Plasma metabolomic profiling reveals a novel circulating biomarker signature in chronic pruritus of unknown origin.

Chronic pruritus of unknown origin (CPUO) is characterized by chronic itch for 6 weeks or greater without an identifiable primary cause. Studies are needed to investigate circulating blood biomarkers to elucidate disease pathogenesis. The objective of this study was to investigate changes in circulating blood metabolites in CPUO patients and to identify potential therapeutic targets. Our cross-sectional study collected plasma from 11 CPUO patients and 11 matched control patients for mass-spectrometry based metabolite data analysis. 15 metabolites differed significantly in the blood of CPUO patients compared to controls, including nine amino acids (isoleucine, L-tyrosine, threonine, DL-tryptophan, L-valine, methionine, glycine, lysine, and L-phenylalanine), four amino acid derivatives (creatinine, DL-carnitine, acetyl-L-carnitine, and indole-3-acrylic acid), and two aromatic and fatty acid derivatives (2-hydroxycinnamic acid and oleamide). These metabolites were also correlated with itch severity. Metabolic set enrichment analysis (MSEA) identified downregulation of several pathways in CPUO: phenylalanine, tyrosine, tryptophan biosynthesis; catecholamine biosynthesis; and glycine, serine, and threonine metabolism. Our study identified decreases in several circulating plasma metabolites in CPUO patients and downregulation of pathways related to catecholamine biosynthesis and tryptophan biosynthesis, providing insight into the pathogenesis of CPUO.

Integrated plasma metabolomic and cytokine analysis reveals a distinct immunometabolic signature in atopic dermatitis.

Importance: Disease models for atopic dermatitis (AD) have primarily focused on understanding underlying environmental, immunologic, and genetic etiologies. However, the role of metabolic mechanisms in AD remains understudied. Objective: To investigate the circulating blood metabolomic and cytokine profile of AD as compared to healthy control patients. Design: This study collected plasma from 20 atopic dermatitis with moderate-to-severe itch (score of ≥5 on the itch Numeric Rating Scale and IGA score ≥3) and 24 healthy control patients. Mass-spectrometry based metabolite data were compared between AD and healthy controls. Unsupervised and supervised machine learning algorithms and univariate analysis analyzed metabolic concentrations. Metabolite enrichment and pathway analyses were performed on metabolites with significant fold change between AD and healthy control patients. To investigate the correlation between metabolites levels and cytokines, Spearman's rank correlation coefficients were calculated between metabolites and cytokines. Setting: Patients were recruited from the Johns Hopkins Itch Center and dermatology outpatient clinics in the Johns Hopkins Outpatient Center. Participants: The study included 20 atopic dermatitis patients and 24 healthy control patients. Main outcomes and measures: Fold changes of metabolites in AD vs healthy control plasma. Results: In patients with AD, amino acids isoleucine, tyrosine, threonine, tryptophan, valine, methionine, and phenylalanine, the amino acid derivatives creatinine, indole-3-acrylic acid, acetyl-L-carnitine, L-carnitine, 2-hydroxycinnamic acid, N-acetylaspartic acid, and the fatty amide oleamide had greater than 2-fold decrease (all P-values<0.0001) compared to healthy controls. Enriched metabolites were involved in branched-chain amino acid (valine, leucine, and isoleucine) degradation, catecholamine biosynthesis, thyroid hormone synthesis, threonine metabolism, and branched and long-chain fatty acid metabolism. Dysregulated metabolites in AD were positively correlated cytokines TARC and MCP-4 and negatively correlated with IL-1a and CCL20. Conclusions and relevance: Our study characterized novel dysregulated circulating plasma metabolites and metabolic pathways that may be involved in the pathogenesis of AD. These metabolic pathways serve as potential future biomarkers and therapeutic targets in the treatment of AD.

Spatial Mass Cytometry-Based Single-Cell Imaging Reveals a Disrupted Epithelial-Immune Axis in Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic, inflammatory skin condition that disproportionately affects African Americans and features intensely pruritic, hyperkeratotic nodules on the extremities and trunk. PN is understudied compared with other inflammatory skin diseases, with the spatial organization of the cutaneous infiltrate in PN yet to be characterized. In this work, we employ spatial imaging mass cytometry to visualize PN lesional skin inflammation and architecture with single-cell resolution through an unbiased machine learning approach. PN lesional skin has increased expression of caspase 3, NF-kB, and phosphorylated signal transducer and activator of transcription 3 compared with healthy skin. Keratinocytes in lesional skin are subdivided into CD14+CD33+, CD11c+, CD63+, and caspase 3-positive innate subpopulations. CD14+ macrophage populations expressing phosphorylated extracellular signal-regulated kinase 1/2 correlate positively with patient-reported itch (P = .006). Hierarchical clustering reveals a cluster of patients with PN with greater atopy, increased NF-kB+ signal transducer and activator of transcription 3-positive phosphorylated extracellular signal-regulated kinase 1/2-positive monocyte-derived myeloid dendritic cells, and increased vimentin expression (P < .05). Neighborhood analysis finds interactions between CD14+ macrophages, CD3+ T cells, monocyte-derived myeloid dendritic cells, and keratinocytes expressing innate immune markers. These findings highlight phosphorylated extracellular signal-regulated kinase-positive CD14+ macrophages as contributors to itch and suggest an epithelial-immune axis in PN pathogenesis.

Dysregulation of the Skin-Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis.

Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin-liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.

