Enhancers in T Cell development and malignant lesions.

Enhancers constitute a vital category of cis-regulatory elements with a Mediator complex within DNA sequences, orchestrating gene expression by activating promoters. In the development of T cells, some enhancers regulate the critical genes, which might also regulate T cell malignant lesions. This review is to comprehensively elucidate the contributions of enhancers in both normal T cell development and its malignant pathogenesis, proposing the idea that the precise subunits of the Mediator complex are the potential drug target for disrupting the specific gene enhancer for T cell malignant diseases.

Hydrochemical insights, water quality, and human health risk assessment of groundwater in a coastal area of southeastern China.

Groundwater is a vital water supply worldwide, but its quality has gradually deteriorated with the development of society. In this study, a total of 40 groundwater samples were collected during the pre- and post-monsoon to analyze the hydrochemical process and assess the groundwater quality and human health risks in a coastal area of southeastern China. The results showed that the concentrations of major ions were in the order of Ca2+ > Mg2+ > Na+ > K+ and HCO3- > SO42- > Cl- > NO3- > F- during the pre- and post-monsoon periods. A slight increase was observed during the post-monsoon period. The Piper diagram suggested that the hydrochemical type of groundwater was predominantly HCO3-Ca. Principal component analysis (PCA), ionic ratios, and saturation index (SI) determined that the water-rock interactions involving silicate and carbonate minerals played a significant role in the hydrochemical process. The results of the entropy-weighted water quality index (EWQI) and irrigation water quality index (IWQI) evaluations revealed that the general qualities of groundwater were suitable for both drinking and irrigation purposes. However, the excesses of NO3- and SO42- were observed locally. Human health risk assessment concluded that groundwater posed a low risk to human health, and infants faced higher risk compared with adults. The study would provide valuable information for groundwater environmental protection.

Identification and validation of a novel five-gene signature in high-risk MYCN-not-amplified neuroblastoma.

OBJECTIVE: High-risk neuroblastoma patients often have poor outcomes despite multi-treatment options. The risk stratification of high-risk MYCN-not-amplified (HR-MYCN-NA) patients remains difficult. This study aims to identify a gene set signature that can help further stratify HR-MYCN-NA patients for a potential personalized therapeutic strategy. METHODS: Three microarrays and one single-cell RNA sequence dataset were acquired and analyzed. Firstly, the prognostic-related genes (PRGs) in HR-MYCN-NA tumor cells were identified using TARGET-NB and GSE137804 datasets. Then, the prognostic model was established by LASSO-Cox regression, and verified in external cohort (GSE49710, GSE45547). Moreover, a time-dependent receiver operating characteristic curve (ROC) and area under the ROC (AUC) was used to assess survival prediction. A nomogram was established to predict the 1-, 3- and 5-year overall survival (OS) of HR-MYCN-NA patients. RESULTS: In the training set, a five-PRGs signature, which include GAL, GFRA3, MARCKS, PSMD13, and ZNHIT3 genes, was identified and successfully stratified HR-MYCN-NA patients into ultra-high risk (UHR) and high-risk (HR) subtypes (HR = 4.29, P < 0.001). ROC curve analysis confirmed its predictive power (AUC = 0.74-0.82), suggesting a good predictive efficacy. Consistently, high-risk scores also predicted worse OS (HR = 2, P = 0.033) in the external validation dataset (AUC = 0.67-0.71). Moreover, the overall C-index of the nomogram was 0.75 (P < 0.001), which indicated good agreement between the observed and predicted survival rates. Further integrating the five PRGs signature with clinical factors, these 5 gene signature (HR = 4.45, P < 0.001) and tumor grade (HR = 4.15, P = 0.02) were found to be independent prognostic factors for HR-MYCN-NA patients. CONCLUSION: The novel five PRGs signature could well predict the survival of HR-MYCN-NA patients, which may provide constructive information for these subsets.

Cbl-b inhibition promotes less differentiated phenotypes of T cells with enhanced cytokine production.

