TSPAN8+ myofibroblastic cancer-associated fibroblasts promote chemoresistance in patients with breast cancer.

Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)+ myofibroblastic CAF (myCAF) subset, which is correlated with therapeutic resistance and poor survival in multiple cohorts of patients with breast cancer (BC). TSPAN8+ myCAFs potentiate the stemness of the surrounding BC cells through secretion of senescence-associated secretory phenotype (SASP)-related factors IL-6 and IL-8 to counteract chemotherapy. NAD-dependent protein deacetylase sirtuin 6 (SIRT6) reduction was responsible for the senescence-like phenotype and tumor-promoting role of TSPAN8+ myCAFs. Mechanistically, TSPAN8 promoted the phosphorylation of ubiquitin E3 ligase retinoblastoma binding protein 6 (RBBP6) at Ser772 by recruiting MAPK11, thereby inducing SIRT6 protein destruction. In turn, SIRT6 down-regulation up-regulated GLS1 and PYCR1, which caused TSPAN8+ myCAFs to secrete aspartate and proline, and therefore proved a nutritional niche to support BC outgrowth. By demonstrating that TSPAN8+SIRT6low myCAFs were tightly associated with unfavorable disease outcomes, we proposed that the combined regimen of anti-TSPAN8 antibody and SIRT6 activator MDL-800 is a promising approach to overcome chemoresistance. These findings highlight that senescence contributes to CAF heterogeneity and chemoresistance and suggest that targeting TSPAN8+ myCAFs is a promising approach to circumvent chemoresistance.

Efficacy and safety of pharmacological intervention for smoking cessation in smokers with diseases: A systematic review and network meta-analysis.

OBJECTIVE: To investigate the most effective and best-tolerated drugs for treating diseased smokers. METHODS: Eight databases were searched for randomized controlled trials (RCTs) involving different pharmacological interventions for smoking cessation in disease patients (January 2023). Network meta-analysis was performed using STATA 15.1 software. The Cochrane Risk of Bias Tool assessed the risk of bias, and confidence in evidence was assessed using CINeMA. RESULTS: A total of 60 RCTs involving 13,009 patients of 12 disease categories were included. All trials reported 13 interventions, resulting in 78 comparisons. Network meta-analysis showed that varenicline (OR = 2.30, 95% CI (1.77, 3.00)) and bupropion (OR = 1.65, 95% CI (1.29, 2.11)) showed favorable abstinence effects compared to placebo in the cardiovascular disease population. Nicotine replacement therapy (NRT) had better withdrawal advantages than placebo (OR = 11.18, 95% CI (2.25, 55.54)) in the chronic obstructive pulmonary disease (COPD) population. Some combination treatments showed better results than monotherapy, such as bupropion + NRT was superior to bupropion (OR = 8.45, 95% CI (1.84, 38.89)) and NRT (OR = 4.98, 95% CI (1.25, 19.78)) in mental illness population. The final surface under the cumulative ranking curve indicated that bupropion + NRT achieved the best smoking cessation effect. Overall confidence in the evidence was low. In a comparison of drugs, the results showed that bupropion + NRT had the best safety. CONCLUSIONS: Most interventions show the benefit of quitting smoking compared with placebo, including monotherapy and combination therapy. Moreover, varenicline or bupropion combined with NRT is superior to some monotherapies.

Effectiveness and Safety of Varenicline for Smoking Cessation: An Overview and Meta-analysis.

OBJECTIVE: An overview, meta-analysis, and trial sequential analysis were conducted to evaluate the efficacy and safety of varenicline for smoking cessation. METHODS: Systematic reviews (SRs) and randomized controlled trials evaluating varenicline versus placebo for smoking cessation were included. A forest plot was used to summarize the effect size of the included SRs. Traditional meta-analysis and trial sequential analysis (TSA) were performed using Stata software and TSA 0.9 software, respectively. Finally, the Grades of Recommendation, Assessment, Development, and Evaluation approach was used to assess the quality of evidence for the abstinence effect. RESULTS: A total of 13 SRs and 46 randomized controlled trials were included. Twelve review studies showed that varenicline was superior to placebo for smoking cessation. The meta-analysis results showed that, compared with the placebo, varenicline significantly increased the odds of smoking cessation (odds ratio = 2.54, 95% confidence interval = 2.20-2.94, P < 0.05, moderate quality). Subgroup analysis showed that there were significant differences in smokers with disease and general smokers ( P < 0.05). Differences were also found in the follow-up time at 12, 24, and 52 weeks ( P < 0.05). The common adverse events were nausea, vomit, abnormal dreams, sleep disturbances, headache, depression, irritability, indigestion, and nasopharyngitis ( P < 0.05). The TSA results confirmed the evidence for the effect of varenicline on smoking cessation. CONCLUSIONS: Existing evidence supports the superiority of varenicline over a placebo for smoking cessation. Varenicline had mild to moderate adverse events but was well tolerated. Future trials should investigate varenicline in combination with other smoking cessation approaches and compare it with other interventions.

