Evaluating the involvement and mutual interaction of wbp2 and yap in embryogenesis with an emphasis on liver function in zebrafish embryos.

The Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) play complex roles in liver health, influencing processes such as fibrosis, cancer development, and regeneration. WW domain binding protein-2 (WBP2) primarily enhances the co-translational activity of YAP/TAZ, which is crucial for the progression of liver diseases. Despite existing knowledge, the specific functions of WBP2 and its interactions with YAP remain inadequately understood. This study investigates the expression levels of WBP2 in zebrafish embryos and its molecular interaction with YAP. We employed morpholino-mediated knockdown of wbp2 and yap, followed by assessments of liver histology, immunofluorescence, and co-immunoprecipitation. Subsequently, RNA sequencing analyses were conducted to elucidate the signaling pathways and mechanisms underlying the interplay between YAP and WBP2 in liver injury. Our findings highlight the significant interaction between WBP2 and YAP, emphasizing their potential as therapeutic targets for liver diseases.

Progress in antibacterial applications of nanozymes.

Bacterial infections are a growing problem, and antibiotic drugs can be widely used to fight bacterial infections. However, the overuse of antibiotics and the evolution of bacteria have led to the emergence of drug-resistant bacteria, severely reducing the effectiveness of treatment. Therefore, it is very important to develop new effective antibacterial strategies to fight multi-drug resistant bacteria. Nanozyme is a kind of enzyme-like catalytic nanomaterials with unique physical and chemical properties, high stability, structural diversity, adjustable catalytic activity, low cost, easy storage and so on. In addition, nanozymes also have excellent broad-spectrum antibacterial properties and good biocompatibility, showing broad application prospects in the field of antibacterial. In this paper, we reviewed the research progress of antibacterial application of nanozymes. At first, the antibacterial mechanism of nanozymes was summarized, and then the application of nanozymes in antibacterial was introduced. Finally, the challenges of the application of antibacterial nanozymes were discussed, and the development prospect of antibacterial nanozymes was clarified.

Tissue-resident T cells in Clinical Response and Immune-related Adverse Events of Immune Checkpoint Blockade.

T cell surveillance of tissues is spatially organized: circulating memory T cells perform surveillance of secondary lymphoid organs while tissue-resident memory T cells act as sentinels in barrier tissues. In the context of infection, tissue-resident memory T cells survive long term in barrier tissues and are poised to respond to re-encounter of infectious agents. The activity of such tissue-resident T cells is regulated by the PD-1 and CTLA-4 inhibitory receptors targeted by cancer immunotherapies. This review investigates the hypothesis that T cells with a tissue residency program play an important role in both protective anti-tumor immunity and immune-related adverse events (irAEs) of immune checkpoint blockade (ICB). A series of translational studies have demonstrated that a higher density of tissue-resident T cells within tumors is associated with favorable survival outcomes in a diverse range of cancer types. Tissue-resident T cells have also been implicated in clinical response to immune checkpoint blockade, and dynamic tracking of T cell populations in pre- and on-treatment tumor samples demonstrated that T cells with a tissue residency program responded early to ICB. Investigation of colitis and dermatitis as examples of irAEs demonstrated that tissue-resident memory T cells were reactivated at these epithelial sites, resulting in a highly cytotoxic state and secretion of inflammatory cytokines IFNγ and TNFα. It will therefore be important to consider how a tissue residency program can be enhanced to promote T cell-mediated tumor immunity while preventing the development of irAEs.