For adoptive therapy with T cell receptor engineered T (TCR-T) cells, the quantity and quality of the final cell product directly affect their anti-tumor efficacy. The post-transfer efficacy window of TCR-T cells is keen to optimizing attempts during the manufacturing process. Cbl-b is a E3 ubiquitin ligase previously shown with critical negative impact in T cell functions. This study investigated whether strategic inclusion of a commercially available small inhibitor targeting Cbl-b (Cbl-b-IN-1) prior to T cell activation could enhance the quality of the final TCR-T cell product. Examination with both PBMCs and TCR-T cells revealed that Cbl-b-IN-1 treatment promoted TCR expression efficiency, T cell proliferation potential and, specifically, cell survival capability post antigenic stimulation. Cbl-b-IN-1 exposure facilitated T cells in maintaining less differentiated states with enhanced cytokine production. Further, we found that Cbl-b-IN-1 effectively augmented the activation of TCR signaling, shown by increased phosphorylation levels of Zeta-chain-associated protein kinase 70 (ZAP70) and phospholipase c-γ1 (PLCγ1). In conclusion, our results evidence that the inclusion of Cbl-b inhibitor immediately prior to TCR-T cell activation may enhance their proliferation, survival, and function potentials, presenting an applicable optimization strategy for immunotherapy with adoptive cell transfer.

Wideband isolator based on one-way surface magnetoplasmons with ultra-high isolation.

In this paper, we present a new type of isolator based on one-way surface magnetoplasmons (SMPs) at microwave frequencies, and it is the first time that an experimental prototype of isolator with wideband and ultra-high isolation is realized using SMP waveguide. The proposed model with gyromagnetic and dielectric layers is systematically analyzed to obtain the dispersion properties of all the possible modes, and a one-way SMP mode is found to have the unidirectional transmission property. In simulation and experiment with metallic waveguide loaded with yttrium-iron-garnet (YIG) ferrite, the scattering parameters and the field distributions agree well with the analysis and verify the one-way transmission property. The isolation is found to be as high as 80 dB and the typical value of insertion loss is 1 dB. Besides, the one-way transmission band can be controlled by changing the magnetic bias. From theoretical analysis and simulation, it is found that with a tiny value of 10 Oe of the magnetic bias, the relative bandwidth can be tuned to be greater than 50%. Compared with conventional isolators, this one-way SMP isolator has the advantages of ultra-high isolation, wide relative frequency band, and requires much smaller bias field, which has promising potential in non-reciprocal applications.

Multi-omics integration reveals potential stage-specific druggable targets in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL), a heterogeneous hematological malignancy, is caused by the developmental arrest of normal T-cell progenitors. The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease. In this study, we performed multi-omics integration analysis, which included mRNA expression, chromatin accessibility, and gene-dependency database analyses, to identify potential stage-specific druggable targets and repositioned drugs for this disease. This multi-omics integration helped identify 29 potential pathological genes for T-ALL. These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle, hematopoietic stem cell differentiation, and the AMPK signaling pathway. Of these, four known druggable targets (CDK6, TUBA1A, TUBB, and TYMS) showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL. The TUBA1A expression level was higher in the early T cell precursor (ETP)-ALL cells, while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage. CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naïve to maturation stages. Furthermore, mebendazole and gemcitabine, which target TUBA1A and TYMS, respectively, exerted stage-specific inhibitory effects on T-ALL cell lines, indicating their potential stage-specific antileukemic role in T-ALL. Collectively, our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.

Causal association of immune cells and endometriosis: a Mendelian randomization study.

Objective: To investigate the causal effect of immune cells on endometriosis (EMS), we performed a Mendelian randomization analysis. Methods: Mendelian randomization (MR) uses genetic variants as instrumental variables to investigate the causal effects of exposures on outcomes in observational data. In this study, we conducted a thorough two-sample MR analysis to investigate the causal relationship between 731 immune cells and endometriosis. We used complementary Mendelian randomization (MR) methods, including weighted median estimator (WME) and inverse variance weighted (IVW), and performed sensitivity analyses to assess the robustness of our results. Results: Four immune phenotypes have been found to be significantly associated with the risk of developing EMS: B cell %lymphocyte (WME: OR: 1.074, p = 0.027 and IVW: OR: 1.058, p = 0.008), CD14 on Mo MDSC (WME: OR: 1.056, p =0.021 and IVW: OR: 1.047, p = 0.021), CD14+ CD16- monocyte %monocyte (WME: OR: 0.947, p = 0.024 and IVW: OR: 0.958, p = 0.011), CD25 on unsw mem (WME: OR: 1.055, p = 0.030 and IVW: OR: 1.048, p = 0.003). Sensitivity analyses confirmed the main findings, demonstrating consistency across analyses. Conclusions: Our MR analysis provides compelling evidence for a direct causal link between immune cells and EMS, thereby advancing our understanding of the disease. It also provides new avenues and opportunities for the development of immunomodulatory therapeutic strategies in the future.

