BACKGROUND:Hematoporphyrin monomethyl ether-mediated photodynamic therapy (HMME-PDT) is an emerging treatment for port-wine stain (PWS). OBJECTIVE:To compare the effectiveness and safety of HMME-PDT with pulsed dye laser (PDL) for PWS on the face and neck. METHODS:A retrospective study was conducted comparing 728 patients treated with HMME-PDT and 655 with PDL. Logistic regression was used to assess effectiveness. An excellent improvement was defined as ≥75% lesion clearance. RESULTS:Before adjustment, 41.5% of patients showed excellent improvement after a median of 2 HMME-PDT sessions and 29.2% after a median of 3 PDL sessions. After adjusting for confounders, the HMME-PDT group was more likely to achieve excellent improvement (odds ratio: 2.90, 95% confidence interval: 2.02-4.15, P < .05) than the PDL group. Effectiveness was primarily influenced by lesion size, thickness, number of treatment sessions, and prior treatment. HMME-PDT showed higher incidences of hyperpigmentation (5.4% vs 1.8%, P < .05) and scarring (3.3% vs 0.5%, P < .05) than PDL. LIMITATIONS:The retrospective design and lack of long-term follow-up. CONCLUSION:HMME-PDT showed superior effectiveness than PDL for treating facial and neck PWS, but it carried a higher risk of hyperpigmentation and scarring.

Background:Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe and potentially lethal adverse drug reaction. Its clinical complexity and heterogeneity pose challenges for diagnosis and management. Methods:We retrospectively reviewed the medical records of patients with DRESS who were admitted to our hospital between 2013 and 2022. Data on demographics, culprit drugs, clinical manifestations, laboratory findings, and treatments were collected. Results:Fifty-one patients were included in the final analysis, with 16 probable and 35 definite cases. The most common causative drugs were antiepileptic drugs (15.7%), anti-tuberculosis drugs (15.7%), and Chinese herbs (9.8%). Common skin manifestations included extensive skin involvement (76.5%), facial edema (66.7%), polymorphic maculopapular lesions (66.7%), and exfoliation (56.9%). Eosinophilia and atypical lymphocytes were noted in 96.1% and 68.6% of the patients, respectively. The liver is the most frequently affected organ. Facial edema, extensive skin involvement, and atypical lymphocytes were correlated with higher Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scores (P<0.05). DRESS induced by antiepileptic drugs, antituberculosis drugs, and Chinese herbs exhibited significant differences in platelet and lymphocyte counts, C-reactive protein (CRP) levels, and transaminase levels (P<0.05). Conclusion:Clinical manifestations of DRESS are complex. Facial edema, extensive skin involvement, and atypical lymphocytes have emerged as significant diagnostic indicators.

Programmed cell death (PCD) is characterized as a cell death pathway governed by specific gene-encoding requirements, plays crucial roles in the homeostasis and innate immunity of organisms, and serves as both a pathogenic mechanism and a therapeutic target for a variety of human diseases. Z-DNA-binding protein 1 (ZBP1) functions as a cytosolic nucleic acid sensor, utilizing its unique Zα domains to detect endogenous or exogenous nucleic acids and its receptor-interacting protein homotypic interaction motif (RHIM) domains to sense or bind specific signaling molecules, thereby exerting regulatory effects on various forms of PCD. ZBP1 is involved in apoptosis, necroptosis, pyroptosis, and PANoptosis and interacts with molecules, such as receptor-interacting protein kinase 3 (RIPK3), to influence cell fate under various pathological conditions. It plays a crucial role in regulating PCD during infections, inflammatory and neurological diseases, cancers, and other conditions, affecting disease onset and progression. Targeting ZBP1-associated PCD may represent a viable therapeutic strategy for related pathological conditions. This review comprehensively summarizes the regulatory functions of ZBP1 in PCD and its interactions with several closely associated signaling molecules and delineates the diseases linked to ZBP1-mediated PCD, along with the potential therapeutic implications of ZBP1 in these contexts. Ongoing research on ZBP1 is being refined across various disease models, and these advancements may provide novel insights for studies focusing on PCD, potentially leading to new therapeutic options for related diseases.

