeks. HemMCs could not be induced to differentiate into endothelial cells in vitro. However, 2 weeks after implantation in vivo, HemMCs in combination with human umbilical vein endothelial cells (HUVECs) formed GLUT1+ IH-like blood vessels, which spontaneously involuted into adipose tissue 4 weeks after implantation.ConclusionsIn conclusion, we identified a specific cell subset that not only showed behavior consistent with the evolution of IH but also recapitulated the unique course of IH. Thus, we speculate that proangiogenic HemMCs may be a potential target for the construction of hemangioma animal models and the study of IH pathogenesis.

The demand for pre-made dishes has increased in China. However, a detailed understanding of residents’ intention to consume pre-made dishes is lacking in the existing studies. This research aims to investigate the consumer motives and intention to consume pre-made dishes. Through in-depth interviews and analysis, this research explores the factors influencing the residents’ intention along the research steps of grounded theory. Fifty-one residents participated in semi-structured interviews via face-to-face or online interviews. Three motives for purchasing pre-made dishes were attitude, subjective norm, and perceived control. These were influenced by external factors, including environmental features and product features. Subjective characteristics are pre-existing characteristics of individuals themselves, including cooking skills, food skills, housework allocation, and eating attitudes, which play a moderating role in the relationship between external factors and consumer motives. Based on the six major categories, this study built a model of the formation mechanism of the consumer intention to consume pre-made dishes. It revealed the psychological attribution of residents’ consumption of pre-made dishes. The finding of this study contributes to the understanding of the internal logic of PMDs’ consumer intention formation. It would be a guide for researchers to map out appropriate business development strategies, and provide evidence for the government in formulating management policies.

Background: We previously reported that interstitial injection of bleomycin (BLM) reduces the size of early-stage extracranial arteriovenous malformation (AVM). Here, we sought to investigate the potential mechanism of BLM in treating extracranial AVM. Methods: Samples of human extracranial AVM (n=3) with no pharmacological treatment were harvested. AVM endothelial cells were isolated and cultured in primary cell culture. The transcriptome was examined using RNA-sequencing, and differentially expressed C-type lectin domain family 14 member A (CLEC14A) was validated at the transcriptomic and protein levels. Immunocytochemical staining of CLEC14A was performed in samples of human extracranial AVM, with and without BLM treatment. Results: Through second-generation sequencing, we found that the expression of 5 689 genes were differentially increased or decreased following 24-h BLM stimulation. We found that CLEC14A may play an important role in the progression of AVM and can be inhibited by BLM treatment. Conclusion: BLM inhibited CLEC14A expression to attenuate the progression of AVM.

Background: Port-wine stain (PWS) has been classified not as the hyperplasia of cells, but rather, as an expansion of malformed vessels. However, previous studies have reported upregulated expression of proangiogenic factors in PWS. Several studies have indicated that the pathology exhibits proliferation of numerous endothelial cells in hypertrophic/nodular PWS. This study aimed to determine the expression of vascular epithelial growth factor (VEGF), matrix metalloproteinase-9 (MMP-9), angiopoietin-2 (ANG-2), and basic fibroblast growth factor (bFGF) in hypertrophic PWS. Methods: Immunohistochemistry was used to analyze skin samples from 33 patients with hypertrophic PWS. Expression levels of VEGF, MMP-9, ANG-2, and bFGF in hypertrophic PWS were determined by multiplying the intensity by the percentage of immunoreactive cells. Immunoreactivity scores were classified as follows: negative (0), low (1), moderate (2, 3, and 4), or high (6). Results: Based on pathological characteristics, hypertrophic PWS was divided into vascular malformation and pyogenic granuloma (PG) types. VEGF, MMP-9, ANG-2, and bFGF were significantly activated in the blood vessels of PG-type PWS samples compared with their counterparts in blood vessels of vascular malformation-type PWS samples and controls. PG-type hypertrophic PWS, which exhibited proliferation of endothelial cells, showed the strongest activation. Conclusion: The exuberant proliferation of endothelial cells in PG-type hypertrophic PWS may be associated with the regulation of proangiogenic factors during development. These proangiogenic factors that function in the angiogenesis and proliferation of endothelial cells may play an important role in the pathogenesis and progression of PWS. Furthermore, these factors may be dynamic and behave differently in various types of hypertrophic PWS.

