A Spatiotemporal Controllable Biomimetic Skin for Accelerating Wound Repair.

Skin injury repair is a dynamic process involving a series of interactions over time and space. Linking human physiological processes with materials' changes poses a significant challenge. To match the wound healing process, a spatiotemporal controllable biomimetic skin is developed, which comprises a three-dimensional (3D) printed membrane as the epidermis, a cell-containing hydrogel as the dermis, and a cytokine-laden hydrogel as the hypodermis. In the initial stage of the biomimetic skin repair wound, the membrane frame aids wound closure through pre-tension, while cells proliferate within the hydrogel. Next, as the frame disintegrates over time, cells released from the hydrogel migrate along the residual membrane. Throughout the process, continuous cytokines release from the hypodermis hydrogel ensures comprehensive nourishment. The findings reveal that in the rat full-thickness skin defect model, the biomimetic skin demonstrated a wound closure rate eight times higher than the blank group, and double the collagen content, particularly in the early repair process. Consequently, it is reasonable to infer that this biomimetic skin holds promising potential to accelerate wound closure and repair. This biomimetic skin with mechanobiological effects and spatiotemporal regulation emerges as a promising option for tissue regeneration engineering.

Effects of UBE3A on the insulin resistance in polycystic ovary syndrome through the ubiquitination of AMPK.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a reproductive hormonal abnormality and a metabolic disorder, which is frequently associated with insulin resistance (IR). We aim to investigate the potential therapeutic effects of Ubiquitin-protein ligase E3A (UBE3A) on IR in the PCOS rats via Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. METHODS: The PCOS and IR rats model was established by dehydroepiandrosterone (DHEA) and high fat diet (HFD) treatment, and the fat rate, glucose tolerance and insulin tolerance were measured. The IR rats numbers were calculated. Besides, the mRNA levels of glucose transporter 4 (GLUT4) and UBE3A were detected by RT-qPCR. Furthermore, the relationship between was demonstrated by co-IP assay. The phosphorylation and ubiquitination of AMPK were analyzed by western blot. RESULTS: UBE3A was up-regulated in the PCOS rats. UBE3A knockdown significantly decreased the fat rate, glucose tolerance and insulin tolerance in the PCOS and IR rats. Additionally, the GLUT4 levels were significantly increased in PCOS + IR rats. Besides, after UBE3A knockdown, the IR rats were decreased, the p-IRS1 and p-AKT levels were significantly up-regulated. Furthermore, UBE3A knockdown enhanced phosphorylation of AMPK through decreasing the ubiquitination of AMPK. AMPK knockdown reversed the role of UBE3A knockdown in the PCOS + IR rats. CONCLUSIONS: UBE3A knockdown inhibited the IR in PCOS rats through targeting AMPK. Our study indicated that UBE3A might become a potential biological target for the clinical treatment of PCOS.

The long non-coding RNA BBOX1 antisense RNA 1 is upregulated in polycystic ovary syndrome (PCOS) and suppresses the role of microRNA-19b in the proliferation of ovarian granulose cells : Short title: BBOX1 antisense RNA 1 in cell proliferation.

BACKGROUND: MicroRNA-19b (miR-19b) has been reported to be downregulated in polycystic ovary syndrome (PCOS), while its upstream regulators are unclear. We speculated that miR-19b could potentially form a binding relationship with BBOX1 antisense RNA 1 (BBOX1-AS1), a long non-coding RNA recognized for its critical role in ovarian cancer. Subsequently, we investigated into their interaction in PCOS. METHODS: The expression of miR-19b and BBOX1-AS1 in follicular fluid from both control women (n = 80) and women with PCOS (n = 80) was detected by RT-qPCR. Correlations were analyzed with Pearson' correlation coefficient. The binding of miR-19b to the wild-type (-wt) ad mutant (-mut) BBOX1-AS1 was determined by RNA-RNA pulldown assay. Their interactions were detected by overexpression assay. Bromodeoxyuridine (BrdU) assay was applied for proliferation analysis. RESULTS: BBOX1-AS1 was highly upregulated, while miR-19b was downregulated in PCOS. There was no close correlation across PCOS and the control samples. Consistently, they did not regulate the expression of each other in granulosa cells. However, BBOX1-AS1-wt, but not BBOX1-AS1-mut, could directly interact with miR-19b. BBOX1-AS1 suppressed the role of miR-19b in inhibiting granulosa cell proliferation. CONCLUSION: BBOX1-AS1 is highly upregulated in PCOS, and it may serve as an endogenous competing RNA for miR-19b to suppress its role in inhibiting granulosa cell proliferation. Our study suggested the role of BBOX1-AS1 as a potential target to treat PCOS.