Student engagement in voluntary service in response to COVID-19 in Guangzhou, China: Implications for disease control and public health education from a cross-sectional study.

Public health students have been seen as a potential force to meet the demand for health workers during the coronavirus disease 2019 (COVID-19) pandemic. However, few studies have provided empirical data. This study was conducted to summarize the experiences of public health students who engaged in voluntary service in response to the COVID-19 outbreak in Guangzhou, China. A cross-sectional study was conducted among postgraduate and undergraduate students at the School of Public Health, Guangdong Pharmaceutical University, in August 2021. A self-designed online questionnaire was used to collect data on the experience of voluntary service during the early stage of the outbreak (in February 2020) and during the normalization stage of the prevention and control of COVID-19 (in June 2021) in China. Among the 96 students, 40 (41.7%) participated in voluntary service in February 2020, and 56 (58.3%) participated in voluntary service in June 2021. Most of the students participated in the voluntary service due to the motivations to help others (55.2%), to apply theoretical knowledge to practice (74.0%), to improve their fieldwork skills (72.9%), and to gain the experience for future careers (80.2%). Most volunteers were driven by professional responsibility (81.3%). More than half (53.1%) of the students felt anxious during their voluntary service. A lower proportion of students felt anxious in June 2021 than in February 2020 (44.6% vs 65.0%, P = .049), while a higher proportion of students found voluntary service harder than expected in June 2021 than in February 2020 (33.9% vs 7.5%, P = .002). Most students improved their knowledge and skills about COVID-19 after the training, but some knowledge and skills still needed improvement after their voluntary service. Public health students could help support the health system during the COVID-19 pandemic by providing adequate training and protection. More efforts should be made to provide psychological support for student volunteers and to optimize the curriculum to bridge the gap in public health education between theoretical knowledge and practical skills in responding to public health emergencies.

The clinical development of antibody-drug conjugates for non-small cell lung cancer therapy.

Despite the emergence of molecular targeted therapy and immune checkpoint inhibitors as standard first-line treatments for non-small cell lung cancer (NSCLC), their efficacy in some patients is limited by intrinsic and acquired resistance. Antibody-drug conjugates (ADCs), a revolutionary class of antitumor drugs, have displayed promising clinical outcomes in cancer treatment. In 2022, trastuzumab deruxtecan (Enhertu) was approved for treating HER2-mutated NSCLC, thereby underscoring the clinical value of ADCs in NSCLC treatment strategies. An increasing number of ADCs, focusing on NSCLC, are undergoing clinical trials, potentially positioning them as future treatment options. In this review, we encapsulate recent advancements in the clinical research of novel ADCs for treating NSCLC. Subsequently, we discuss the mechanisms of action, clinical efficacy, and associated limitations of these ADCs.

Targeting Trop2 in solid tumors: a look into structures and novel epitopes.

Trophoblast cell surface antigen 2 (Trop2) exhibits limited expression in normal tissues but is over-expressed across various solid tumors. The effectiveness of anti-Trop2 antibody-drug conjugate (ADC) in managing breast cancer validates Trop2 as a promising therapeutic target for cancer treatment. However, excessive toxicity and a low response rate of ADCs pose ongoing challenges. Safer and more effective strategies should be developed for Trop2-positive cancers. The dynamic structural attributes and the oligomeric assembly of Trop2 present formidable obstacles to the progression of innovative targeted therapeutics. In this review, we summarize recent advancements in understanding Trop2's structure and provide an overview of the epitope characteristics of Trop2-targeted agents. Furthermore, we discuss the correlation between anti-Trop2 agents' epitopes and their respective functions, particularly emphasizing their efficacy and specificity in targeted therapies.

Effects of climbing exercise intervention on gross motor development in children aged 8 to 9 years / 中国学校卫生

Objective@#The purpose of this study was to determine the effect of climbing exercise intervention on gross motor function in children aged 8 to 9 years, and to provide a theoretical basis and scientific reference for the application of climbing exercise in the improvement of children health.@*Methods@#Random sampling method was used to select 53 children aged 8-9 from a public school in Haidian District in Beijing, and children were randomly divided into control group (n=30) and exercise group (n=23), children in the exercise group received climbing exercises for 8 weeks . KTK test was used to assess gross motor development.@*Results@#After intervention, the gross motor level of male and female children in Exercise group were significantly higher than before (in male group, before intervention, KTK score：217.5±32.3，after intervention, KTK score：245.1±24.2，P<0.01；in female group, before intervention, KTK score: 219.6±30.3, after intervention, KTK score: 246.9±23.2，P<0.01); while the gross motor level in control group had no significant change compared to the intervention state before(in male group, before intervention, KTK score：219.9±26.8，after intervention, KTK score：224.8±30.2，P>0.05；in female group, before intervention, KTK score: 216.6±18.1，after intervention, KTK score:214.8±28.6，P>0.05). There were no differences of gross motor level between sham and exercise group at baseline (P>0.05). After intervention, except the MS scores (P>0.05), other test program scores were higher than those of control group (in exercise group, WB: 52.1±6.8; HH: 61.7±8.7; JS: 73.7±7.6; in control group, WB: 43.1±9.9; HH: 54.5±15.2; JS: 64.9±6.8) (P<0.01).@*Conclusion@#Our research shows that climbing exercise intervention helps promoting the children’s physical quality, and establishes substantial foundation for the formation and promotion of sports cognition and complex motor skills.