Efficacy and safety of antidepressants for smoking cessation: A systematic review and network meta-analysis.

To evaluate the effectiveness, safety and tolerability of antidepressants in helping smokers quit tobacco dependence, five databases were searched for randomized controlled trials (RCTS ) on different antidepressant interventions involving smoking cessation in populations (September 2022). The STATA 15.1 software was used to perform network meta-analysis. The Cochrane bias risk tool was used to assess the risk of bias, and CINeMA was used to evaluate the evidence credibility for the effect of different interventions on smoking cessation. In all, 107 RCTs involving 42 744 patients were included. Seven studies were rated as having a low risk of bias. All trials reported 18 interventions and 153 pairwise comparisons were generated. The network meta-analysis showed that compared with placebo, varenicline + bupropion (OR = 3.53, 95% CI [2.34, 5.34]), selegiline + nicotine replacement therapy (NRT) (OR = 3.78, 95% CI [1.20, 11.92]), nortriptyline + NRT (OR = 2.33, 95% CI [1.21, 4.47), nortriptyline (OR = 1.58, 95% CI [1.11,2.26]), naltrexone + bupropion (OR = 3.84, 95% CI [1.39, 10.61]), bupropion + NRT (OR = 2.29, 95% CI [1.87, 2.81]) and bupropion (OR = 1.70, 95% CI [1.53, 1.89]) showed benefits with respect to smoking cessation. In addition, bupropion + NRT showed better effects than bupropion (OR = 1.35, 95% CI [1.12, 1.64]) and NRT (OR = 1.38, 95% CI [1.13, 1.69]) alone. The final cumulative ranking curve showed that varenicline + bupropion was the most likely to be the best intervention. There was moderate- to very-low-certainty evidence that most interventions showed benefits for smoking cessation compared with placebo, including monotherapy and combination therapies. Varenicline + bupropion had a higher probability of being the best intervention for smoking cessation.

SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway.

Cancer cells consistently utilize the unfolded protein response (UPR) to encounter the abnormal endoplasmic reticulum (ER) stress induced by the accumulation of misfolded proteins. Extreme activation of the UPR could also provoke maladaptive cell death. Previous reports have shown that NRF2 antioxidant signaling is activated by UPR and serves as noncanonical pathway to defense and reduce excessive ROS levels during ER stress. However, the mechanisms of regulating NRF2 signaling upon ER stress in glioblastoma have not been fully elucidated. Here we identify that SMURF1 protects against ER stress and facilitates glioblastoma cell survival by rewiring KEAP1-NRF2 pathway. We show that ER stress induces SMURF1 degradation. Knockdown of SMURF1 upregulates IRE1 and PERK signaling in the UPR pathway and prevents ER-associated protein degradation (ERAD) activity, leading to cell apoptosis. Importantly, SMURF1 overexpression activates NRF2 signaling to reduce ROS levels and alleviate UPR-mediated cell death. Mechanistically, SMURF1 interacts with and ubiquitinates KEAP1 for its degradation (NRF2 negative regulator), resulting in NRF2 nuclear import. Moreover, SMURF1 loss reduces glioblastoma cell proliferation and growth in subcutaneously implanted nude mice xenografts. Taken together, SMURF1 rewires KEAP1-NRF2 pathway to confer resistance to ER stress inducers and protect glioblastoma cell survival. ER stress and SMURF1 modulation may provide promising therapeutic targets for the treatment of glioblastoma.

Cerebrospinal fluid metabolic markers predict prognosis behavior of primary central nervous system lymphoma with high-dose methotrexate-based chemotherapeutic treatment.