Differential Response of Mycosis Fungoides Cells to Vorinostat.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.

Multiprocedural Facial Feminization Surgery: A Review of Complications in a Cohort of 31 Patients.

OBJECTIVE: Facial feminization surgery (FFS) is instrumental in gender affirmation for transgender patients. Multiprocedural FFS, the combination of multiple facial feminization procedures across multiple depths and planes during one surgery, crosses sterile and nonsterile planes in the oropharynx, nose, and frontal sinus. A closer look at the prevention and management of resulting complications of such reconstruction is necessary. METHODS: We performed a retrospective review of patient demographics, operative variables, and postoperative complications on 31 FFS patients. Patients who underwent FFS between January 2020 and June 2021 were eligible for inclusion. Associations between prevention methods, procedure type, and complications were assessed by the Fisher exact test. The main effect of patient age and number of procedures on complication rate was assessed via the nonparametric Kruskal-Wallis test. RESULTS: A total of 31 patients, with a mean age of 37 years (range: 19-65 y, SD: 13.3 y), underwent 257 procedures. Patients underwent a mean of 8 procedures (SD: 2.2) lasting 3.5 to 6 hours (mean: 5.0 h, SD: 0.9 h). Overall, 68% of patients experienced no complications. Six patients experienced a postoperative infection; 4 of these patients required return for a washout. Preventative measures implemented include: preoperative dental check, intraoperative antibiotic irrigation, locking sutures, and postoperative antibiotics. After measures were implemented, there were no further procedure-related infections recorded. CONCLUSIONS: Patients do not suffer from major complications after multiprocedural FFS. Factors such as age, irrigation method, and dental history may be important variables affecting FFS outcomes.

Study on the pharmacokinetics, tissue distribution and excretion of laurolitsine from Litsea glutinosa in Sprague-Dawley rats.

CONTEXT: Laurolitsine is an aporphine alkaloid and exhibits potent antihyperglycemic and antihyperlipidemic effects in ob/ob mice. OBJECTIVE: To investigate the pharmacokinetics, tissue distribution and excretion of laurolitsine. MATERIALS AND METHODS: A LC-MS/MS method was established and validated to determine laurolitsine concentrations in the biological matrix of rats (plasma, tissue homogenate, urine and faeces). 10 Sprague-Dawley (SD) rats were used for plasma exposure study: 5 rats were injected with 2.0 mg/kg of laurolitsine via the tail vein, and the other 5 rats were administered laurolitsine (10.0 mg/kg) by gavage. 25 SD rats used for tissue distribution study and 5 SD rats for urine and faeces excretion study: rats administered laurolitsine (10.0 mg/kg) by gavage. After administered, serial blood, tissue, urine and faeces were collected. Analytical quantification was performed by a previous LC-MS/MS method. The pharmacokinetics, bioavailability, tissue distribution and excretion of laurolitsine were described. RESULTS: The pharmacokinetic parameters of oral and intravenous administration with Tmax were 0.47 and 0.083 h, t1/2 were 3.73 and 1.67 h, respectively. Oral bioavailability was as low as 18.17%. Laurolitsine was found at a high concentration in the gastrointestinal tract, liver, lungs and kidneys (26 015.33, 905.12, 442.32 and 214.99 ng/g at 0.5 h, respectively) and low excretion to parent laurolitsine in urine and faeces (0.03 and 1.20% in 36 h, respectively). CONCLUSIONS: This study established a simple, rapid and accurate LC-MS/MS method to determine laurolitsine in different rat samples and successful application in a pharmacokinetic study.

Simultaneous measurement of tadehaginoside and its principal metabolite in rats by HPLC-MS/MS and its application in pharmacokinetics and tissue distribution study.