Immunomodulatory effects and multi-omics analysis of Codonopsis Pilosula Extract in septic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Codonopsis Pilosula (CP), as a well-known traditional Chinese medicine (TCM) with medicinal and edible herb, is one of the most representative tonic Chinese herbal medicine. It has been widely used for regulating immune function with hardly any adverse effects in clinical practice. AIM OF THE STUDY: This study aimed to elucidate the immunomodulatory effect and to explore probable mechanism of Codonopsis Pilosula Extract (CPE) in septic rats. MATERIALS AND METHODS: The model of septic rat was established by cecal ligation and perforation (CLP). The thymus index, spleen index and cerebral index were calculated. Histological changes were observed by Hematoxylin-eosin (HE). The positive expression of CD4+ T cells was determined in the thymus and spleen by immunohistochemical (IHC). The expression level of 24 h CD4 was corroborated by real-time quantitative polymerase chain reaction (RT-QPCR). Infectious factors, immune factors and inflammatory factors were determined by enzyme-linked immunosorbent assay (ELISA). Blood cells were detected by automatic biochemical analyzer. The metabolite changes and gene expression levels, the potential targets and pathways of CPE in regulating immune function of thymus were analyzed by integrative analysis of transcriptomic and metabolomic methods. RESULTS: High dose of CPE increased the thymus index and spleen index of septic rats at different stages, and the brain index at different stages could be increased at medium dose and high dose. Medium and high doses of CPE reduced the pathological changes of thymus, spleen and brain tissue. CPE promoted the expression levels of CD4 in the thymus and spleen. CPE improved the levels of red blood cells (RBC), lymphocytes (LYM) and hemoglobin (HGB), and decreased the levels of neutrophils (NEUT), NLR (NEUT/LYM) and PLR (PLT/LYM). CPE dynamically regulated the levels of white blood cells (WBC) and PLT (platelet). CPE dynamically regulated the expression levels of infectious factors, immune factors, and inflammatory factors related to disease severity. CONCLUSION: CPE has the ability to dynamically modulate the expression levels of infectious factors, immune factors, and inflammatory factors related to disease severity, and alleviate the damages of immune organs. The research has provided a global view of the integration of metabolomics and transcriptomics to elucidate the immunomodulatory effects and mechanisms of CPE. CPE could affect a series of biological processes in glycerophospholipid metabolism by interfering with the B cell receptor (BCR) signaling pathway in the thymus, to maintain immune homeostasis of septic rats on the whole, especially humoral immunity.

Increased Epstein‒Barr virus reactivation following prophylaxis for cytomegalovirus infection after haploidentical haematopoietic stem cell transplantation.

Letermovir (LTV) prophylaxis is effective in reducing the incidence of clinically significant cytomegalovirus (CMV) infection (cs CMVi) after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Since our centre began administering LTV prophylaxis in June 2022, we have observed a certain increase in the incidence of Epstein-Barr virus (EBV) reactivation after haploidentical HSCT. We retrospectively analysed 230 consecutive patients who underwent haploidentical HSCT with rabbit anti-thymocyte globulin (ATG) from October 2022 to June 2023. The LTV group included 133 patients who received LTV prophylaxis, and the control group included 97 patients who did not receive LTV prophylaxis. At 1 year after HSCT, EBV reactivation was observed in 36 patients (27%) in the LTV group and 13 patients (13%) in the control group (p = 0.012). All patients with EBV reactivation had EBV-DNAemia, and one patient in each group developed EBV-associated posttransplantation lymphoproliferative disorder (PTLD). The proportion of patients with low EBV-DNA loads (> 5 × 102 to < 1 × 104 copies/mL) was greater in the LTV group than in the control group (23% vs. 10%, p = 0.01). The proportion of patients with CMV reactivation was lower in the LTV group than in the control group (35% vs. 56%, p = 0.002). There was no significant difference between the groups in terms of neutrophil and platelet count recovery, the cumulative incidence of acute/chronic graft-versus-host disease, overall survival, cumulative relapse rate or nonrelapse mortality. Our results show that the increased incidence of EBV reactivation may be associated with LTV prophylaxis for CMV after haploidentical HSCT.

Analysis of genetic evolutionary differences among four Tibetan pig populations in China.

Tibetan pigs are a locally bred domestic pig breed originating from the Tibetan Plateau in China. They can be categorized into four distinct groups based on their geographical locations: Sichuan Tibetan pigs, Tibetan pigs from Tibet, Yunnan Tibetan pigs, and Gansu Tibetan pigs. This study aimed to explore population diversity, genetic structure and selection signals among Tibetan pigs in four Chinese national nature reserves. The results show that there is different observed heterozygosity among Tibetan pig populations (0.1957-0.1978). Ratio of runs of homozygosity (Froh) calculation of four Tibetan pig populations by runs of homozygosity (ROH) revealed the presence of inbreeding within the population (0.0336-0.0378). Analysis of the genetic structure demonstrated distinct population stratification among the four Tibetan pig populations, with each showing relatively independent evolutionary directions. Furthermore, Five methods (FST, Piratio, ROD, Tajima's D, XP-CLR) were used to artificially select evolutionary trajectories. The results mainly involved processes such as DNA repair, immune regulation, muscle fat deposition and adaptation to hypoxia. In conclusion, this study enhances our understanding of the genetic characteristics of Tibetan pig populations and provides a theoretical reference for the conservation of resources across different populations of Tibetan pigs.