Identification of an HLA-A*11:01-restricted neoepitope of mutant PIK3CA and its specific T cell receptors for cancer immunotherapy targeting hotspot driver mutations.

Hotspot driver mutations presented by human leukocyte antigens might be recognized by anti-tumor T cells. Based on their advantages of tumor-specificity and immunogenicity, neoantigens derived from hotspot mutations, such as PIK3CAH1047L, may serve as emerging targets for cancer immunotherapies. NetMHCpan V4.1 was utilized for predicting neoepitopes of PIK3CA hotspot mutation. Using in vitro stimulation, antigen-specific T cells targeting the HLA-A*11:01-restricted PIK3CA mutation were isolated from healthy donor-derived peripheral blood mononuclear cells. T cell receptors (TCRs) were cloned using single-cell PCR and sequencing. Their functionality was assessed through T cell activation markers, cytokine production and cytotoxic response to cancer cell lines pulsed with peptides or transduced genes of mutant PIK3CA. Immunogenic mutant antigens from PIK3CA and their corresponding CD8+ T cells were identified. These PIK3CA mutation-specific CD8+ T cells were subsequently enriched, and their TCRs were isolated. The TCR clones exhibited mutation-specific and HLA-restricted reactivity, demonstrating varying degrees of functional avidity. Identified TCR genes were transferred into CD8+ Jurkat cells and primary T cells deficient of endogenous TCRs. TCR-expressing cells demonstrated specific recognition and reactivity against the PIK3CAH1047L peptide presented by HLA-A*11:01-expressing K562 cells. Furthermore, mutation-specific TCR-T cells demonstrated an elevation in cytokine production and profound cytotoxic effects against HLA-A*11:01+ malignant cell lines harboring PIK3CAH1047L. Our data demonstrate the immunogenicity of an HLA-A*11:01-restricted PIK3CA hotspot mutation and its targeting therapeutic potential, together with promising candidates of TCR-T cell therapy.

Is Aggressive Surgery Always Necessary for Suspected Early-Onset Surgical Site Infection after Lumbar Surgery? A 10-Year Retrospective Analysis.

OBJECTIVE: Surgical site infection (SSI) after spinal surgery is still a persistent worldwide health concern as it is a worrying and devastating complication. The number of samples in previous studies is limited and the role of conservative antibiotic therapy has not been established. This study aims to evaluate the clinical efficacy and feasibility of empirical antibiotic treatment for suspected early-onset deep spinal SSI. METHODS: We conducted a retrospective study to identify all cases with suspected early-onset deep SSI after lumbar instrumented surgery between January 2009 and December 2018. We evaluated the potential risks for antibiotic treatment, examined the antibiotic treatment failure rate, and applied logistic regression analysis to assess the risk factors for empirical antibiotic treatment failure. RESULTS: Over the past 10 years, 45 patients matched the inclusion criteria. The success rate of antibiotic treatment was 62.2% (28/45). Of the 17 patients who failed antibiotic treatment, 16 were cured after a debridement intervention and the remaining one required removal of the internal fixation before recovery. On univariate analysis, risk factors for antibiotic treatment failure included age, increasing or persisting back pain, wound dehiscence, localized swelling, and time to SSI (cut-off: 10 days). Multivariate analysis revealed that infection occurring 10 days after primary surgery and wound dehiscence were independent risk factors for antibiotic treatment failure. CONCLUSION: Appropriate antibiotic treatment is an alternative strategy for suspected early-onset deep SSI after lumbar instrumented surgery. Antibiotic treatment for suspected SSI occurring within 10 days after primary surgery may improve the success rate of antibiotic intervention. Patients with wound dehiscence have a significantly higher likelihood of requiring surgical intervention.

Causal relationships between modifiable risk factors and polycystic ovary syndrome: a comprehensive Mendelian randomization study.