Chemoresistance is the leading cause of cancer-related death. How chemotherapy subjugates the cellular crosstalk in the tumour microenvironment to cause chemoresistance remains to be defined. Here we find chemotherapy enables immunosuppressive SDF1+ endothelial niche to evade immunosurveillance in ovarian and breast cancers. We integrated human patient data and mouse models to show that chemotherapy selectively activates PARP1-SDF1 axis in tumour endothelial cells (ECs). This angiocrine SDF1 interferes with antitumour interplay between CXCL10+ macrophages and CXCR3+CD8+ T cells and promotes tumour progression in ovarian and breast cancers. Proteome-based screening revealed that endothelial PARP1 PARylates MLKL, a key necroptosis effector to upregulate angiocrine SDF1 in ECs. In sum, we identify PARylation-dependent necroptosis in tumour ECs as an important step in subverting the tumour microenvironment to evade immunosurveillance.

The Son of Sevenless 1 (SOS1) guanine nucleotide exchange factor, prevalent across eukaryotic species, plays a pivotal role in facilitating the attachment of RAS protein to GTP, thereby regulating the activation of intracellular RAS proteins. This regulation is part of a feedback mechanism involving SOS1, which allows both activators and inhibitors of SOS1 to exert control over downstream signaling pathways, demonstrating potential anti-tumor effects. Predominantly, small molecule modulators that target SOS1 focus on a hydrophobic pocket within the CDC25 protein domain. The effectiveness of these modulators largely depends on their ability to interact with specific amino acids, notably Phe890 and Tyr884. This interaction is crucial for influencing the protein-protein interaction (PPI) between RAS and the catalytic domain of SOS1. Currently, most small molecule modulators targeting SOS1 are in the preclinical research phase, with a few advancing to clinical trials. This progression raises safety concerns, making the assurance of drug safety a primary consideration alongside the enhancement of efficacy in the development of SOS1 modulators. This review encapsulates recent advancements in the chemical categorization of SOS1 inhibitors and activators. It delves into the evolution of small molecule modulation targeting SOS1 and offers perspectives on the design of future generations of selective SOS1 small molecule modulators.

The protein kinase ataxia telangiectasia mutated (ATM) is a constituent of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, exerting a pivotal influence on diverse cellular processes, notably the signaling of double-strand DNA breaks (DSB) and stress response. The dysregulation of ATM is implicated in the pathogenesis of cancer and other diseases such as neurodegeneration. Hence, ATM is deemed a promising candidate for potential therapeutic interventions across a spectrum of diseases. Presently, while ATM small molecule inhibitors are not commercially available, various selective inhibitors have progressed to the clinical research phase. Specifically, AZD1390, WSD0628, SYH2051, and ZN-B-2262 are under investigation in clinical studies pertaining to glioblastoma multiforme and advanced solid tumors, respectively. In this Perspective, we encapsulate the structure, biological functions, and disease relevance of ATM. Subsequently, we concentrate on the design concepts and structure–activity relationships (SAR) of ATM inhibitors, delineating potential avenues for the development of more efficacious ATM-targeted inhibitors.

Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.

G9a, a histone lysine methyltransferase, is instrumental in regulating gene expression through epigenetic modifications. Its overexpression is closely linked to the progression of various human diseases, including cancers. Therefore, targeting G9a enzyme is a promising strategy for treating various diseases. Although no G9a inhibitors have yet reached clinical trials, several small molecule inhibitors have demonstrated strong preclinical efficacy. For instance, the orally available inhibitor 16 (DS79932728) shows significant potential for treating sickle cell disease, while 34 (compound 15h) has shown promising treatment of rhabdomyosarcoma. This Perspective summarizes the protein structure and biological functions of G9a, along with its association with various diseases. We highlight the design strategies, structure–activity relationships, and biological activity assessments of G9a inhibitors. Additionally, we discuss the unique advantages of the mechanisms of novel G9a inhibitors, offering insights for the future development of more effective drugs targeting G9a.