The role of fibrinogen combined with platelet-rich plasma in enhancing microfracture for cartilage damage: a retrospective study of 113 patients with knee osteoarthritis.

OBJECTIVE: Knee osteoarthritis is the most common osteoarthritis and imposes a significant burden on patients' lives. Several treatment methods can promote cartilage repair to varying extents, but there are limited studies on the combined application of different treatments. The purpose of this study is to evaluate the clinical efficacy of microfracture combined with fibrinogen and platelet-rich plasma (PRP) under arthroscopic in treating knee osteoarthritis, so as to provide a basis for clinical treatment decisions. METHOD: A total of 113 patients with knee osteoarthritis who received orthopedic treatment from January 2021 to June 2022 were selected. They were divided into two groups according to whether they received fibrinogen and PRP treatment in addition to microfracture treatment. The two groups were analyzed to compare the differences in knee joint function and quality of life at different points. RESULTS: The study compared changes in knee joint function scores and quality of life between the two groups after treatment and found that the quality of life of patients in the combined treatment group was significantly better than that of patients who received microfracture only (at 12-month follow-up, EuroQol-VAS scores were 64.32 ± 5.63 for the microfracture group (MFx) and 75.65 ± 8.57 for the fibrinogen combined with platelet-rich plasma-assisted microfracture group (FPRPA MFx); P = 0.015; at 24-month follow-up, EuroQol-VAS scores were 66.47 ± 5.18 for the MFx group and 79.40 ± 7.43 for the FPRPA MFx group, P = 0.022). There was also a strong correlation between patients' quality of life and knee joint function score index (IKDC score correlation coefficient r=-0.375, Lysholm score correlation coefficient r = 0.497, MOCART score correlation coefficient r = 0.579, VAS score correlation coefficient r = 0.242, T2 value correlation coefficient r=-0.293, P < 0.001). Age-stratified analysis of the patients in the microfracture combined with fibrinogen platelet-rich plasma treatment group showed that the effect of the combined treatment was more pronounced in elderly patients. CONCLUSIONS: The results of the study showed that compared with microfracture alone, microfracture combined with fibrinogen platelet-rich plasma therapy can further improve patients' knee joint-related function and their quality of life after treatment. The improvement was more obvious in elderly patients.

Genome-Wide Association Studies of Hair Whorl in Pigs.

BACKGROUND: In pigs, a hair whorl refers to hairs that form a ring of growth around the direction of the hair follicle at the dorsal hip. In China, a hair whorl is considered a negative trait that affects marketing, and no studies have been conducted to demonstrate whether hair whorl affects pig performance and provide an explanation for its genetic basis. METHODS: Performance-measured traits and slaughter-measured traits of hair whorl and non-hair whorl pigs were differentially analyzed, followed by genome-wide association analysis (GWAS) and copy number variation (CNV) methods to investigate the genetic basis of hair whorl in pigs. RESULTS: Differential analysis of 2625 pigs (171 hair whorl and 2454 non-hair whorl) for performance measures showed that hair whorl and non-hair whorl pigs differed significantly (p < 0.05) in traits such as live births, total litter size, and healthy litter size (p < 0.05), while differential analysis of carcass and meat quality traits showed a significant difference only in the 45 min pH (p = 0.0265). GWAS identified 4 SNP loci significantly associated with the hair whorl trait, 2 of which reached genome-significant levels, and 23 candidate genes were obtained by annotation with the Ensembl database. KEGG and GO enrichment analyses showed that these genes were mainly enriched in the ErbB signaling, endothelial apoptosis regulation, and cell proliferation pathways. In addition, CNV analysis identified 652 differential genes between hair whorl and non-hair whorl pigs, which were mainly involved in the signal transduction, transcription factor activity, and nuclear and cytoplasmic-related pathways. CONCLUSIONS: The candidate genes and copy number variation differences identified in this study provide a new theoretical basis for pig breeding efforts.