ABSTRACT: Background: Despite many advances in the treatment for extracranial arteriovenous malformations (AVMs), they still result in tedious dissection and potential unacceptable complications, particularly in children. Therefore, this study aimed to investigate the efficacy and safety of intralesional interstitial injection of bleomycin for the treatment of children with AVMs. Methods: A total of 10 children (6 boys and 4 girls) with AVMs were treated with serial interstitial bleomycin injections between May 2014 and January 2017. Maximum single doses of 15 U and 1 U/kg per session were administered for six sessions at a 1-month interval. Therapeutic effectiveness was evaluated and classified into four categories: complete response (CR), partial response (PR), no response, and worsening at 3 months after the last session. Further clinical follow-up outcomes were classified as improved, stable, or aggravated. Adverse events were recorded according to the Society of Interventional Radiology classification. Results: All 10 children completed the sessions and follow-ups. CR occurred in 3 (30%) patients, PR in 6 (60%), and no response in 1 (20%). Minor complications (class A) included maculopapular rash, bulla, vomiting, and hyperpigmentation, whereas no major complications occurred. Conclusion: Intralesional interstitial injection of bleomycin is a feasible approach for the treatment of AVMs in children and provides safe and effective outcomes. This method may be an earlier treatment alternative in children to prevent potential destructive progression, considering the serious complications of currently available therapeutic methods.

ABSTRACT: Objective: To investigate the developmental history of cosmetic surgery and cosmetic medicine in China. Methods: The history of cosmetic surgery and cosmetology in China was explored via a review of the literature reported across the globe and the archeological discoveries recorded in China. Results: The ancient underground city of “Sanxingdui”, discovered in Guanghan, Sichuan, China, was built between 1 800 and 2 800 BC. Many bronze figure sculptures with decorative perforations in the earlobe area were unearthed there, making it perhaps the earliest record of cosmetic surgery practice in the world. The practice of decorative perforations in the earlobe predates the practice of nose jobs found in ancient India. The Prescriptions for Fifty-two Diseases from the Western Han Dynasty, unearthed in Mawangdui, Changsha, Hunan Province, recorded the treatment of vitiligo in traditional Chinese medicine. This might be one of the earliest records of aesthetic medicine in the world. Conclusion: China is one of the earliest birthplaces of cosmetic surgery and cosmetology in the world. The practice of cosmetic medicine in China predates the practice of nasal reconstruction found in ancient India.

As an important form of posttranslational modification, protein ubiquitination regulates a wide variety of biological processes, including different aspects of T cell development and differentiation. During T cell development, thymic seeding progenitor cells (TSPs) in the thymus undergo multistep maturation programs and checkpoints, which are critical to build a functional and tolerant immune system. Currently, a tremendous amount of research has focused on the transcriptional regulation of thymocyte development. However, in the past few years, compelling evidence has revealed that the ubiquitination system also plays a crucial role in the regulation of thymocyte developmental programs. In this review, we summarize recent findings on the molecular mechanisms and cellular pathways that regulate thymocyte ubiquitination and discuss the roles of E3 ligases and deubiquitinating enzymes (DUBs) involved in these processes. Understanding how T cell development is regulated by ubiquitination and deubiquitination will not only enhance our understanding of cell fate determination via gene regulatory networks but also provide potential novel therapeutic strategies for treating autoimmune diseases and cancer.

T cell development in the thymus is tightly controlled by complex regulatory mechanisms at multiple checkpoints. Currently, many studies have focused on the transcriptional and posttranslational control of the intrathymic journey of T-cell precursors. However, over the last few years, compelling evidence has highlighted cell metabolism as a critical regulator in this process. Different thymocyte subsets are directed by distinct metabolic pathways and signaling networks to match the specific functional requirements of the stage. Here, we epitomize these metabolic alterations during the development of a T cell and review several recent works that provide insights into equilibrating metabolic quiescence and activation programs. Ultimately, understanding the interplay between cellular metabolism and T cell developmental programs may offer an opportunity to selectively regulate T cell subset functions and to provide potential novel therapeutic approaches to modulate autoimmunity.