Background: Polycystic Ovary Syndrome (PCOS) is a heritable condition with an as yet unclear etiology. Various factors, such as genetics, lifestyle, environment, inflammation, insulin resistance, hyperandrogenism, iron metabolism, and gut microbiota, have been proposed as potential contributors to PCOS. Nevertheless, a systematic assessment of modifiable risk factors and their causal effects on PCOS is lacking. This study aims to establish a comprehensive profile of modifiable risk factors for PCOS by utilizing a two-sample Mendelian Randomization (MR) framework. Methods: After identifying over 400 modifiable risk factors, we employed a two-sample MR approach, including the Inverse Variance Weighted (IVW) method, Weighted Median method, and MR-Egger, to investigate their causal associations with PCOS. The reliability of our estimates underwent rigorous examination through sensitivity analyses, encompassing Cochran's Q test, MR-Egger intercept analysis, leave-one-out analysis, and funnel plots. Results: We discovered that factors such as smoking per day, smoking initiation, body mass index, basal metabolic rate, waist-to-hip ratio, whole body fat mass, trunk fat mass, overall health rating, docosahexaenoic acid (DHA) (22:6n-3) in blood, monounsaturated fatty acids, other polyunsaturated fatty acids apart from 18:2 in blood, omega-3 fatty acids, ratio of bisallylic groups to double bonds, omega-9 and saturated fatty acids, total lipids in medium VLDL, phospholipids in medium VLDL, phospholipids in very large HDL, triglycerides in very large HDL, the genus Oscillibacter, the genus Alistipes, the genus Ruminiclostridium 9, the class Mollicutes, and the phylum Tenericutes, showed a significant effect on heightening genetic susceptibility of PCOS. In contrast, factors including fasting insulin interaction with body mass index, sex hormone-binding globulin, iron, ferritin, SDF1a, college or university degree, years of schooling, household income, the genus Enterorhabdus, the family Bifidobacteriaceae, the order Bifidobacteriales, the class Actinobacteria, and the phylum Actinobacteria were determined to reduce risk of PCOS. Conclusion: This study innovatively employs the MR method to assess causal relationships between 400 modifiable risk factors and the susceptibility of PCOS risk. It supports causal links between factors like smoking, BMI, and various blood lipid levels and PCOS. These findings offer novel insights into potential strategies for the management and treatment of PCOS.

Evaluation of HPV infection and presence of licensed HPV vaccine genotypes among genital warts in Foshan, China.

Objective: This study aimed to evaluate the prevalence of human papillomavirus (HPV) infection and presence of licensed HPV vaccine genotypes among patients with genital warts in Foshan, China from 2015 to 2022, to provide useful references for the detection, prevention and control of genital warts in Foshan. Methods: The present study retrospectively analyzed the HPV detection rates in patients with genital warts. A total of 1,625 patients were seen at the Second People's Hospital of Foshan, Guangdong Province, China, from 2015 to 2022. Samples were collected from various lesions and genotyped for 21 genotypes of HPV by infusion hybridization. The classification principle of HPV genotypes in this study: (1) Based on the relationship between HPV and carcinogenicity; (2) Based on the number of HPV genotypes infected; (3) Based on the HPV genotypes of licensed HPV vaccines. Results: The detection rate of any HPV in patients with genital warts was 80.37% (1,306/1,625). The detection rates of HPV for low-risk infection, co-infection and high-risk infection were 49.48% (804/1,625), 24.92% (405/1,625) and 5.97% (97/1,625), respectively. Single infection was the predominant type (51.94%, 844/1625). HPV-6 and HPV-11 were the predominant types of single infection; HPV-6 and HPV-52 were the predominant types of paired combinations of multiple infection. 82.22% (1,336/1,625) of the cases had an age distribution of ≤ 24, 25-34, and 35-44. The distribution of some HPV genotypes had age specificity, annual specificity and gender specificity. The genotype detection rates of 2v, 4v and 9v showed a decreasing trend with ages (all P < 0.05). The genotype detection rates of 4v and 9v showed a decreasing trend over the 8-year period (both P < 0.05). The genotype detection rates of 4v and 9v in the male group were higher than those in the female group (both P < 0.05). The genotype detection rate of 9v was significantly higher than that of 2v and 4v in the female group (both P < 0.05). Conclusion: Our study demonstrated that low-risk infection and single infection were the main types of HPV infection in patients with genital warts, mainly among young patients. Our study provides epidemiological data for the detection, prevention and control of genital warts in China.

Identification and characterization of emGalaseE, a ß-1,4 galactosidase from Elizabethkingia meningoseptica, and its application on living cell surface.