Background: Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin's B-cell lymphoma which normally treated by high-dose methotrexate (HD-MTX)-based chemotherapy. However, such treatment cannot always guarantee a good prognosis (GP) outcome while suffering several side effects. Thus, biomarkers or biomarker-based models that can predict PCNSL patient prognosis would be beneficial. Methods: We first collected 48 patients with PCNSL and applied HPLC-MS/MS-based metabolomic analysis on such retrospective PCNSL patient samples. We then selected the highly dysregulated metabolites to build a logical regression model that can distinguish the survival time length by a scoring standard. Finally, we validated the logical regression model on a 33-patient prospective PCNSL cohort. Results: Six metabolic features were selected from the cerebrospinal fluid (CSF) that can form a logical regression model to distinguish the patients with relatively GP (Z score ≤0.06) from the discovery cohort. We applied the metabolic marker-based model to a prospective recruited PCNSL patient cohort for further validation, and the model preformed nicely on such a validation cohort (AUC = 0.745). Conclusions: We developed a logical regression model based on metabolic markers in CSF that can effectively predict PCNSL patient prognosis before the HD-MTX-based chemotherapy treatments.

Network Meta-Analysis of Behavioral Programs for Smoking Cessation in Healthy People.

INTRODUCTION: Smoking is a risk factor for most chronic diseases and premature death, with a global prevalence of more than 1 billion people who smoke. This network meta-analysis aimed to investigate the impact of different behavioral interventions on smoking cessation. METHODS: Four electronic databases were searched for RCTs from inception to August 29, 2022. The risk of bias for the included RCTs was evaluated using the revised version of Cochrane tool for assessing risk of bias and the certainty of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation approach. The network meta-analysis was performed using Stata 16SE and R 4.1.3 software. RESULTS: A total of 119 included RCTs enrolled 118,935 participants. For the 7-day-point prevalence abstinence rate, video counseling had a best intervention effect than brief advice, followed by financial incentives, self-help materials plus telephone counseling, motivational interview, health education, telephone counseling, and text messages. For the 30-day-point prevalence abstinence rate, face-to-face cognitive education and financial incentives were superior to brief advice. For the continuous abstinence rate, motivational interview and financial incentives were more effective than brief advice. The certainty of evidence was very low to moderate for these studies. DISCUSSION: From the results of the network meta-analysis, different behavioral interventions resulted in positive impacts on smoking cessation compared with that of brief advice, especially video counseling, face-to-face cognitive education, and motivational interviews. Owing to the poor quality of evidence, high-quality trials should be conducted in the future to provide more robust evidence.

Metabolic Profiling and Potential Taste Biomarkers of Two Rambutans during Maturation.

The metabolite-caused taste variation during rambutan maturation is unknown due to a lack of systematic investigation of all components. In this study, three growing stages, including unripe (S1), half-ripe (S2), and full-ripe (S3) BY2 and BY7 rambutans were compared and profiled by UPLC-MS/MS-based widely targeted metabolomics analysis. We demonstrated that the sugar-acid ratios of two rambutans were greatly improved between the S2 and S3 stages. A total of 821 metabolites were identified, including 232, 205, 204, and 12 differential metabolites (DMs) in BY2-S1 vs. BY2-S2, BY2-S2 vs. BY2-S3, BY7-S1 vs. BY7-S2, and BY7-S2 vs. BY7-S3, respectively. A correlation analysis showed that gamma-aminobutyric acid (GABA) could be the sugar-acid ratio biomarker of BY2 rambutan. Methionine (Met), alanine (Ala), and S-methyl-L-cysteine (SMC) could be total amino acid biomarkers of BY2 and BY7 rambutans. In addition, UPLC-MS/MS-based quantitative verification of the above biomarkers exhibited the same variations as metabolomics analysis. This study not only provides useful nutritive information on rambutans but also valuable metabolic data for rambutan breeding strategies.

Design, synthesis, and anticancer evaluation of N6 -hydrazone purine derivatives with potential antiplatelet aggregation activity.

