The effects of laryngeal mask versus endotracheal tube on atelectasis after general anesthesia induction assessed by lung ultrasound: A randomized controlled trial.

STUDY OBJECTIVE: This study aims to evaluate the impact of Supreme™ laryngeal masks versus endotracheal tubes on atelectasis during general anesthesia using lung ultrasound (LUS), and provide evidence for respiratory management. DESIGN: A single-center, double-blind, randomized controlled trial was conducted. SETTING: The study was conducted in both the operating room and the post-anesthesia care unit, with follow-up assessments performed in the ward. PATIENTS: Enrollment included 180 cases undergoing non-laparoscopic surgeries in gynecology, urology, and orthopedic limb surgeries. INTERVENTIONS: Patients were randomly assigned 1:1 to the endotracheal intubation or laryngeal mask group. MEASUREMENTS: LUS scores were recorded across 12 lung regions at baseline, 15 min after airway establishment, at the end of surgery, and 30 min following airway removal. Outcome measures encompassed the oxygenation index, dynamic lung compliance, incidence of postoperative pulmonary complications, throat pain, and other postoperative complications assessed at 24 and 48 h postoperatively. The primary outcome focused on the LUS score in all 12 lung regions at 15 min after airway establishment. MAIN RESULTS: Intention-to-treat analysis of 177 subjects revealed endotracheal intubation led to significantly higher LUS scores at 15 min {P < 0.001, mean difference 4.15 ± 0.60, 95% CI [2.97, 5.33]}, end of surgery (P < 0.001, mean difference 3.37 ± 0.68, 95% CI [2.02, 4.72]), and 30 min post-removal (P < 0.001, mean difference 2.63 ± 0.48, 95% CI [1.68, 3.58]). No major complications occurred in the two groups. CONCLUSIONS: Compared to endotracheal intubation, laryngeal masks effectively reduce atelectasis formation and progression in gynecological, urological non-laparoscopic, and orthopedic limb surgeries. However, caution is warranted when generalizing these findings to surgeries with a higher risk of laryngeal mask leakage or obese patients. Additionally, the efficacy of laryngeal masks in reducing postoperative atelectasis remains uncertain when comprehensive monitoring of muscle relaxation and reversal therapy is employed.

ZBTB7A regulates LncRNA HOTAIR-mediated ELAVL1/SOX17 axis to inhibit malignancy and angiogenesis in endometrial carcinoma.

BACKGROUND: Endometrial cancer (EC) is the sixth most frequent cancer in women worldwide and has higher fatality rates. The pathophysiology of EC is complex, and there are currently no reliable methods for diagnosing and treating the condition. Long non-coding RNA (lncRNA), according to mounting evidence, is vital to the pathophysiology of EC. HOTAIR is regarded as a significant prognostic indicator of EC. ZBTB7A decreased EC proliferation and migration, according to recent studies, however the underlying mechanism still needs to be clarified. METHODS: The research utilized RT-qPCR to measure HOTAIR expression in clinical EC tissues and various EC cell lines. Kaplan-Meier survival analysis was employed to correlate HOTAIR levels with patient prognosis. Additionally, the study examined the interaction between ZBTB7A and HOTAIR using bioinformatics tools and ChIP assays. The experimental approach also involved manipulating the expression levels of HOTAIR and ZBTB7A in EC cell lines and assessing the impact on various cellular processes and gene expression. RESULTS: The study found significantly higher levels of HOTAIR in EC tissues compared to adjacent normal tissues, with high HOTAIR expression correlating with poorer survival rates and advanced cancer characteristics. EC cell lines like HEC-1 A and KLE showed higher HOTAIR levels compared to normal cells. Knockdown of HOTAIR in these cell lines reduced proliferation, angiogenesis, and migration. ZBTB7A was found to be inversely correlated with HOTAIR, and its overexpression led to a decrease in HOTAIR levels and a reduction in malignant cell behaviors. The study also uncovered that HOTAIR interacts with ELAVL1 to regulate SOX17, which in turn activates the Wnt/ß-catenin pathway, promoting malignant behaviors in EC cells. CONCLUSION: HOTAIR is a critical regulator in EC, contributing to tumor growth and poor prognosis. Its interaction with ZBTB7A and regulation of SOX17 via the Wnt/ß-catenin pathway underlines its potential as a therapeutic target.