The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for the treatment of cancer and other diseases. PROTACs have demonstrated significant advantages in targeting undruggable targets and overcoming drug resistance. However, despite the efficient degradation of targeted proteins achieved by PROTACs, they still face challenges related to selectivity between normal and cancer cells, as well as issues with poor membrane permeability due to their substantial molecular weight. Additionally, the noteworthy toxicity resulting from off-target effects also needs to be addressed. To solve these issues, Degrader-Antibody Conjugates (DACs) have been developed, leveraging the targeting and internalization capabilities of antibodies. In this review, we elucidates the characteristics and distinctions between DACs, and traditional Antibody-drug conjugates (ADCs). Meanwhile, we emphasizes the significance of DACs in facilitating the delivery of PROTACs and delves into the impact of various components on DAC activity. These components include antibody targets, drug-antibody ratio (DAR), linker types, PROTACs targets, PROTACs connections, and E3 ligase ligands. The review also explores the suitability of different targets (antibody targets or PROTACs targets) for DACs, providing insights to guide the design of PROTACs better suited for antibody conjugation.

Hepatocellular carcinoma is one of the leading cancers worldwide and is a potential consequence of fibrosis. Therefore, the identification of key cellular and molecular mechanisms involved in liver fibrosis is an important goal for the development of new strategies to control liver-related diseases. Here, single-cell RNA sequencing data (GSE136103 and GES181483) of clinical liver non-parenchymal cells were analyzed to identify cellular and molecular mechanisms of liver fibrosis. The proportion of endothelial subpopulations in cirrhotic livers was significantly higher than that in healthy livers. Gene ontology and gene set enrichment analysis of differentially expressed genes in the endothelial subgroups revealed that extracellular matrix (ECM)-related pathways were significantly enriched. Since anthrax toxin receptor 2 (ANTXR2) interacts with the ECM, the expression of ANTXR2 in the liver endothelium was analyzed. ANTXR2 expression in the liver endothelium of wild-type (WT) mice significantly decreased after a 4-time sequential injection of carbon tetrachloride (CCl4) to induce liver fibrosis. Next, conditional knockout mice selectively lacking Antxr2 in endothelial cells were generated. After endothelial-specific Antxr2 knockout mice were subjected to the CCl4 model, the degree of liver fibrosis in the knockout group was significantly more severe than that in the control group. In addition, ANTXR2 in human umbilical vein endothelial cells promoted matrix metalloproteinase 2 (MMP2) activation to degrade the ECM in vitro. Finally, endothelial-specific overexpression of Antxr2 alleviated the development of liver fibrosis following adeno-associated virus treatment. Collectively, these results suggested that endothelial ANTXR2 plays a protective role in liver fibrosis. This function of ANTXR2 may be achieved by promoting MMP2 activation to degrade the ECM.

BackgroundThe management of acne requires the consideration of its severity; however, a universally adopted evaluation system for clinical practice is lacking. Artificial intelligence (AI) evaluation systems hold the promise of enhancing the efficiency and reproducibility of assessments. Artificial intelligence (AI) evaluation systems offer the potential to enhance the efficiency and reproducibility of assessments in this domain. While the identification of skin lesions represents a crucial component of acne evaluation, existing AI systems often overlook lesion identification or fail to integrate it with severity assessment. This study aimed to develop an AI-powered acne grading system and compare its performance with physician image-based scoring.MethodsA total of 1,501 acne patients were included in the study, and standardized pictures were obtained using the VISIA system. The initial evaluation involved 40 stratified sampled frontal photos assessed by seven dermatologists. Subsequently, the three doctors with the highest inter-rater agreement annotated the remaining 1,461 images, which served as the dataset for the development of the AI system. The dataset was randomly divided into two groups: 276 images were allocated for training the acne lesion identification platform, and 1,185 images were used to assess the severity of acne.ResultsThe average precision of our model for skin lesion identification was 0.507 and the average recall was 0.775. The AI severity grading system achieved good agreement with the true label (linear weighted kappa = 0.652). After integrating the lesion identification results into the severity assessment with fixed weights and learnable weights, the kappa rose to 0.737 and 0.696, respectively, and the entire evaluation on a Linux workstation with a Tesla K40m GPU took less than 0.1s per picture.ConclusionThis study developed a system that detects various types of acne lesions and correlates them well with acne severity grading, and the good accuracy and efficiency make this approach potentially an effective clinical decision support tool.