Key Magnetized Exosomes for Effective Targeted Delivery of Doxorubicin Against Breast Cancer Cell Types in Mice Model.

Introduction: Exosomes (Exos) are promising drug delivery systems due to their low immunogenicity, minimal toxicity, high biocompatibility, and effective delivery capabilities. However, addressing the cardiotoxicity and other toxic side effects associated with anthracyclines has proven challenging. Methods: In this study, we loaded doxorubicin (Dox) into Exos derived from human placental mesenchymal stem cells (MSCs) and modified them with carboxylated Fe3O4 nanoparticles (NPs) to create an Exo-Dox-NP delivery system. Using an external magnetic force (MF), we regulated the distribution of Exos for targeted Dox delivery in breast cancer treatment. We characterized and determined the drug-loading efficiency of Exo-Dox-NPs, their uptake by tumor cells, and the modulation of drug release. The therapeutic efficacy of Exo-Dox-NPs was evaluated through both in vitro and in vivo anti-tumor experiments. Results: Our results indicated that Exo-Dox-NPs remain stable in the bloodstream while releasing the drug in the acidic environment of tumor cells and their lysosomes. As a drug delivery system, Exo-Dox-NPs enhanced Dox absorption by tumor cells, demonstrating high targeting specificity. Moreover, Exo-Dox-NPs inhibited the migration of breast cancer cells, as confirmed by scratch migration and Transwell Matrigel invasion assays. In vivo experiments confirmed the effective targeting and delivery of Dox to malignant tumors using Exo-Dox-NPs/MFs, with the Exo-Dox-NP/MF formulation exhibiting the most potent anti-tumor activity. Conclusion: The utilization of Exos as carriers for Dox showed promising efficacy in breast cancer management. Carboxylated Fe3O4 NPs demonstrated to be suitable targeting agents, potentially advancing the development of natural nanocarriers for combination cancer therapy.

The outcome of advanced and recurrent cervical cancer patients treated with first-line platinum and paclitaxel with or without indication for immune checkpoint inhibitors: the comparative study.

OBJECTIVE: Immune checkpoint inhibitor (ICI) therapy activates the immune system to recognize and eliminate cancer cells that have escaped surveillance. This study aimed to compare the treatment outcome of advanced and recurrent cervical cancer patients treated with first-line platinum and paclitaxel with or without ICI. METHODS: Data from 69 advanced and recurrent cervical cancer patients treated with first-line ICI plus platinum and paclitaxel (N = 33) or first-line platinum and paclitaxel (N = 36) were reviewed between March 2020 and January 2023 in this retrospective study. Patients chose treatment based on the actual disease condition, patient willingness, and medical advice. Additionally, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were calculated, and adverse events were gained. RESULTS: There was no difference in baseline data between patients receiving the two different treatments (all P > 0.05). Complete response rate (18.2% vs. 8.3%; P = 0.294), ORR (48.5% vs. 30.6%; P = 0.127), and DCR (81.8% vs. 72.2%; P = 0.345) tended to ascend in patients treated with ICI plus platinum and paclitaxel compared to those treated with platinum and paclitaxel, although there was no statistical significance. In patients treated with ICI plus platinum and paclitaxel, the median PFS was 10.3 months and the median OS was not reached. Meanwhile, the median PFS and OS were 7.7 and 16.9 months in patients treated with platinum and paclitaxel. PFS (P = 0.036) and OS (P = 0.033) were increased in patients treated with ICI plus platinum and paclitaxel versus those treated with platinum and paclitaxel, which was verified by multivariate Cox regression analyses (both P < 0.05). No difference was observed in the occurrence of adverse events between patients receiving the two different treatments (all P > 0.05). CONCLUSION: First-line ICI plus platinum and paclitaxel yields better treatment responses, longer survival, and non-differential adverse events versus first-line platinum and paclitaxel in advanced and recurrent cervical cancer patients.

Prognostic value of PLEKHA4 and its correlation with tumor-infiltrating immune cells in breast cancer: a comprehensive study based on bioinformatics and clinical analysis validation.