Efficacy and Molecular Mechanism of Quercetin on Constipation Induced by Berberine via Regulating Gut Microbiota.

Berberine (BBR) is used to treat cancer, inflammatory conditions, and so on. But the side effects of BBR causing constipation should not be ignored. In clinical application, the combination of Amomum villosum Lour. (AVL) and BBR can relieve it. However, the effective ingredients and molecular mechanism of AVL in relieving constipation are not clear. A small intestine propulsion experiment was conducted in constipated mice to screen active ingredients of AVL. We further confirmed the molecular mechanism of action of the active ingredient on BBR-induced constipation. Quercetin (QR) was found to be the effective ingredient of AVL in terms of relieving constipation. QR can efficiently regulate the microbiota in mice suffering from constipation. Moreover, QR significantly raised the levels of substance P and motilin while lowering those of 5-hydroxytryptamine and vasoactive intestinal peptide; furthermore, it also increased the protein expression levels of calmodulin, myosin light-chain kinase, and myosin light chain. The use of QR in combination with BBR has an adverse effect-reducing efficacy. The study provides new ideas and possibilities for the treatment of constipation induced by BBR.

Coagulation and fibrinolytic markers offer utility when distinguishing between benign and malignant gallbladder tumors: A cross-sectional study.

BACKGROUND: The metabolic or proliferative abnormalities that are characteristic of tumor cells can lead to abnormal fibrinolysis or coagulation system activity, with certain tumors exhibiting hypercoagulability or existing in a fibrinolytic state. However, the utility of biomarkers of coagulation and fibrinolysis when seeking to differentiate between benign gallbladder disease and malignant gallbladder tumors remains uncertain. METHODS: This study included a total of 81 patients with benign gallbladder polyps and 94 patients with malignant gallbladder tumors. Pre-biopsy or pretreatment levels of PT, APTT, FIB, D-dimer, FDP, PLT, PIC, TAT, TM, and t-PAIC from these patients were compared using Mann-Whitney tests. The baseline data of the patients were analyzed using chi-square tests, and the diagnostic utility of these biomarkers in distinguishing between benign and malignant gallbladder lesions was evaluated using ROC curves, and Spearman correlation analysis was employed to assess the correlation between these indicators and tumor parameters. RESULTS: The average age of malignant gallbladder tumor group was higher than benign gallbladder polyp group. And the base line analysis showed that there was a statistic difference in age, history of smoking, drinking, biliary tract disease, BMI of over weight between these two groups. In patients with malignant gallbladder tumors, FIB, D-dimer, FDP, PIC, TAT, TM, and t-PAIC levels were significantly elevated relative to those in patients affected by benign gallbladder polyp. The AUC for FIB, D-dimer, and FDP was 0.8469, 0.6514, 0.5950, while for PIC, TAT, TM, t-PAIC and four biomarker combined diagnosed was 0.8455, 0.6554, 0.7130, 0.6806, and 0.8859. Among these, TM was associated with the vascular invasion of tumor patients; TAT and t-PAIC were associated with neural invasion; D-dimer and FDP were related to the maximum tumor diameter; and FDP had a certain correlation with the tumor stage. CONCLUSIONS: In gallbladder tumor patients, conventional coagulation metrics like FIB, D-dimer, and FDP, as well as newer thrombotic indicators such as PIC, TAT, TM, and t-PAIC, were obviously increased. Correlations with tumor parameters suggested their potential as biomarkers to distinguish benign from malignant gallbladder growths.

Molecular mechanism of Chang Shen Hua volatile oil modulating brain cAMP-PKA-CREB pathway to improve depression-like behavior in rats.