Bacterial infections are characterized by their rapid and widespread proliferation, leading to significant morbidity. Despite the availability of a variety of antimicrobial drugs, the resistance exhibited by pathogenic microorganisms towards these drugs demonstrates a consistent upward trajectory year after year. This trend can be attributed to the abuse or misuse of antibiotics. Although antimicrobial peptides can avoid the emergence of drug resistance to a certain extent, their clinical application has been hindered by factors such as their high production cost, poor in vivo stability, and potential cytotoxicity. Consequently, there arises an urgent need for the development of novel antimicrobial drugs. Small-molecule amphiphatic antimicrobials have a good prospect for research and development. These peptides hold the potential to address several issues, including the high cost of antimicrobial peptide production, poor in vivo stability, and cytotoxicity. Moreover, they exhibit the capability to overcome bacterial resistance, thereby considerably satisfying market demands and clinical needs. This paper reviews recent research pertaining to small molecule host-defending amphiphatic antimicrobials with cationic amphiphilic structures. It focuses on the design concepts, inherent relationships, drug-like properties, antimicrobial activities, application prospects, and emerging screening methods for novel antimicrobial. This review assumes paramount importance in mitigating the current shortcomings of antimicrobial agents. It also provides potential new ideas and methodologies for the research and development of antimicrobial agents.

Background and objectives Port-wine stains are defined as congenital benign vascular lesions. The treatment of port-wine stains remains a challenge, worldwide. This study aimed to analyze the histological characteristics in different types of port-wine stains and provide guidance for clinical decision-making. Methods and materials Biopsies were from the hospital from 2015 to 2021. H&E staining, Immunofluorescence staining, Masson's trichrome staining and Weigert staining were performed on the tissues. Results A total of 35 port-wine stains patients were included in the study of four distinct types, namely red port-wine stains (11 cases), purple port-wine stains (seven cases), hypertrophic port-wine stains (nine cases) and nodular port-wine stains (eight cases). The mean vessel diameter of the different types was 38.7 ± 5.9 μm, 93.5 ± 9.7 μm, 155.6 ± 21.8 μm and 155.6 ± 29.54 μm, respectively. Mean vessel depth was 396.4 ± 31 μm, 944.2 ± 105.4 μm, 2,971 ± 161.3 μm and 3,594 ± 364.6 μm, respectively. The vessels in red port-wine stains, purple port-wine stains and hypertrophic port-wine stains were mainly composed of capillary and venous malformations, whereas those in nodular port-wine stains were venous or arteriovenous malformations. Limitation The main limitation of the current study was the small number of patients. Conclusion As the disease progresses, vessel diameters become larger, the vessel wall becomes thicker and vessels were found in a greater depth. A treatment plan should be scientifically formulated keeping in mind the histological characteristics of port-wine stains.