Lung cancer is one of the leading causes of cancer-related deaths. Thus, it is important to find its biomarkers. Furthermore, there is an increasing number of studies reporting that long noncoding RNAs (lncRNAs) demonstrate dense linkages with multiple human complex diseases. Inferring new lncRNA-disease associations help to identify potential biomarkers for lung cancer and further understand its pathogenesis, design new drugs, and formulate individualized therapeutic options for lung cancer patients. This study developed a computational method (LDA-RLSURW) by integrating Laplacian regularized least squares and unbalanced bi-random walk to discover possible lncRNA biomarkers for lung cancer. First, the lncRNA and disease similarities were computed. Second, unbalanced bi-random walk was, respectively, applied to the lncRNA and disease networks to score associations between diseases and lncRNAs. Third, Laplacian regularized least squares were further used to compute the association probability between each lncRNA-disease pair based on the computed random walk scores. LDA-RLSURW was compared using 10 classical LDA prediction methods, and the best AUC value of 0.9027 on the lncRNADisease database was obtained. We found the top 30 lncRNAs associated with lung cancers and inferred that lncRNAs TUG1, PTENP1, and UCA1 may be biomarkers of lung neoplasms, non-small–cell lung cancer, and LUAD, respectively.

ABSTRACT: Background: Ethanol embolotherapy is considered an optimal choice for the treatment of arteriovenous malformations (AVMs); however, there are some complications associated with this treatment. This study aimed to prospectively investigate systemic hemodynamic changes in high-flow AVMs using ethanol embolotherapy. Methods: From September 2012 to September 2014, 34 male patients and 26 female patients with AVMs who underwent embolotherapy (100 sessions in total) with absolute ethanol were included in this study. Invasive systolic blood pressure (SBP) and heart rate (HR) were recorded before and after each injection and throughout the procedure. Differences between the initial and highest SBP (ΔmaxSP) and HR values (ΔmaxHR), as well as the initial and final SBP (ΔSP) and HR (ΔHR) values, were analyzed. We aimed to explore the potential association between these values and the amount of ethanol that was used. Results: The total ethanol used was variable (0.01–0.40 mL/kg; mean, 0.20 mL/kg). SBP and HR increased after ethanol injection in most sessions (91 in 100 sessions). SBP decreased in 9 sessions (9 in 100 sessions), while HR, oxygen saturation, and end-tidal CO2 decreased in one of the 9 sessions. ΔmaxSP and ΔmaxHR averaged 38.4 mmHg and 27.8 bpm, respectively (both P

Hyperpigmentation is a common complaint and distressing problem in dermatology, and tranexamic acid (TA) is an effective treatment agent but limited by the delivery to melanocytes in the epidermis. Herein, a novel TA naogels (named HA/TA-LP), combining the advantages of liposomes and hyaluronic acid (HA), are prepared and assessed for topical hyperpigmentation treatment with targeting delivery and minimizing epidermal diffusion. Morphological characteristics indicate numerous TA-loaded liposomes packed in HA gels. In vitro cell studies using human A375 melanoma cells show that HA/TA-LP can promote the uptake of TA by targeting delivery with resulting inhibition of tyrosinase activity and melanin production. Guinea pigs are used to construct hyperpigmentation models and investigate the topical delivery and treatment efficacy of HA/TA-LP. In vivo topical delivery studies indicate HA/TA-LP realize the effective delivery into melanocytes with an ideal balance of effective permeability and minimizing epidermal diffusion. Subsequently, hyperpigmentation treatment assessments reveal that HA/TA-LP inhibit tyrosinase activity and melanin production under the radiation of UVB. Our study identifies favorable properties of HA/TA-LP for treating hyperpigmentation, and provides an experimental basis for further clinical application.

ABSTRACT: BACKGROUND: Percutaneous sclerotherapy can be used to successfully treat venous malformations (VMs) of the head, neck, and limbs. However, the standard curative effect of sclerotherapy has rarely been analyzed, and there is currently no accurate statistical method to measure the volume of VMs after sclerotherapy. Here, we propose a novel three-dimensional (3D) reconstruction method to evaluate this effect. OBJECTIVE: To test the feasibility of 3D software (MIMICS 19.0) to evaluate the treatment effect of sclerotherapy. METHODS: This retrospective study included patients with VMs on the head, neck, and limbs who were treated with ethanol sclerotherapy or foam sclerotherapy every 8 weeks. MIMICS 19.0 was used to calculate the performance of the lesion after treatment and measure the VM volumes before and after the treatment. The effect of the clinical treatment dose on the lesion was evaluated, and the treatment effect of each patient was recorded. The relationship between the number of treatments and the reduced volume of VMs was analyzed. RESULTS: Based on the MIMICS-calculated regions of interest (ROI), we found that 1 mL of ethanol reduced the lesion by 473 mm3 and that one dosage of foam (1 mL of polidocanol and 4 mL air content) reduced the lesion by 2 138 mm3, demonstrating that the foam sclerosing agent exhibited greater efficacy in this study. CONCLUSIONS: The MIMICS 3D volume reconstruction method can effectively and safely evaluate the efficacy of sclerotherapy and provide a preoperative evaluation. This method is simple, accurate, and feasible.