In our research on novel anticancer agents, a series of N6 -hydrazone purine derivatives were designed and synthesized by analysis of a pharmacophore model for ATP-competitive inhibitors. The activities screening results showed that N6 -hydrazone purine derivatives 21 and 26 not only showed potential antiproliferative activity against the A549 and MCF-7 cell lines comparable to Vandetanib as a positive control but also had moderate antiplatelet aggregation activity. In order to investigate the possible targets, a molecular docking study was carried out on the fourteen kinases associated with anticancer and antiplatelet aggregation activities. The results indicated that compounds 21 and 26 had the potential activity to target VEGFR-2, PI3Kα, EGFR, and HER2 kinases. The inhibition of the kinases assay showed that compound 26 could target VEGFR-2, PI3Kα, and EGFR (IC50  = 0.822, 3.040 and 6.625 µM). All results indicated that compound 26 will be an encouraging framework as potential new multi-target anticancer agent with potential antiplatelet aggregation activity.

Advantages of applying digital chest drainage system for postoperative management of patients following pulmonary resection: a systematic review and meta-analysis of 12 randomized controlled trials.

OBJECTIVES: This meta-analysis aimed to evaluate the value of the chest digital drainage system for the postoperative management of patients who have undergone pulmonary resection. METHODS: We searched the PubMed, EMBASE, the Cochrane Library, and Web of Science databases for included randomized controlled trials (RCTs) on the application of digital drainage systems versus the analog drainage system for patients with lung disease after pulmonary resection. Dichotomous variables were evaluated using risk ratios (RRs) and 95% confidence intervals (CIs), and mean and standardized mean differences (MDs and SMDs, respectively) with 95% CIs were used to calculate continuous variables. Statistical analyses were performed using Stata and RevMan software. RESULTS: In total, 12 RCTs involving 2000 patients were analyzed. Significant differences in duration of chest tube placement (SMD = -0.49; 95% CI = -0.78 to -0.20), length of hospital stay (MD =-0.79 days; 95% CI = -1.24 to -0.34), and number of chest tube clamping tests (RR = 0.74; 95% CI = 0.36-1.49) were observed between the two groups, which did not significant differ in the occurrence of prolonged air leak or cardiopulmonary complication rate. CONCLUSIONS: The digital chest drainage system is mainly advantageous in the duration of chest tube placement, length of hospital stay, and number of chest tube clamping tests. Future research should evaluate the requirements and economic impact of using digital system in routine clinical practice.

Enhanced Rishirilide Biosynthesis by a Rare In-Cluster Phosphopantetheinyl Transferase in Streptomyces xanthophaeus.

Phosphopantetheinyl transferases (PPTases) play important roles in activating apo-acyl carrier proteins (apo-ACPs) and apo-peptidyl carrier proteins (apo-PCPs) in both primary and secondary metabolism. PPTases catalyze the posttranslational modifications of those carrier proteins by covalent attachment of the 4'-phosphopantetheine group to a conserved serine residue. The protein-protein interactions between a PPTase and a cognate acyl or peptidyl carrier protein have important regulatory functions in microbial biosynthesis, but the molecular mechanism underlying their specific recognition remains elusive. In this study, we identified a new rishirilide biosynthetic gene cluster with a rare in-cluster PPTase from Streptomyces xanthophaeus no2. The function of this Sfp-type PPTase, SxrX, in rishirilide production was confirmed using genetic mutagenesis and biochemical characterization. We applied molecular modeling and site-directed mutagenesis to identify key residues mediating the protein-protein interaction between SxrX and its cognate ACP. In addition, six natural products were isolated from wild-type S. xanthophaeus no2 and the ΔsxrX mutant, including rishirilide A and lupinacidin A, that exhibited antimicrobial and anticancer activities, respectively. SxrX is the first Sfp-type PPTase identified from an aromatic polyketide biosynthetic gene cluster and shown to be responsible for high-level production of rishirilide derivatives. IMPORTANCE Genome mining has been a vital means for natural product drug discovery in the postgenomic era. The rishirilide-type polyketides have attracted attention due to their potent bioactivity, but the poor robustness of production hosts has limited further research and development. This study not only identifies a hyperproducer of rishirilides but also reveals a rare, in-cluster PPTase SxrX that plays an important role in boosting rishirilide biosynthesis. Experimental and computational investigations revealed new insights on the protein-protein interaction between SxrX and its cognate ACP with wide implications for understanding polyketide biosynthesis.