CONTEXT: Tadehaginoside, an active ingredient isolated from Tadehagi triquetrum (Linn.) Ohashi (Leguminosae), exhibited various biological activities. However, the pharmacokinetics and tissue distribution which affect tadehaginoside's therapeutic actions and application remain elusive. OBJECTIVE: To clarify the metabolism of tadehaginoside in vivo. MATERIALS AND METHODS: The pharmacokinetics and tissue distribution of tadehaginoside and its metabolite p-hydroxycinnamic acid (HYD) were investigated using LC-MS/MS. Pharmacokinetic parameters were determined in 10 Sprague-Dawley rats divided into two groups, the intravenous group (5 mg/kg) and the oral group (25 mg/kg). For the tissue-distribution study, 20 rats were intravenously given tadehaginoside (5 mg/kg) before the experiment (n = 4). Biological samples were collected before drug administration (control group) and after drug administration. RESULTS: The linearity, accuracy, precision, stability, recovery and matrix effect of the method were well-validated and the results satisfied the requirements of biological sample measurement. Treatment with tadehaginoside via intragastric and intravenous administration, the calculated Cmax in rats was 6.01 ± 2.14 ng/mL and 109.77 ± 4.29 ng/mL, and Tmax was 0.025 ± 0.08 h and 0.08 h, respectively. The results indicated that the quick absorption of tadehaginoside was observed following intravenous administration, and tadehaginoside in plasma of rats with intragastric administration showed relatively low concentration may be due to the formation of its metabolite. Tissue-distribution study indicated that kidney and spleen were the major distribution organs for tadehaginoside in rats and there was no long-term accumulation in most tissues. DISCUSSION AND CONCLUSION: These results could provide clues for exploring the bioactivity of tadehaginoside based on its pharmacokinetic characteristics.

Effects of cyclosporine A on proliferation, invasion and migration of HTR-8/SVneo human extravillous trophoblasts.

As shown in our previous study, cyclosporine A (CsA) promotes the proliferation, invasion and migration of villous trophoblasts, thus improving embryo implantation. In addition, the incidence of preeclampsia (PE) is decreased in patients with recurrent spontaneous abortion (RSA) and repeated implantation failure (RIF) treated with CsA during the first trimester. Abnormal function of extravillous trophoblasts (EVTs) in early pregnancy is recognized as the pathogenetic mechanism of PE. EVTs share homology and function with pre-villous trophoblasts and villous trophoblasts; thus, we hypothesized that CsA may have the same regulatory effect on EVTs. In this study, we investigated the effects of CsA on HTR-8/SVneo trophoblasts in the extravillous layer and explored the underlying mechanisms. QPCR and Western blot (WB) analyses were performed to detect expression alterations in relevant proliferation and invasion proteins in response to different concentrations of CsA. We used an Affymetrix IVT expression microarray to examine the target genes of CsA in preeclamptic placentas versus normal placentas. Our results showed that certain concentrations of CsA could promote the proliferation, invasion and migration of HTR8/SVneo cells. CsA was also found to promote the expression of titin, MMP9, EGFR, and PRR15. TRAIL may be a target gene for CsA-mediated regulation of EVTs. CONCLUSIONS: By promoting the expression of related proteins and regulating the functions of HTR8/SVneo cells, CsA can promote vascular recasting and placental function, which may affect the pathogenesis of PE.

High-Throughput Chemometric Quality Assessment of Extra Virgin Olive Oils Using a Microtiter Plate Reader.

A commercially available microtiter plate reader was applied as a high-throughput counterpart of ultraviolet-visible (UV-Vis) spectrophotometer to identify the producing location of extra virgin olive oils (EVOOs). Multiplicative scatter correction and the first derivative was used to denoise the UV-Vis spectra and eliminate the effects of background drift. The spectra were analyzed using chemometrics methods including the principal component analysis (PCA) and the partial least squares-discriminant analysis (PLS-DA). The PLS-DA model on full spectra using 5 latent variables showed a classification accuracy of 97.92% by cross-validation. The overall results demonstrated that the use of a UV-Vis spectrophotometer based on the microtiter plate reader combined with chemometrics can be applied to the quality assessment of EVOOs. It is demonstrated that the microtiter plate reader can be a high-throughput tool in the quality assessment of food ingredients.

In vitro dentin tubule occlusion by an arginine-containing dentifrice.

PURPOSE: To evaluate the ability of an arginine-containing dentifrice to occlude dentin tubules. METHODS: Dentin discs were divided equally into premolar and molar groups, which were then utilized in three treatment groups: a blank control group (distilled water treatment), a negative control group (common dentifrice with calcium carbonate) and an experimental group [dentifrice with 8% (w/w) arginine]. Each dentin disk was brushed with the dentifrice twice daily for 7 consecutive days. After this period, each disc was separated into two equal halves. One half was used for scanning electron microscopy (SEM) and energy-dispersive spectrometer (EDS) examinations, while the other half was brushed with distilled water twice daily for another 7 days prior to SEM observation. RESULTS: The plugging rate in the arginine dentifrice group was significantly higher and more sustainable than in the negative control group. The surface deposition of calcium and phosphorus on the dentin discs in the arginine dentifrice group was also significantly higher. CLINICAL SIGNIFICANCE: This study provided evidence that using arginine as an active ingredient in dentifrice can improve its ability to occlude dentin tubules, thus supporting future efforts to improve dentin hypersensitivity.