Background: Pleckstrin homology containing family A, number 4 (PLEKHA4) plays a role in a number of biological processes in human cells, including cell polarization, growth, and proliferation. However, the relationship between PLEKHA4 expression and survival in breast cancer (BC) remains unclear. The aim of this study is to investigate the potential of PLEKHA4 as a prognostic indicator in BC. Methods: We obtained gene expression profiles of BC and normal tissues from the Tumor Immune Estimation Resource (TIMER), UALCAN web. Immunohistochemistry (IHC) staining was performed to investigate the protein expression and prognostic value of PLEKHA4 in BC patients. The prognostic value was analyzed using Kaplan-Meier curve analysis and Cox regression analysis in R software after downloading The Cancer Genome Atlas (TCGA) databases. The correlations between PLEKHA4 and tumor immune infiltrates were investigated via gene set variation analysis (GSVA). Signaling pathways related to PLEKHA4 expression were identified by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Results: Both bioinformatics and IHC results showed that PLEKHA4 was expressed at low levels in BC tissues compared with the adjacent tissues. Furthermore, the expression of PLEKHA4 was negatively correlated with ages (χ2=6.394, P=0.01), molecular subtype (χ2=15.606, P=0.001), lymph node metastasis (χ2=13.753, P=0.004), tumor-node-metastasis (TNM) stage (χ2=22.616, P<0.001). Kaplan-Meier curves implicated low expression of PLEKHA4 was associated with worse survival of BC patients [hazard ratio (HR) =0.46, P=0.01]. Cox regression models showed that low PLEKHA4 expression could be an independent risk factor for BC (HR =0.911, P=0.006). The results of gene set enrichment analysis (GSEA) showed that cell cycle, Notch signaling pathway, nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, and Rho GTPases were highly enriched in the low PLEKHA4 expression group, as identified by GO and KEGG. Additionally, in BC, PLEKHA4 expression displayed a positive correlation with the infiltration of natural killer (NK) cells (P<0.001), CD8+ T cells (P<0.001), B cells (P<0.001), neutrophils (P<0.001), and dendritic cells (DCs) (P<0.001). Conclusions: The findings indicate that PLEKHA4 is an independent prognostic biomarker associated with key signaling pathways and immune infiltration in BC. Targeting PLEKHA4 may contribute to improving immunotherapy for BC.

Applications and challenges of photodynamic therapy in the treatment of skin malignancies.

Photodynamic Therapy (PDT), as a minimally invasive treatment method, has demonstrated its distinct advantages in the management of skin malignant tumors. This article examines the current application status of PDT, assesses its successful cases and challenges in clinical treatment, and anticipates its future development trends. PDT utilizes photosensitizers to interact with light of specific wavelengths to generate reactive oxygen species that selectively eradicate cancer cells. Despite PDT's exceptional performance in enhancing patients' quality of life and prognosis, the limitation of treatment depth and the side effects of photosensitizers remain unresolved issues. With the advancement of novel photosensitizers and innovative treatment technology, the application prospects of PDT are increasingly expansive. This article delves into the mechanism of PDT, its application in various skin malignancies, its advantages and limitations, and envisions its future development. We believe that through continuous technological enhancements and integration with other treatment technologies, PDT has the potential to assume a more pivotal role in the treatment of skin malignancies.

Aspirin enhances radio/chemo-therapy sensitivity in C. elegans by inducing germ cell apoptosis and suppresses RAS overactivated tumorigenesis via mtROS-mediated DNA damage and MAPK pathway.