The biological function of terminal galactose on glycoprotein is an open field of research. Although progress had being made on enzymes that can remove the terminal galactose on glycoproteins, there is a lack of report on galactosidases that can work directly on living cells. In this study, a unique beta 1,4 galactosidase was isolated from Elizabethkingia meningoseptica (Em). It exhibited favorable stability at various temperatures (4-37 °C) and pH (5-8) levels and can remove ß-1, 4 linked galactoses directly from glycoproteins. Using Alanine scanning, we found that two acidic residues (Glu-468, and Glu-531) in the predicted active pocket are critical for galactosidase activity. In addition, we also demonstrated that it could cleave galactose residues present on living cell surface. As this enzyme has a potential application for living cell glycan editing, we named it emGalaseE or glycan-editing galactosidase I (csgeGalaseI). In summary, our findings lay the groundwork for further investigation by presenting a simple and effective approach for the removal of galactose moieties from cell surface.

The whitening efficacy of a compound formula examined using an ultraviolet-induced skin melanization model.

BACKGROUND: In Eastern culture, a fair complexion is the standard of beauty, leading to appearance-related distress among women with darker skin or facial pigmentation. Women seek whitening cosmetics to enhance their skin tone or correct their pigmentation, but their safety and effectiveness are paramount factors to consider. In this study, we evaluated the safety and whitening effects of a compound formula denoted as TEST comprising astaxanthin, nicotinamide, arbutin, and tranexamic acid. METHODS: Primary skin irritation and skin-whitening efficacy were examined. Three qualified melanization areas were treated with TEST, 7% ascorbic acid, or a blank. Skin color, the individual type angle (ITA°), and the melanin index (MI) were compared among treatment areas. RESULTS: TEST did not induce a skin response and exhibited a significantly higher ITA° than the blank, while no significant difference was observed with that of 7% ascorbic acid. Furthermore, the MI of TEST was significantly reduced posttreatment. CONCLUSIONS: TEST could be integrated into spot-fading and skin-whitening cosmeceuticals or functional cosmetics.

Functional prediction of the potential NGLY1 mutations associated with rare disease CDG.

Genetic diseases are currently diagnosed by functional mutations. However, only some mutations are associated with disease. It is necessary to establish a quick prediction model for clinical screening. Pathogenic mutations in NGLY1 cause a rare autosomal recessive disease known as congenital disorder of deglycosylation (NGLY1-CDDG). Although NGLY1-CDDG can be diagnosed through gene sequencing, clinical relevance of a detected mutation in NGLY1 needs to be further confirmed. In this study, taken NGLY1-CDDG as an example, a comprehensive and practical predictive model for pathogenic mutations on NGLY1 through an NGLY1/Glycopeptide complex model was constructed, the binding sites of NGLY1 and glycopeptides were simulated, and an in vitro enzymatic assay system was established to facilitate quick clinical decisions for NGLY1-CDDG patients. The docking model covers 42 % of reported NGLY1-CDDG missense mutations (5/12). All reported mutations were subjected to in vitro enzymatic assay in which 18 mutations were dysfunctional (18/30). In addition, a full spectrum of functional R328 mutations was assayed and 11 mutations were dysfunctional (11/19). In this study, a model of NGLY1 and glycopeptides was built for potential functional mutations in NGLY1. In addition, the effect of potential regulatory compounds, including N-acetyl-l-cysteine and dithiothreitol, on NGLY1 was examined. The established in vitro assay may serve as a standard protocol to facilitate rapid diagnosis of all mutations in NGLY1-CDDG. This method could also be applied as a comprehensive and practical predictive model for the other rare genetic diseases.

[Reversal Effect of Arctigenin on the Drug Resistance in Leukemia K562/A02 Cells and Its Mechanism].