Technical note: Nontargeted detection of adulterated plant proteins in raw milk by UPLC-quadrupole time-of-flight mass spectrometric proteomics combined with chemometrics.

We built and validated a chemometric model to detect possible milk adulteration with plant proteins. Specifically, we extracted proteins in raw milk, treated with tryptic digestion, and obtained peptide fingerprints by UPLC-quadrupole time-of-flight-mass spectrometry with proteomics to differentiate authentic milks from their counterparts adulterated with nonmilk proteins. This approach is able to detect soybean and pea powder-adulterated milks at as low as 1% (wt/wt). Additionally, we obtained the characteristic peptide sequences for milk authentication by principal component analysis. The prediction accuracies for milk authentication by partial least-squares-discriminant analysis were greater than 95%. These results indicated that peptide fingerprints with the chemometric analysis could be successfully applied for milk quality control.

Exploring the regulatory role of Linc00893 in asthenozoospermia: Insights into sperm motility and SSC viability.

The role of long intergenic noncoding RNA 00893 (Linc00893) in asthenozoospermia (AS) and its impact on sperm motility remains unclear The present study explored the effect of Linc00893 on AS, specifically its effect on sperm motility and its relationship with spermatogonial stem cell (SSC) vitality and myosin heavy chain 9 (MYH9) protein expression. Linc00893 expression was analyzed in semen samples using reverse transcription­quantitative PCR, revealing a significant downregulation in samples from individuals with AS compared with those from healthy subjects. This downregulation was found to be negatively correlated with parameters of sperm motility. To further understand the role of Linc00893, small interfering RNA was used to knockdown its expression in SSCs. This knockdown led to a marked decrease in cell vitality and an increase in apoptosis. Notably, Linc00893 knockdown was shown to inhibit MYH9 expression by competitively binding with microRNA­107, a finding verified by dual­luciferase reporter and RNA immunoprecipitation assays. Furthermore, using the GSE160749 dataset from the Gene Expression Omnibus database, it was revealed that MYH9 protein expression was downregulated in AS samples. Subsequently, lentiviral vectors were constructed to induce overexpression of MYH9, which in turn reduced SSC apoptosis and counteracted the apoptosis triggered by Linc00893 knockdown. In conclusion, the present study identified the role of Linc00893 in AS, particularly its regulatory impact on sperm motility, SSC vitality and MYH9 expression. These findings may provide information on the potential regulatory mechanisms in AS development, and identify Linc00893 and MYH9 as possible targets for diagnosing and treating AS­related disorders.

Effects of sn-2 Palmitic Triacylglycerols and the Ratio of OPL to OPO in Human Milk Fat Substitute on Metabolic Regulation in Sprague-Dawley Rats.

In this study, the influence of total sn-2 palmitic triacylglycerols (TAGs) and ratio of 1-oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL) to 1,3-dioleoyl-2-palmitoylglycerol (OPO) in human milk fat substitute (HMFS) on the metabolic changes were investigated in Sprague-Dawley rats. Metabolomics and lipidomics profiling analysis indicated that increasing the total sn-2 palmitic TAGs and OPL to OPO ratio in HMFS could significantly influence glycine, serine and threonine metabolism, glycerophospholipid metabolism, glycerolipid metabolism, sphingolipid metabolism, bile acid biosynthesis, and taurine and hypotaurine metabolism pathways in rats after 4 weeks of feeding, which were mainly related to lipid, bile acid and energy metabolism. Meanwhile, the up-regulation of taurine, L-tryptophan, and L-cysteine, and down-regulations of lysoPC (18:0) and hypoxanthine would contribute to the reduction in inflammatory response and oxidative stress, and improvement of immunity function in rats. In addition, analysis of targeted biochemical factors also revealed that HMFS-fed rats had significantly increased levels of anti-inflammatory factor (IL-4), immunoglobulin A (IgA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px), and decreased levels of pro-inflammatory factors (IL-6 and TNF-α) and malondialdehyde (MDA), compared with those of the control fat-fed rats. Collectively, these observations present new in vivo nutritional evidence for the metabolic regulatory effects of the TAG structure and composition of human milk fat substitutes on the host.