Varenicline and related interventions on smoking cessation: A systematic review and network meta-analysis.

BACKGROUND: Based on randomized controlled trials, a network meta-analysis was conducted to compare treatment effects across varenicline and related smoking interventions. METHODS: English databases were screened for randomized controlled trials reporting the effect of varenicline as treatment for smoking. The risk of bias in included trials was assessed using the Cochrane Handbook tool. Stata 15.1 software was used to perform network meta-analysis, and the GRADE approach was used to assess the evidence credibility on the tobacco treatment effects of different interventions. RESULTS: Thirty-four studies involving 26,130 smokers were included in the network meta-analysis. Varenicline and 11 other interventions were reported, yielding 66 pairs of comparisons. Network meta-analysis showed that varenicline monotherapy or its combination with other interventions were superior in achieving smoking cessation compared to bupropion, nicotine replacement therapy, counselling, and placebo. Furthermore, compared to the varenicline, evident abstinence superiority was found in varenicline + bupropion (odds ratio = 1.49, 95% confidence interval [1.02, 2.18]). Finally, the surface under the cumulative ranking curve value indicated that varenicline + bupropion has the highest probability to become the best intervention. CONCLUSIONS: Varenicline monotherapy increased the odds of smoking cessation further than bupropion monotherapy, nicotine replacement therapy, counselling, and placebo, while varenicline combined with other interventions may even achieve a better abstinence effect. More credible evidence has been reported indicating that the combination of varenicline and bupropion is a superior treatment for smoking.

Identification of Cofilin-1 as a novel biomarker of atopic dermatitis using iTRAQ quantitative proteomics.

BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin condition; however, little is known about the pathogenesis and serum biomarker of this disease. METHODS: Isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic assay was adopted to identify and quantify the differentially expressed proteins (DEPs) in the serum of AD patients. Bioinformatic analysis, including GO, Reactome, GSEA, PPI, and ssGSEA analysis, were used to identified the enriched pathways, hub proteins and immune cells. The expression level and distribution of hub proteins were confirmed by ELISA and IHC. RESULTS: Sixty-six DEPs were identified with iTRAQ proteomic assay by analyzing serum from AD patients and normal subjects. GO and Reactome analysis shown the alternated pathway were mainly involved in immunity, oxidative stress, and actin cytoskeleton. The GSEA and PPI network analysis among the DEPs were carried out and identified Cofilin-1 and profilin-1 as the core components of this network. Additionally, the disruption of Th1/Th2/Th17 cell balance and the significantly reducing of Treg, MDSC, and γδT cells was also found in AD patients using the ssGSEA analysis. Further ELISA and IHC assay validated the significantly elevated expression of Cofilin-1 in AD patients. CONCLUSION: Our results suggested that Cofilin-1 may serve as a novel biomarker for AD diagnosis.

Development of pyrazolo[3,4-d]pyrimidin-4-one scaffold as novel CDK2 inhibitors: Design, synthesis, and biological evaluation.

A series of pyrazolo[3,4-d]pyrimidin-4-one scaffold were designed and synthesized as novel CDK2 inhibitors. By analyzing the common motifs of various known inhibitors, the designed compounds 1 were virtually screen for their inhibitory activity by docking into the active pocket of CDK2. The influence of different substitutes on the docking results was investigated. A total of 15 pyrazolo[3,4-d]pyrimidin-4-ones 1 were synthesized by Paal-Knorr reaction, pyrimidine ring closure, bromination, Suzuki coupling reaction, amide formation and Knoevenagel condensation. The Cell Counting Kit-8 (CCK-8) was used to evaluate the inhibitory activity of pyrazolo[3,4-d]pyrimidin-4-ones 1 in the breast cancer cell line MCF-7 in vitro using Etoposide as a reference control substance. The screening results demonstrated that the designed compounds have significant antiproliferative activity, and compounds 1e and 1j were the most active compounds with IC50 values of 10.79 µM and 10.88 µM, respectively, being better than that of Etoposide (IC50 = 18.75 µM). The enzyme inhibition assay was carried out against CDK2, the results indicated that the compounds 1e and 1j significantly inhibited CDK2 with IC50 values of 1.71 µM and 1.60 µM.

Discovery of novel serum metabolic biomarkers in patients with polycystic ovarian syndrome and premature ovarian failure.