Previous studies have demonstrated that combination therapy involving radiotherapy and aspirin decreases the survival rate of cancer cells. However, the mechanism by which aspirin exerts its radiation sensitization effect at the in vivo level remains largely unclear. In this study, we employed Caenorhabditis elegans (C. elegans) as a model organism to investigate the effect of aspirin combined with radio/chemo-therapy on tumors at the individual level. Here, we illustrate that high-dose aspirin increases the expression of genes involved in core apoptosis pathways (egl-1, ced-9, ced-4 and ced-3) and induces germ cell apoptosis in C. elegans through mitochondrial outer membrane permeabilization (MOMP) and elevation of reactive oxygen species (ROS) levels. Crucially, aspirin-induces ROS upregulates the expression of genes critical for DNA damage response (hus-1, clk-2 and cep-1) and genes involved in MAPK pathways (lin-45, mek-2, mpk-1, sek-1 and pmk-1), thereby mediating the enhanced sensitivity of radio/chemo-therapy by aspirin. Notably, aspirin fails to induce germ cell apoptosis and enhance radio/chemo-therapy in C. elegans lacking the expression of each of those genes. Furthermore, in a C. elegans tumor-like symptom model, aspirin enhances radio/chemo-therapy sensitivity through ROS induction. However, low-dose aspirin can diminish the apoptotic signal of reproductive cells in C. elegans and exert anti-inflammatory effects. Our research results suggest that the tumor-suppressive and radio/chemo-therapy sensitizing effects of aspirin provide robust experimental evidence for improving the clinical efficacy of tumor radio/chemo-therapy and deepening our understanding of aspirin's mechanism of action in cancer.

Safety and efficacy of traditional Chinese manual therapy for cervicogenic dizziness: study protocol for a randomized, controlled, multicenter trial.

Background: Cervicogenic dizziness is a clinical syndrome characterized by neck pain and dizziness, which has a rising incidence in recent years. In China, manual therapy has been widely used in the treatment of cervicogenic dizziness, but there is no high-quality medical evidence to support its effectiveness and safety. The purpose of this study was to assess the safety and efficacy of Shi's manual therapy (SMT) on the treatment of cervicogenic dizziness. Methods: A multicenter randomized controlled trial (RCT) will perform on 106 patients (18≤ages≤65) who meet the diagnostic criteria of cervicogenic dizziness. Patients will be randomly allocated to the intervention group and the control group at a ratio of 1:1. Participants in the control group will be treated with Merislon (Betahistine Mesilate Tablets). Participants in the intervention group will be treated with SMT. The primary outcome is the response rate at week 2, which is defined as the proportion of patients who reduce their disability level measured by the Dizziness Handicap Inventory (DHI) score relative to baseline. Key secondary outcomes include DHI scores at weeks 1, 2, and 6 and changes from baseline, time to disappearance of dizziness symptoms, and recurrence rate of dizziness symptoms. Safety will be assessed by adverse events, physical examination and vital signs. Discussion: This trial aims to provide high-quality evidence-based medical data to demonstrate that SMT can reduce dizziness in patients with cervicogenic dizziness effectively and safely. Trial registration: Clinical Trial Registration Center NCT05604937. Registered on Nov 3, 2022. Protocol version: 1.0, November 20, 2022.

Accumulation of rare earth elements in human gallstones: a perspective from dietary and human health.

BACKGROUND: Gallstone disease poses a global threat to human health and is strongly linked to environmental factors. However, there is currently no data on the presence of rare earth elements (REEs) in human gallstones. This paper investigates the concentration and distribution of REEs in gallstones for the first time, aiming to explore the environmental implications on human health. METHODS: A total of 25 gallstone samples were collected in Shanghai and the content of REEs was measured by Inductively coupled plasma-Mass Spectrometry (ICP-MS) to explore the distribution of REEs in gallstones. RESULTS: The concentration of REEs in gallstones ranged from 4.89 to 190.8 ng/g (mean 39.21). In most of the gallstone analyses, REEs have been detected and generally attributed to environmental exposure or food contamination. The Y/Ho ratio of gallstones was lower than that of continental rocks, similar to that in the blood, indicating limited fractionation during fluid transport processes in the gallbladder. CONCLUSIONS: The upper continental crust (UCC)-normalized REEs pattern in gallstones showed depletion of light REEs, while most showed enrichment of heavy REEs. Positive Gd anomalies were found in most samples, while few samples suggested anthropogenic influence. Whether exogenous inputs or in vivo biofractionation lead to changes in REEs fractionated patterns require further analyses.

Cell-free adipose tissue extracts as a novel treatment for rosacea by downregulating TRPV1.