Identification of potential biomarkers and pathways for asthenozoospermia by bioinformatics analysis and experiments.

Background: Asthenozoospermia, a type of male infertility, is primarily caused by dysfunctional sperm mitochondria. Despite previous bioinformatics analysis identifying potential key lncRNAs, miRNAs, hub genes, and pathways associated with asthenospermia, there is still a need to explore additional molecular mechanisms and potential biomarkers for this condition. Methods: We integrated data from Gene Expression Omnibus (GEO) (GSE22331, GSE34514, and GSE160749) and performed bioinformatics analysis to identify differentially expressed genes (DEGs) between normozoospermia and asthenozoospermia. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to gain insights into biological processes and signaling pathways. Weighted Gene Co-expression Network Analysis (WGCNA) identified gene modules associated with asthenozoospermia. Expression levels of key genes were assessed using datasets and experimental data. Gene Set Enrichment Analysis (GSEA) and correlation analysis identified pathways associated with the hub gene and explore the relationship between the ZNF764 and COQ9 and mitochondrial autophagy-related genes. Competitive endogenous RNA (ceRNA) networks were constructed, and in vitro experiments using exosome samples were conducted to validate this finding. Results: COQ9 was identified as a marker gene in asthenozoospermia, involved in autophagy, ATP-dependent chromatin remodeling, endocytosis, and cell cycle, etc. The ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) was constructed, and PCR demonstrated that LINC00893 and COQ9 were downregulated in asthenozoospermia, while miR-125a-5p and m6A methylation level of LINC00893 were upregulated in asthenozoospermia compared to normozoospermic individuals. Conclusion: The ceRNA regulatory network (LINC00893/miR-125a-5p/COQ9) likely plays a crucial role in the mechanism of asthenozoospermia. However, further functional experiments are needed to fully understand its significance.

Transcriptomic and proteomic analysis of tumor suppressive effects of GZ17-6.02 against mycosis fungoides.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). Despite having a wide variety of therapeutic agents available for the treatment of MF, patients often suffer from a significant decrease in quality of life and rarely achieve long-term remission or complete cure, highlighting a need to develop novel therapeutic agents for this disease. The present study was undertaken to evaluate the efficacy of a novel anti-tumor agent, GZ17-6.02, which is composed of curcumin, harmine, and isovanillin, against MF in vitro and in murine models. Treatment of HH and MyLa cells with GZ17-6.02 inhibited the growth of both cell lines with IC50 ± standard errors for growth inhibition of 14.37 ± 1.19 µg/mL and 14.56 ± 1.35 µg/mL, respectively, and increased the percentage of cells in late apoptosis (p = .0304 for HH; p = .0301 for MyLa). Transcriptomic and proteomic analyses revealed that GZ17-6.02 suppressed several pathways, including tumor necrosis factor (TNF)-ɑ signaling via nuclear factor (NF)-kB, mammalian target of rapamycin complex (mTORC)1, and Pi3K/Akt/mTOR signaling. In a subcutaneous tumor model, GZ17-6.02 decreased tumor volume (p = .002) and weight (p = .009) compared to control conditions. Proteomic analysis of tumor samples showed that GZ17-6.02 suppressed the expression of several proteins that may promote CTCL growth, including mitogen-activated protein kinase (MAPK)1, MAPK3, Growth factor receptor bound protein (GRB)2, and Mediator of RAP80 interactions and targeting subunit of 40 kDa (MERIT)40.

Immune stimulus exposure as a trigger for the development of chronic pruritus and circulating blood type 2 inflammation.

Background: Chronic pruritus (CP) is a poorly characterized condition associated with intense pruritus without a primary skin eruption. This condition tends to emerge more commonly in older adults, and there is limited research on triggering factors. Objective: To explore the clinical characteristics and pathophysiology of CP following exposure to an immune stimulus. Methods: Clinical characteristics and plasma samples were collected from 15 patients who developed CP following an immune stimulus such as checkpoint inhibitors or vaccination. A multiplex panel was used to analyze plasma cytokine concentrations within these patients. Results: Most immunotherapy-treated patients experienced CP during treatment or after 21 to 60 days of receiving treatment, while vaccine-stimulated patients developed pruritus within a week of vaccination. Plasma cytokine analysis revealed elevated levels of 12 cytokines in patients with immune-stimulated CP compared to healthy controls. Notably, T helper 2 (Th2) related cytokines interleukin (IL)-5 (fold change 2.65; q < 0.25) and thymic stromal lymphopoietin (fold change 1.61 q < 0.25) were upregulated. Limitations: Limitations of this study include limited sample size, particularly in the plasma cytokine assay. Conclusions and Relevance: This study reveals triggers of CP development and describes alterations in blood Th2 markers in patients with CP, including IgE, increased blood eosinophils, and cytokines IL-5 and thymic stromal lymphopoietin.