BACKGROUND: Depression is a common and complex mental illness that manifests as persistent episodes of sadness, loss of interest, and decreased energy, which might lead to self-harm and suicide in severe cases. Reportedly, depression affects 3.8 % of the world's population and has been listed as one of the major global public health concerns. In recent years, aromatherapy has been widely used as an alternative and complementary therapy in the prevention and treatment of depression; people can relieve anxiety and depression by sniffing plant aromatic essential oils. Acorus tatarinowii and Panax ginseng essential oils in Chang Shen Hua volatile oil (CSHVO) are derived from Acorus tatarinowii and Panax ginseng, respectively, the main medicines in the famous Chinese medicine prescription Kai Xin San (KXS), Then, these oils are combined with the essential oil of Albizia julibrissin flower to form a new Chinese medicine inhalation preparation, CSHVO. KXS has been widely used in the treatment of depression; however, whether CSHVO can ameliorate depression-like behavior, its pharmacological effects, and the underlying mechanisms of action are yet to be elucidated. STUDY DESIGN AND METHODS: A rat model of chronic and unpredictable mild stimulation (CUMS) combined with orphan rearing was treated with CSHVO for 4 weeks. Using behavioral tests (sucrose preference, force swimming, tail suspension, and open field), the depression-like degree was evaluated. Concurrently, brain homogenate and serum biochemistry were analyzed to assess the changes in the neurotransmitters and inflammatory and neurotrophic factors. Furthermore, tissue samples were collected for histological and protein analyses. In addition, network pharmacology and molecular docking analyses of the major active compounds, potential therapeutic targets, and intervention pathways predicted a role of CSHVO in depression relief. Subsequently, these predictions were confirmed by in vitro experiments using a corticosterone (CORT)-induced PC12 cell damage model. RESULTS: CSHVO inhalation can effectively improve the weight and depression-like behavior of depressed rats and regulate the expression of inflammatory factors and neurotransmitters. Hematoxylin-eosin, Nissl, and immunofluorescence staining indicated that compared to the model group, the pathological damage to the brain tissues of rats in the CSHVO groups was improved. The network pharmacological analysis revealed that 144 CSHVO active compounds mediate 71 targets relevant to depression treatment, most of which are rich in the cAMP signaling and inflammatory cytokine pathways. Protein-protein interaction analysis showed that TNF, IL6, and AKT are the core anti-depressive targets of CSHVO. Molecular docking analysis showed an adequate binding between the active ingredients and the key targets. In vitro experiments showed that compared to the model group, the survival rate of PC12 cells induced by CSHVO intervention was increased, the apoptosis rate was decreased, and the expression of inflammatory cytokines in the cell supernatant was improved. Western blot analysis and immunofluorescence staining confirmed that CSHVO regulates PC12 cells in the CORT model through the cAMP-PKA-CREB signaling pathway, and pretreatment with PKA blocker H89 eliminates the protective effect of CSHVO on CORT-induced PC12 cells. CONCLUSIONS: CSHVO improves CORT-induced injury in the PC12 cell model and CUMS combined with orphan rearing-induced depression model in rats. The antidepressant mechanism of CSHVO is associated with the modulation of the cAMP-PKA-CREB signaling pathway.

Validating the 2023 FIGO staging system: A nomogram for endometrioid endometrial cancer and adenocarcinoma.

BACKGROUND: To find the factors impacting overall survival (OS) prognosis in patients with endometrioid endometrial carcinoma (EEC) and adenocarcinoma and to establish a nomogram model to validate the 2023 International Federation of Obstetrics and Gynecology (FIGO) staging system for endometrial cancer. METHODS: Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) training cohort. An independent validation cohort was obtained from the First Affiliated Hospital of Anhui Medical University between 2008 and 2023. Cox regression analysis identified independent prognostic factors for OS in EEC and adenocarcinoma patients. A nomogram predicting OS was developed and validated utilizing the C-index, calibration curves, receiver operating characteristic (ROC) curves, and decision curve analysis (DCA). The relationship between the tumor grade and prognosis of EEC and adenocarcinoma was quantified using net reclassification improvement (NRI), propensity score matching (PSM), and Kaplan-Meier curves. RESULTS: Cox regression analysis identified age, race, marital status, tumor grade, tumor stage, tumor size, and chemotherapy as independent prognostic factors for OS. A nomogram for predicting OS was developed based on these factors. The C-indexes for the OS nomogram was 0.743 and 0.720 for the SEER training set and external validation set, respectively. The area under the ROC (AUC) for the OS nomogram was 0.755, 0.757, and 0.741 for the SEER data subsets and 0.844, 0.719, and 0.743 for the external validation subsets. Calibration plots showed high concordance between the nomogram-predicted and observed OS. DCA also demonstrated the clinical utility of the OS nomogram. NRI, PSM, and survival analyses revealed that tumor grade was the most important histopathological factor for EEC and adenocarcinoma prognosis. CONCLUSION: Seven independent prognostic variables for the OS of patients with EEC and adenocarcinoma were identified. The established OS nomogram has good predictive ability and clinical utility and validates the 2023 endometrial cancer FIGO staging system.