Background:Port-wine stains (PWS) are predominantly located on the face and neck. Hence, PWS affect not only aesthetic appearance but may also cause psychological distress. However, very few studies have researched on the quality of life (QoL) in Chinese patients with PWS.Aim:To evaluate QoL in patients with PWS.Methods and Materials:Skindex-29 and Dermatology Life Quality Index (DLQI) were used to investigate the QoL of the patients with PWS and healthy controls.Results:In total, 198 adults with PWS and 200 healthy controls were included. The scores of symptomatic, emotional and functional dimensions of Skindex-29 in the observational group were significantly higher as compared with the control group (P<0.05). Female gender, lesion location and the treatment history (such as pulsed dye laser or photodynamic therapy) had a negative impact on the scores (emotional and functional dimensions) of the patients with PWS. The median DLQI score was 3 points in the observational group and 0 points in the control group (P<0.05), and QoL of patients who had a history of previous treatments was diminished.Conclusion:The QoL of patients with PWS is impaired. Patients' QoL is negatively influenced by female gender, lesion location and treatment history. The Skindex-29 scale seems to be more applicable to the study of QoL of patients with PWS.

Hypoxic-ischemic encephalopathy (HIE) is associated with excessive inflammation, blood-brain barrier dysfunction, and oxidative stress. Irisin can reduce inflammation and ameliorate oxidative stress; however, its effects on hypoxic-ischemic brain damage in newborns are unknown. Newborn Sprague-Dawley rats were subjected to hypoxic-ischemic injury and irisin treatment. TUNEL staining assays, the albumin-Evans blue dye extravasation method, an antioxidants detection kit, quantitative reverse-transcriptase PCR, enzyme linked immunosorbent assay, Western blot analysis, immunohistochemistry, and electron microscopy were used to investigate the possible mechanisms underlying the prevention of HIE by irisin. We discovered that rats affected by HIE and administered irisin had lower levels of IL-6 (but not TNF-α or IL-1β) less oxidative stress, and enhanced blood-brain barrier integrity. Irisin can effectively attenuate brain damage by reducing oxidative stress and protecting the blood-brain barrier.

Port wine stain (PWS) is a congenital and progressive capillary malformation characterized by structural abnormalities of intradermal capillaries and postcapillary venules. The visible manifestation is often considered a disfigurement and the accompanying social stigma often causes serious emotional and physical impact. Hematoporphyrin monomethyl ether (HMME) is a newly authorized photosensitizer for treating PWS in China. Hematoporphyrin monomethyl ether photodynamic therapy (HMME-PDT) has successfully treated thousands of Chinese patients with PWS since 2017, and HMME-PDT may be one of the most promising strategies for the treatment of PWS. However, there are few reviews published about the clinical use of HMME-PDT. So in this article, we want to briefly review the mechanism, efficacy evaluation, effectiveness and influencing factors, and the common postoperative reactions and treatment suggestions of HMME-PDT in the treatment of PWS.

Lung metastasis of breast cancer is closely associated with patient morbidity and mortality, which correlates with myeloid cells in the lung microenvironment. However, the heterogeneity and specificity of metastasis-associated myeloid cells have not been fully established in lung metastasis. Here, by integrating and analyzing single-cell transcriptomics, we found that myeloid subpopulations (Tppp3(+) monocytes, Isg15(+) macrophages, Ifit3(+) neutrophils, and Il12b(+) DCs) play critical roles in the formation and development of the metastatic niche. Gene enrichment analyses indicate that several tumor-promoting pathways should be responsible for the process, including angiogenesis (Anxa1 and Anxa2 by Tppp3(+) monocytes), immunosuppression (Isg15 and Cxcl10 by Isg15(+) macrophages; Il12b and Ccl22 by Il12b(+) DCs), and tumor growth and metastasis (Isg15 and Isg20 by Ifit3(+) neutrophils). Furthermore, we have validated these subpopulations in lung microenvironment of MMTV-PyVT transgenic mice and verified their association with poor progression of human breast cancer. Also, our results elucidated a crosstalk network among four myeloid subpopulations by cell-cell communication analysis. This study, therefore, highlights the crucial role of myeloid cells in lung metastasis and provides insights into underlying molecular mechanisms, which pave the way for therapeutic interventions in breast cancer metastasis to lung.