Comprehensive plasma cytokine and chemokine profiling in prurigo nodularis reveals endotypes in Type 2 inflammation.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/µL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.

Evaluating the causal relationship between five modifiable factors and the risk of spinal stenosis: a multivariable Mendelian randomization analysis.

Background: Spinal stenosis is a neurological disorder related to the compression of the spinal cord or nerve roots, and its incidence increases yearly. We aimed to use Mendelian randomization (MR) to investigate the causal relationship between several modifiable risk factors and the risk of spinal stenosis. Methods: We obtained genome-wide association study summary data of large-sample projects (more than 100,000 individuals) from public databases. The data were associated with traits, including years of schooling (educational attainment) from the IEU OpenGWAS Project, smoking behavior (never vs. initiation) from the IEU OpenGWAS Project, body mass index (BMI) from the UK Biobank, length of mobile phone use from the UK Biobank, time spent watching television (TV) from the UK Biobank, and spinal stenosis from FinnGen biobank. Spinal stenosis was used as the outcome, whereas the other four traits were used as exposures. Inverse variance weighted (IVW) regressions were used as a primary to estimate the causal-effect size. Several sensitive analyses (including consistency, heterogenicity, and pleiotropy analyses) were conducted to test the stability and reliability of causal estimates. Results: Univariable MR analyses showed that genetically predicted higher educational attainment (IVW; odds ratio (OR) = 0.606; 95% confidence interval (CI): 0.507-0.724; P = 3.37 × 10-8) and never smoking (IVW; OR = 1.388; 95% CI [1.135-1.697]; P = 0.001) were negatively correlated with the risk of spinal stenosis. Meanwhile, a higher BMI (IVW; OR = 1.569; 95% CI [1.403-1.754]; P = 2.35 × 10-8), longer time spent using a mobile phone (IVW; OR = 1.895; 95% CI [1.306-2.750]; P = 0.001), and watching TV (IVW; OR = 1.776; 95% CI [1.245-2.532]; P = 0.002) were positively associated with the risk of spinal stenosis. Multivariable MR analysis indicated that educational attainment (IVW; OR = 0.670; 95% CI [0.465-0.967]; P = 0.032) and BMI (IVW; OR = 1.365; 95% CI [1.179-1.580]; P = 3.12 × 10-5) were independently causally related to the risk of spinal stenosis. Conclusion: Our findings supported the potential causal associations of the five factors (educational attainment, smoking behavior, BMI, length of mobile phone use, and watching TV) with the risk for spinal stenosis. While replication studies are essential, these findings may provide a new perspective on prevention and intervention strategies directed toward spinal stenosis.

Mendelian randomization investigation identified the causal relationship between body fat indexes and the risk of bladder cancer.

Background: Observational studies have suggested that obesity is associated with the risk of bladder cancer (BCa). However, their causal relationship remains unclear. This study aimed to prove the causal relationship between obesity and the risk of BCa by using Mendelian randomization. Methods: Single-nucleotide polymorphisms (SNPs) correlated with body fat indexes were screened from several genome-wide association studies (GWAS) with more than 300,000 individuals. Summary-level genetic data of BCa-related GWAS were obtained from a European cohort with a sample size of 218,792. An inverse-variance-weighted (IVW) method was used as the major MR analysis. The MR-Egger regression, IVW regression, leave-one-out test, and MR-Pleiotropy Residual Sum and Outlier methods were used to test the reliability and stability of MR results. Results: Genetically predicted per 1-SD increase in body fat indexes (whole body fat mass, and the right leg, left leg, right arm, left arm, and trunk fat mass) were associated with increased BCa risk with values of 51.8%, 77.9%, 75.1%, 67.2%, 59.7%, and 36.6%, respectively. Sensitivity analyses suggested that the genetically determined risk effect of obesity on BCa was stable and reliable. Conclusions: Our study provided powerful evidence to support the causal hypothesis that the genetically predicted high body fat mass was associated with a risk increase for BCa. The finding is a new idea for drawing up prevention strategies for BCa.