Abstract Congenital melanocytic nevus (CMN) represent a benign proliferative skin disease in the epidermis and dermis. CMN are historically known to be associated with activating NRAS or BRAF mutations. Melanoma frequently harbors the BRAF p.Val600Glu mutation, which is also commonly found in benign nevi. A recent study reported mutation of MAP2K1, a downstream effector of the RAS-RAF-MEK pathway, in melanoma with an overall frequency of 8%. Later, in 2019, Jansen P detected one activating MAP2K1 mutation in acral nevi. However, it is unknown whether MAP2K1 mutations are common in CMN, and how MAP2K1 contributes to the pathogenesis of CMN remains to be determined. In this study, we report one patient clinically and histologically diagnosed with CMN, with the MAP2K1 germline mutation and a BRAF p.Val600Glu somatic hit in the lesion. To the best of our knowledge, this is the first report of the coexistence of mutated BRAF and MAP2K1 in CMN, which may suggest that MAP2K1 mutations contribute to the occurrence and development of nevus expanding our knowledge of the genetics of CMN.

Abstract Capillary malformation-arteriovenous malformations (CM-AVMs) caused by a RASA-1 or EPHB4 mutation are characterized as hereditary sporadic or multifocal capillary malformations (CMs), associated with potential fast-flow vascular anomalies underlying erythema lesions. Because of the similar phenotype, CM-AVMs should be considered in the differential diagnosis of isolated CMs as well as other disorders with an erythema phenotype, such as hereditary hemorrhagic telangiectasia (HHT). Herein, we report a male patient with facial erythema. Red lesions were located in the V1 region of his left face, the V2 and V3 regions on his right side, and the nasal back. The patient was initially thought to have PWSs because of the unilateral and segmental distribution of his red facial lesions. In contrast to a previous diagnosis, we diagnosed the child with capillary malformation-arteriovenous malformation type 2 (CM-AVM2) based on a family history of erythema, the results of physical examination and ultrasound raising potential fast-flow lesions, and a genetic study revealing a germline EPHB4 mutation. This study emphasizes the importance of differential diagnosis for PWS and CM-AVM. A single clinical diagnosis can be limited, and molecular diagnosis is recommended to provide more information for the evaluation of the potential risk of fast-flow lesions underlying erythema lesions if necessary.

Abstract Congenital melanocytic nevus (CMN) is a benign proliferative skin disease in the epidermis and dermis. Large to giant CMNs are estimated to be associated with an increased lifetime risk of malignancy. It is necessary to estimate and monitor the risk of malignant transformation for giant CMNs. To date, the clinical “ABCD” criteria and immunohistochemistry studies can be confusing and, to some extent, subjective. Accordingly, the elucidation of genomic analyses of nevi is required to better understand the malignant transformation of CMNs. Here, we describe two large to giant CMNs of the scalp with opposite clinical-histological and molecular evaluations of potential malignancy risk. To our knowledge, this is the first description of a genetic study of large to giant CMNs of the scalp in East Asia. We recommend reviewing the molecular diagnosis together with careful medical history and histological information to facilitate the evaluation of the potential malignancy risk.

ABSTRACT: Background: Eccrineangiomatoushamartoma (EAH) is a rare benign disease that comprises vascular and eccrine malformations. Pain is one of the most common symptoms and surgical resection is generally required. Objective: To report a novel surgical technique that can alleviate severe pain caused by a large lesion in an EAH patient. Methods: On magnetic resonance imaging (MRI), a subcutaneous abnormal signal was detected in the right hip and groin area of an 18-year-old male. The lesion was carefully elevated from the normal tissue above the plane of the deep fascia and was sutured in situ. Additionally, a small sample of the central lesion tissue was collected for histological examination. Results: The visual analog scale score of pain decreased from 9 points to 2 points at 1week and to 0 points at 2 weeks after the surgery. The only complication observed was local numbness, which recovered spontaneously. No recurrence of pain was observed after 1 year of surgery. Histological findings demonstrated that the numbers of eccrine sweat glands and abnormal vessels decreased post-surgery. Conclusion: The surgical procedure used in our case may represent a novel, easy, safe, and effective option for the treatment of a large, severely painful EAH.