OBJECTIVE: To study the effect of arctigenin(ARG) on adriamycin(ADM) resistance of leukemia cell line K562/A02 and the underlying mechanism. METHODS: Human leukemia cell line K562 and ADM-resistant cell line K562/A02 were cultured and treated with 2.5-50 µmol/L ADM. Cell proliferation was measured using CCK-8 method, and half maximal inhibitory concentration (IC50) was calculated. K562/A02 cells were treated with different concentrations of ARG (1, 2, 4, 8, 16 mmol/L) to detect the effect of ARG on K562/A02 cells, and a suitable concentration (2 mmol/L) was selected for subsequent experiments. K562/A02 cells were treated with 2 mmol/L ARG and 5 µmol/L ADM, and cell apoptosis was detected by flow cytometry, the expression of P-gp, MRP, cleaved caspase-3, Bax, Bcl-2 proteins and the TLR4/NF-κB signaling pathway-related proteins were measured by Western blot. TLR4 overexpression plasmid was transfected into K562/A02 cells which were co-treated with ARG and ADM, then drug sensitivity and cell apoptosis were measured. RESULTS: The IC50 value of ADM on K562/A02 cells was 36.57 µmol/L, which was significantly higher than that on K562 cells (1.30 µmol/L). ARG with a concentration of ≤2 mmol/L did not have a significant effect on K562/A02 cells. 2 mmol/L ARG significantly reduced the IC50 of ADM on K562/A02 cells. In 5 µmol/L ADM-treated K562/A02 cells, compared with the control group, the apoptosis rate of K562/A02 cells in the ARG group was significantly increased, the expressions of cleaved caspase-3, Bax proteins were significantly upregulated, the expressions of P-gp, MRP, Bcl-2, TLR4, MyD88, and p-NF-κB proteins were significantly downregulated, and the differences were statistically significant (P < 0.05). After transfection with TLR4 overexpression plasmid, the sensitivity of ARG-treated K562/A02 cells to ADM was reduced (P < 0.05), the cell apoptosis was decreased, and the expressions of P-gp, MRP, Bcl-2 and TLR4/NF-κB signaling pathway-related proteins were significantly elevated, while the expressions of cleaved caspase-3 and Bax proteins were significantly decreased (all P < 0.05). CONCLUSION: ARG may reverse the resistance of human leukemia cell line K562/A02 to ADM by inhibiting TLR4/NF-κB signaling pathway.

[Analysis of the results for genetic disease screening among 1 000 newborns from Huzhou].

OBJECTIVE: To analyze the types and distribution of pathogenic variants for neonatal genetic diseases in Huzhou, Zhejiang Province. METHODS: One thousand neonates (48 ~ 42 h after birth) born to Huzhou region were selected as the study subjects. Dry blood spot samples were collected from the newborns, and targeted capture high-throughput sequencing was carried out for pathogenic genes underlying 542 inherited diseases. Candidate variants were verified by Sanger sequencing. RESULTS: Among the 1 000 newborns, the male to female ratio was 1.02 : 1.00. No pathogenic variants were detected in 253 cases, whilst 747 cases were found to carry at least one pathogenic variant, which yielded a carrier rate of 74.7%. The most frequently involved pathogenic gene was FLG, followed by GJB2, UGT1A1, USH2A and DUOX2. The variants were classified as homozygous, compound heterozygous, and hemizygous variants. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), 213 neonates were verified to have carried pathogenic and/or likely pathogenic variants, with a positive rate of 21.3%. The most commonly involved genes had included UGT1A1, FLG, GJB2, MEFV and G6PD. CONCLUSION: Newborn screening based on high-throughput sequencing technology can expand the scope of screening and improve the positive predictive value. Genetic counseling based on the results can improve the patients' medical care and reduce neonatal mortality and childhood morbidity, while provide assistance to family members' health management and reproductive decisions.

QSAR analysis of VEGFR-2 inhibitors based on machine learning, Topomer CoMFA and molecule docking.

VEGFR-2 kinase inhibitors are clinically approved drugs that can effectively target cancer angiogenesis. However, such inhibitors have adverse effects such as skin toxicity, gastrointestinal reactions and hepatic impairment. In this study, machine learning and Topomer CoMFA, which is an alignment-dependent, descriptor-based method, were employed to build structural activity relationship models of potentially new VEGFR-2 inhibitors. The prediction ac-curacy of the training and test sets of the 2D-SAR model were 82.4 and 80.1%, respectively, with KNN. Topomer CoMFA approach was then used for 3D-QSAR modeling of VEGFR-2 inhibitors. The coefficient of q2 for cross-validation of the model 1 was greater than 0.5, suggesting that a stable drug activity-prediction model was obtained. Molecular docking was further performed to simulate the interactions between the five most promising compounds and VEGFR-2 target protein and the Total Scores were all greater than 6, indicating that they had a strong hydrogen bond interactions were present. This study successfully used machine learning to obtain five potentially novel VEGFR-2 inhibitors to increase our arsenal of drugs to combat cancer.