Several widely recognized metabolites play a role in regulating the pathophysiological processes of various disorders. Nonetheless, the lack of effective biomarkers for the early diagnosis of polycystic ovarian syndrome (PCOS) and premature ovarian failure (POF) has led to the discovery of serum-based metabolic biomarkers for these disorders. We aimed to identify various differentially expressed metabolites (DEMs) through serum-based metabolic profiling in patients with PCOS and POF and in healthy individuals by using liquid chromatography-mass spectrometry analysis. Furthermore, heatmap clustering, correlation, and Z-score analyses were performed to identify the top DEMs. Kyoto Encyclopedia of Genes and Genomes enriched pathways of DEMs were determined using metabolite-based databases. Moreover, the clinical significance of these DEMs was evaluated on the basis of area under the receiver operating characteristic curve. Significantly dysregulated expressions of several metabolites were observed in the intergroup comparisons of the PCOS, POF, and healthy control groups. Furthermore, 6 DEMs were most frequently observed among the three groups. The expressions of these DEMs were not only directly correlated but also exhibited potential significance in patients with PCOS and POF. Novel metabolites with up/downregulated expressions can be discovered in patients with PCOS and POF using serum-based metabolomics; these metabolites show good diagnostic performance and can act as effective biomarkers for the early detection of PCOS and POF. Furthermore, these metabolites might be involved in the pathophysiological mechanisms of PCOS and POF via interplay with corresponding genes.

Protection against Doxorubicin-Related Cardiotoxicity by Jaceosidin Involves the Sirt1 Signaling Pathway.

The clinical use of doxorubicin (DOX) is largely limited by its cardiotoxicity. Previous studies have shown that jaceosidin has many biological activities. However, little is known about whether jaceosidin can attenuate DOX-related acute cardiotoxicity. Here, we investigated the therapeutic effects of jaceosidin on DOX-induced acute cardiotoxicity. Mice were intraperitoneally injected with a single dose of DOX to establish an acute cardiac injury model. To explore the protective effects, mice were orally administered jaceosidin daily for 7 days, with dosing beginning 2 days before DOX injection. The results demonstrated that jaceosidin dose-dependently reduced free radical generation, inflammation accumulation, and cell loss induced by DOX in cardiomyocytes. Further studies showed that jaceosidin treatment inhibited myocardial oxidative damage and the inflammatory response and attenuated myocardial apoptotic death, thus improving cardiac function in mice injected with DOX. The inhibitory effects of jaceosidin on DOX-related acute cardiotoxicity were mediated by activation of the sirtuin1 (Sirt1) signaling pathway. Jaceosidin lost its protective effect against DOX-related injury in Sirt1-deficient cardiomyocytes and mice. In conclusion, jaceosidin has protective potential in treating DOX-related cardiac injury through activation of the Sirt1 signaling pathway.

The Immune Atlas of Human Deciduas With Unexplained Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) is a common fertility problem that affects 1%-2% of couples all over the world. Despite exciting discoveries regarding the important roles of the decidual natural killer cell (dNK) and regulatory T cell in pregnancy, the immune heterogeneity in patients with unexplained recurrent pregnancy loss (URPL) remains elusive. Here, we profiled the transcriptomes of 13,953 CD45+ cells from three normal and three URPL deciduas. Based on our data, the cellular composition revealed three major populations of immune cells including dNK cell, T cell, and macrophage, and four minor populations including monocytes, dendritic cell (DC), mast cell, and B cell. Especially, we identified a subpopulation of CSF1+ CD59+ KIRs-expressing dNK cells in normal deciduas, while the proportion of this subpopulation was decreased in URPL deciduas. We also identified a small subpopulation of activated dDCs that were accumulated mainly in URPL deciduas. Furthermore, our data revealed that in decidua at early pregnancy, CD8+ T cells exhibited cytotoxic properties. The decidual macrophages expressed high levels of both M1 and M2 feature genes, which made them unique to the conventional M1/M2 classification. Our single-cell data revealed the immune heterogeneity in decidua and the potentially pathogenic immune variations in URPL.

HCV poly U/UC sequence-induced inflammation leads to metabolic disorders in vulvar lichen sclerosis.