ABSTRACT: Objectives: Infantile hemangioma (IH) is defined as a benign vascular tumor composed of immature vascular endothelial cells, with the unique characteristics of rich vascularization and self-regression into fibro-fatty tissue. CD133-positive hemangioma stem cells (HemSCs), present in the proliferating IH tissue, can be used to establish the IH animal model, which has highlighted the pathogenesis of IH in recent years. This study focused on the biological characteristics and differentiation capacity of HemSCs and aimed to provide a theoretical possibility for its application in tissue engineering. Methods: To further confirm our hypothesis, we used fluorescence-activated cell sorting (FACS), in vitro multipotent induced differentiation, angiogenesis assay, and antibody array to identify the surface markers, multipotent differential potential, angiogenesis potential, and secreted factors of HemSCs, respectively, utilizing human adipose stem cells(hADSCs) as the control. Results: We successfully isolated and cultured HemSCs. FACS indicated that, on average, more than 80% of HemSCs matched the criteria of mesenchymal stem cell (MSC) surface markers. Our results confirmed that HemSCs could differentiate into adipocytes, osteocytes, and chondrocytes. Additionally, compared with fibroblasts or hADSCs, HemSCs could promote angiogenesis through para-secretion. Conclusions: HemSCs may originate from normal MSCs, and owing to their powerful proliferative and angiogenic abilities, they could be considered an IH pathogenic factor. These characteristics demonstratet heir potential as a candidate seed cell in tissue engineering.

As a major reason for tumor metastasis, circulating tumor cell (CTC) is one of the critical biomarkers for cancer diagnosis and prognosis. On the one hand, CTC count is closely related to the prognosis of tumor patients; on the other hand, as a simple blood test with the advantages of safety, low cost and repeatability, CTC test has an important reference value in determining clinical results and studying the mechanism of drug resistance. However, the determination of CTC usually requires a big effort from pathologist and is also error-prone due to inexperience and fatigue. In this study, we developed a novel convolutional neural network (CNN) method to automatically detect CTCs in patients’ peripheral blood based on immunofluorescence in situ hybridization (imFISH) images. We collected the peripheral blood of 776 patients from Chifeng Municipal Hospital in China, and then used Cyttel to delete leukocytes and enrich CTCs. CTCs were identified by imFISH with CD45+, DAPI+ immunofluorescence staining and chromosome 8 centromeric probe (CEP8+). The sensitivity and specificity based on traditional CNN prediction were 95.3% and 91.7% respectively, and the sensitivity and specificity based on transfer learning were 97.2% and 94.0% respectively. The traditional CNN model and transfer learning method introduced in this paper can detect CTCs with high sensitivity, which has a certain clinical reference value for judging prognosis and diagnosing metastasis.

Infantile hemangiomas (IH) leave sequelae after involution. Topical application of timolol maleate (TM) is the mainstream treatment for superficial lesions but is limited by its low penetrable properties. We aimed to develop a superior skin permeation drug while maintaining the therapeutic properties of timolol. We predict that this drug will promote the involution of thick and deep IH lesions and avoid sequelae. We chemically modified drug structure to prepare butyryl timolol maleate (BT) prodrug and conducted in vitro and in vivo toxicity evaluations of BT with rat dorsal skin and normal skin cells. Skin permeation and absorption comparisons of TM and BT were conducted using rat and porcine skin models. Conversion efficiency of BT to timolol was also tested on human skin ex vivo. BT did not cause skin irritation on rat dorsal skin and exhibited low cytotoxicity overall. BT exhibited superior skin permeation ability compared with that of TM, whilst maintaining a low systemic absorbance. Further, BT was converted to timolol in human skin in a time-dependent manner. Noticeably, timolol accumulation in the skin from BT was higher than that from TM. Finally, BT demonstrated similar biocompatibility with TM in the IH tumor. BT enhances local delivery of timolol and its skin permeation. Using BT, we could eliminate thicker IH lesions that are prone to leave sequelae, and potentially help young children avoid dermal sequelae, disfigurement, and concomitant therapy.

Abstract Capillary malformation-arteriovenous malformation (CM-AVM) is a clinical entity newly identified in 2003 that is caused by mutation of the RASA-1 gene, which encodes the protein p120-RasGAP. To date, most of the clinical reports on CM-AVM in the literature involve samples entirely consisting of Caucasians of European and North American descent, while reports from China or East Asia are few. Here, we describe a genetic clinical report of CM-AVM. Sequencing revealed a novel stop mutation in the RASA-1 gene causing loss of function (LOF) of the RasGAP domain. To our knowledge, this is the first genetic clinical report of a CM-AVM patient in East Asia. This report may extend our understanding and support further studies of CM-AVM in East Asia.