Rosacea is a chronic inflammatory skin disease that typically affects the central facial area. Its main clinical symptoms include paroxysmal flushing, telangiectasia, and non-temporary erythema. Cell-free adipose tissue extracts (ATEs) are liquid components extracted from human adipose tissue that contain large amounts of growth factors. Despite the scar-reducing, anti-aging, and wound-healing effects of ATEs, the efficacy of ATEs in rosacea remains unknown. Therefore, the anti-rosacea effects of ATEs were investigated in human cathelicidin peptide (LL-37) induced rosacea mice and capsaicin (CAP)-stimulated HaCaT keratinocytes. In vitro, ATEs significantly reduced TRPV1 expression, intracellular calcium ions influx and the release of inflammatory factors (such as KLK5, IL-6, IL-8 and TNF-α) after intervening in CAP-stimulated cells. The in vivo results revealed that ATEs alleviated rosacea symptoms, such as erythema score, erythema area, transepidermal water loss, abnormal epidermal thickness, mast cell infiltration and telangiectasia upon downregulating TRPV1 and CD31 expression. Moreover, the up-regulated TRPV1 protein expression was also recovered by ATEs administration in vivo and in vitro. Meanwhile, ATEs demonstrated good biocompatibility. In summary, ATEs could be a potential therapeutic agent for rosacea by regulating inflammation and alleviating telangiectasia.

Mutations in ADAMTSL4 cause a unique form of autosomal-recessive congenital ectopia lentis.

Several unique mutations of ADAMTSL4 leading to congenital ectopia lentis (CEL) have been previously reported by our team. The purpose of this study is to find out the possible mechanism of a recurrent novel intronic variant in ADAMTSL4 led to CEL. Twelve novel ADAMTSL4 mutations with a unique form congenital ectopic lentis were detected previously by panel-based NGS. Genetic analysis verified a novel heterozygous ADAMTSL4 variation c.2177+4A > G on Intron 11 in two unrelated patients with iris and lens abnormalities. MINI-Gene assay showed two splicing modes of mRNA that process two different bands A and B, and mutant-type shows replacement with the splicing mode of Exon 11 skipping. Construction of wild-type and mutant ADAMTSL4 vector showed the appearance of premature termination codons (PTC). In vitro expression detection showed significant down-regulated expression level of ADAMTSL4 mRNAs and proteins in cells transfected with mutant vectors compared with in wild-type group. On the contrary, translation inhibitor CHX and small interfering RNA of UPF1 (si-UPF1) significantly increased mRNA or protein expression of ADAMTSL4 in cells transfected with the mutant vectors. 12 novel mutations in ADAMTSL4 gene have been previously reported by our team in 6 CEL patients with a unique series of ocular abnormalities. The recurrent novel ADAMTSL4 mutation c.2177+4A > G triggering the splicing mode of Exon 11 skipping and NMD would cause the decrease of ADAMTSL4 proteins that participate in biosynthesis and assembly of microfibers, which might lead to CEL, and suggest that sequencing of certain intronic splicing varition might be a vital tool for genetic counseling and prenatal diagnoses.

3D-Printed Breast Prosthesis that Smartly Senses and Targets Breast Cancer Relapse.

Breast reconstruction is essential for improving the appearance of patients after cancer surgery. Traditional breast prostheses are not appropriate for those undergoing partial resections and cannot detect and treat locoregional recurrence. Personalized shape prostheses that can smartly sense tumor relapse and deliver therapeutics are needed. A 3D-printed prosthesis that contains a therapeutic hydrogel is developed. The hydrogel, which is fabricated by crosslinking the polyvinyl alcohol with N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N1, N1, N3, N3-tetramethylpropane-1,3-diaminium, is responsive to reactive oxygen species (ROS) in the tumor microenvironment. Specifically, RSL3, a ferroptosis inducer that is loaded in hydrogels, can trigger tumor ferroptosis. Intriguingly, RSL3 encapsulated in the ROS-responsive hydrogel exerts antitumor effects by increasing the numbers of tumor-infiltrated CD4+ T cells, CD8+ T cells, and M1 macrophages while reducing the number of M2 macrophages. Therefore, this new prosthesis not only allows personalized shape reconstruction, but also detects and inhibits tumor recurrence. This combination of aesthetic appearance and therapeutic function can be very beneficial for breast cancer patients undergoing surgery.