Vulvar lichen sclerosis (VLS) is a dermatologic disorder that affects women worldwide. Women with VLS have white, atrophic papules on the vulva. They suffer from life-long intense pruritus. Corticosteroids are the first-line of treatments and the most effective medicines for VLS. Although VLS has been speculated as an autoimmune disease for a long time, its pathogenesis and the molecular mechanism is largely unknown. We performed a comprehensive multi-omics analysis of paired samples from VLS patients as well as healthy donors. From the RNA-seq analysis, we found that VLS is correlated to abnormal antivirus response because of the presence of Hepatitis C Virus poly U/UC sequences. Lipidomic and metabolomic analysis revealed that inflammation-induced metabolic disorders of fatty acids and glutathione were likely the reasons for pruritus, atrophy, and pigment loss in the vulva. Thus, the present study provides an initial interpretation of the pathogenesis and molecular mechanism of VLS and suggests that metabolic disorders that affect the vulva may serve as therapeutic targets for VLS.

Detection of a New Tert-Leucinate Synthetic Cannabinoid 5F-MDMB-PICA and Its Metabolites in Human Hair: Application to Authentic Cases.

Methyl 2 -[ [ 1- (5- fluoropentyl) indole - 3- carbonyl] amino] -3, 3- dimethyl - butanoate (5F-MDMB-PICA) is a new synthetic cannabinoid characterized by valinate or tert-leucinate moieties. In recent years, 5F-MDMB-PICA has been abused in the form of "spice-like" herbal incenses or electronic cigarette oil. A UHPLC-MS/MS method was developed to detect 5F-MDMB-PICA and its metabolites in human hair. Approximately 20 mg of hair was weighed and pulverized with methanol below 4°C. After ultrasonication, centrifugation and filtration, 200 µL of supernatant was placed into an autosampler vial and analyzed on a Waters Acquity UPLC HSS T3 column (100 mm × 2.1 mm, 1.8 µm particle size) using an acetonitrile-20 mmol/L ammonium acetate (0.1% formic acid, 5% acetonitrile) gradient with a run time of 8 min. The limit of detection (LOD) ranged from 0.5 to 5 pg/mg, and the lower limit of quantitation (LLOQ) ranged from 1 to 5 pg/mg. The method was shown to be linear over a concentration range of 1-200 pg/mg. The linear correlation (R 2) of the calibration curves for all analytes was >0.999. The accuracy varied from 95.4 to 107.4%, while the intra- and inter-day precision RSD values were 0.7-10.6% and 1.7-12.2%, respectively. Recoveries were within the range of 61.1-93.3%, and matrix effects were in the range of 19.1-102.6%. The validated method was successfully applied to the identification and quantification of 5F-MDMB-PICA and its metabolites in hair from authentic forensic cases.

Oestrogen induces epithelial-mesenchymal transition in endometriosis via circ_0004712/miR-148a-3p sponge function.

Endometriosis is a common, chronic gynaecologic disease affecting up to 10% of women in their reproductive age and leading to pain and infertility. Oestrogen (E2 )-induced epithelial-mesenchymal transition (EMT) process has been considered as a key factor of endometriosis development. Recently, the dysregulated circular RNAs (circRNAs) have been discovered in endometriosis tissues. However, the molecular mechanism of circRNAs on the E2 -induced EMT process in endometriosis is still unknown. Here, we demonstrated that circ_0004712 up-regulated by E2 treatment in endometrial epithelial cells. Knock-down the expression of circ_0004712 significantly suppressed E2 -induced cell migration activity. Meanwhile, we identified miR-148a-3p as a potential target miRNA of circ_0004712. Inhibited the expression of miR-148a-3p could recovered the effect of circ_0004712 knock-down in E2 -treated endometrial epithelial. Furthermore, Western blot assay showed that E2 treatment could increase the expression and activity of ß-catenin, snail and N-cadherin and reduce the expression of E-cadherin. The expression and activity of ß-catenin pathway were recovered by circ_0004712 knock-down or miR-148a-3p overexpression. Altogether, the results demonstrate that circ_0004712/miR-148a-3p plays an important role in E2 -induced EMT process in the development of endometriosis, and the molecular mechanism may be associated with the ß-catenin pathway. This work highlighted the importance of circRNAs in the development of endometriosis and provide a new biomarker for diagnosis and therapies.