Herpesviruses constitute a large family of disease-causing DNA viruses. Each herpesvirus strain is capable of infecting particular organisms with a specific cell tropism. Upon infection, pattern recognition receptors (PRRs) recognize conserved viral features to trigger signaling cascades that culminate in the production of interferons and pro-inflammatory cytokines. To invoke a proper immune response while avoiding collateral tissue damage, signaling proteins involved in these cascades are tightly regulated by post-translational modifications (PTMs). Herpesviruses have developed strategies to subvert innate immune signaling pathways in order to ensure efficient viral replication and achieve persistent infection. The ability of these viruses to control the proteins involved in these signaling cascades post-translationally, either directly via virus-encoded enzymes or indirectly through the deregulation of cellular enzymes, has been widely reported. This ability provides herpesviruses with a powerful tool to shut off or restrict host antiviral and inflammatory responses. In this review, we highlight recent findings on the herpesvirus-mediated post-translational control along PRR-mediated signaling pathways.

Kaposi's sarcoma-associated herpesvirus (KSHV) latently infects host cells and establishes lifelong persistence as an extra-chromosomal episome in the nucleus. To persist in proliferating cells, the viral genome typically replicates once per cell cycle and is distributed into daughter cells. This process involves host machinery utilized by KSHV, however the underlying mechanisms are not fully elucidated. In present study, we found that N-Myc downstream regulated gene 1 (NDRG1), a cellular gene known to be non-detectable in primary B cells and endothelial cells which are the major cell types for KSHV infection in vivo, was highly upregulated by KSHV in these cells. We further demonstrated that the high expression of NDRG1 was regulated by latency-associated nuclear antigen (LANA), the major viral latent protein which tethers the viral genome to host chromosome and plays an essential role in viral genome maintenance. Surprisingly, knockdown of NDRG1 in KSHV latently infected cells resulted in a significant decrease of viral genome copy number in these cells. Interestingly, NDRG1 can directly interact with proliferating cell nuclear antigen (PCNA), a cellular protein which functions as a DNA polymerase clamp during DNA replication. Intriguingly, we found that NDRG1 forms a complex with LANA and PCNA and serves as a scaffold protein bridging these two proteins. We further demonstrated that NDRG1 is critical for mediating LANA to recruit PCNA onto terminal repeat (TR) of KSHV genome, and facilitates viral DNA replication and episome persistence. Taken together, our findings suggest that NDRG1 plays an important role in KSHV viral genome replication, and provide new clues for understanding of KSHV persistence.

BACKGROUND AND OBJECTIVES:Photodynamic therapy (PDT) has shown potentially beneficial results in treating port-wine stain, but its benefit-risk profile remains undefined. This study aimed to evaluate the efficacy and safety of PDT conducted with hemoporfin and a 532 nm continuous wave laser to treat port-wine stain clinically. PATIENTS AND METHODS:This randomized clinical trial was conducted in eight hospitals in China. Participants were adolescent and adult patients (age range: 14-65 years old) with port-wine stain. During stage 1 (day 1 to week 8) all patients were randomized at a 3:1 ratio to treatment (532 nm laser irradiation (96-120 J/cm2) with hemoporfin (5mg/kg; PDT-hemoporfin, n = 330)) or placebo groups (irradiation with placebo (PDT-placebo, n = 110)); during stage 2 (week 8 to 16) patients in both groups were offered treatment. Clinician-evaluators, who were blind to the study, classified each case on the following four-level scale according to assessment of before and after standardized pictures of the lesion area: no improvement:

Metabolism and immune responses are two fundamental biological processes that serve to protect hosts from viral infection. As obligate intracellular pathogens, viruses have evolved diverse strategies to activate metabolism, while inactivating immune responses to achieve maximal reproduction or persistence within their hosts. The two-way virus-host interaction with metabolism and immune responses choreograph cytokine production via reprogramming metabolism of infected cells/hosts. In return, cytokines can affect the metabolism of virus-infected and bystander cells to impede viral replication processes. This review aims to summarize our current understanding of the cross-talk between metabolic reprogramming and cytokine responses, and to highlight future potential research topics. Although the focus is placed on viral pathogens, relevant findings from other microbes are integrated to provide an overall picture, particularly when corresponding information on viral infection is lacking.