Exploration of the Dynamic Variations of the Characteristic Constituents and the Degradation Products of Catalpol during the Process of Radix Rehmanniae.

Radix Rehmanniae (RR), a famous traditional Chinese medicine (TCM) widely employed in nourishing Yin and invigorating the kidney, has three common processing forms in clinical practice, including fresh Radix Rehmanniae (FRR), raw Radix Rehmanniae (RRR), and processed Radix Rehmanniae (PRR). However, until now, there has been less exploration of the dynamic variations in the characteristic constituents and degradation products of catalpol as a representative iridoid glycoside with the highest content in RR during the process from FRR to PRR. In this study, an ultra-performance liquid chromatography coupled with photodiode array detector (UPLC-PDA) method was successfully established for the simultaneous determination of ten characteristic components to explore their dynamic variations in different processed products of RR. Among them, iridoid glycosides, especially catalpol, exhibited a sharp decrease from RRR to PRR. Then, three degradation products of catalpol were detected under simulated processing conditions (100 °C, pH 4.8 acetate buffer solution), which were isolated and identified as jiofuraldehyde, cataldehyde, and norviburtinal, respectively. Cataldehyde was first reported as a new compound. Moreover, the specificity of norviburtinal in self-made PRR samples was discovered and validated, which was further confirmed by testing in commercially available PRR samples. In conclusion, our study revealed the decrease in iridoid glycosides and the production of new degradation substances during the process from FRR to PRR, which is critical for unveiling the processing mechanism of RR.

IL-33 Induces Cellular and Exosomal miR-146a Expression as a Feedback Inhibitor of Mast Cell Function.

IL-33 is an inflammatory cytokine that promotes allergic disease by activating group 2 innate lymphoid cells, Th2 cells, and mast cells. IL-33 is increased in asthmatics, and its blockade suppresses asthma-like inflammation in mouse models. Homeostatic control of IL-33 signaling is poorly understood. Because the IL-33 receptor, ST2, acts via cascades used by the TLR family, similar feedback mechanisms may exist. MicroRNA (miR)-146a is induced by LPS-mediated TLR4 signaling and serves as a feedback inhibitor. Therefore, we explored whether miR-146a has a role in IL-33 signaling. IL-33 induced cellular and exosomal miR-146a expression in mouse bone marrow-derived mast cells (BMMCs). BMMCs transfected with a miR-146a antagonist or derived from miR-146a knockout mice showed enhanced cytokine expression in response to IL-33, suggesting that miR-146a is a negative regulator of IL-33-ST2 signaling. In vivo, miR-146a expression in plasma exosomes was elevated after i.p. injection of IL-33 in wild-type but not mast cell-deficient KitW-sh/W-sh mice. Finally, KitW-sh/W-sh mice acutely reconstituted with miR-146a knockout BMMCs prior to IL-33 challenge had elevated plasma IL-6 levels compared with littermates receiving wild-type BMMCs. These results support the hypothesis that miR-146a is a feedback regulator of IL-33-mediated mast cell functions associated with allergic disease.

Practice guideline on ovarian tissue cryopreservation and transplantation in the prevention and treatment of iatrogenic premature ovarian insufficiency.

Premature ovarian insufficiency (POI) refers to the decline of ovarian function before the age of 40. POI causes a reduction in or loss of female fertility, accompanied by different degrees of menopausal symptoms, which increases the risk of chronic diseases related to early menopause and seriously affects patients' quality of life and health. It is conservatively estimated that at least one million prepubertal girls and women of reproductive age in China are at risk of iatrogenic POI caused by radiotherapy and chemotherapy every year. With the development of medical technology and the breakthrough of scientific and technological advances, preventing and treating iatrogenic POI have become possible. International and national guidelines consider cryopreserved ovarian tissue transplantation to be the most promising method of preserving the ovarian function and fertility of prepubertal girls and women of reproductive age who cannot delay radiotherapy and chemotherapy. In order to guide the clinical application of ovarian tissue cryopreservation and transplantation technology in China, the Guideline Working Group finally included 14 scientific questions and 18 recommendations through a questionnaire survey, field investigation, and consultation of a large number of Chinese and English literature databases in order to provide a reference for colleagues in clinical practice.