CLCN3 in mediating the proliferation of human ovarian cancer cells.

Background: Chloride channel-3 (CLCN3), a crucial component of the voltage-gated chloride channel family, is implicated in numerous physiological and pathophysiological processes. This study aimed to investigate the characteristics of CLCN3 in pancancer and its influence on the immune response through the use of a range of databases. Concurrently, we assessed the impact of CLCN3 on the proliferation of ovarian cancer (OC) cells and explored its potential mechanisms. Methods: We employed the Tumor Immune Estimation Resource (TIMER) 2.0 and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases to examine the messenger RNA (mRNA) and the protein expression of CLCN3 across various cancers. The prognostic significance of CLCN3 was evaluated using the Gene Expression Profiling Interactive Analysis 2.0 (GEPIA 2.0) database. The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) facilitated the analysis of CLCN3 promoter methylation levels. The association between CLCN3 expression and tumor-infiltrating immune cells was investigated using various algorithms. The cBioportal database facilitated the analysis of CLCN3 mutations and mutation sites across various cancers. The Tumor-Immune System Interactions Database (TISIDB) database was employed to explore the correlation between CLCN3 expression and immune or molecular subtypes across a variety of cancer types. We collected ovarian tissue samples, encompassing both normal ovarian and OC tissues. The human OC cell lines, SKOV3 cells and OVCAR433 cells, were cultured. CLCN3 expression was determined via reverse-transcription quantitative polymerase chain reaction (RT-qPCR), while phosphatidylinositol 3-kinase/Akt kinase (PI3K/AKT) expression was detected using Western blot. We utilized small interfering RNA (siRNA) technology to suppress CLCN3 expression. The proliferative capacity of SKOV3 and OVCAR433 cells was assessed using the Cell Counting Kit 8 (CCK-8) assay. Results: CLCN3 demonstrated an aberrant expression in a number of cancer types and was markedly reduced in OC tissues. Poor prognosis in cervical squamous cell cancer and myeloid leukemia was linked to excessive expression of CLCN3. The examination of immune cell infiltration, which included CD8+ T cells, B cells, T regulatory cells, and cancer-associated fibroblast cells, showed a strong association with aberrant CLCN3 expression. Following the use of siRNA technology, the ability of the ovarian carcinoma cell line SKOV3 and OVCAR433 to proliferate as well as the expression of PI3K/AKT both increased. Conclusions: CLCN3 is a possible biomarker for immune-related processes and the prognosis of cancer, and the PI3K/AKT signaling pathway may affect OC cells' ability to proliferate.

5-Aza-2'-Deoxycytidine Ameliorates Choroidal Neovascularization by Inhibiting the Wnt/ß-Catenin Signaling Pathway.

Purpose: Choroidal neovascularization (CNV) can constitute the final pathology of many ocular diseases and result in severe vision loss. Studies have demonstrated that DNA methylation is critical in retinal development, aging, and disorders. The current work investigated the effects and underlying mechanism of 5-Aza-2'-deoxycytidine (5-aza-dC), a suppressor of DNA methylation, in the pathological progression of CNV. Methods: The DNA methylation profiles of retinal pigment epithelial (RPE)/choroidal complexes in normal and laser-induced CNV mice were assessed by Arraystar Mouse RefSeq Promoter Arrays. The CNV area and blood flow density and intensity were observed by optical coherence tomography angiography, and fluorescence leakage was examined by fundus fluorescein angiography in CNV mice with systemic administration of 5-aza-dC. The effects of 5-aza-dC on the biological functions of bEnd.3 cells were estimated by related assays. Notum gene promoter methylation was measured using bisulfite sequencing PCR. Methyltransferases and Wnt signaling-related genes were detected in animal and cell culture experiments by real-time PCR and immunoblot. Results: Methyltransferases were upregulated, but Notum (a secretion inhibitor of Wnt signaling) was downregulated in the RPE/choroidal complexes of mice with experimental CNV. Intraperitoneal injection of 5-aza-dC inactivated the Wnt pathway and ameliorated the lesion area and the intensity and density of blood flow, as well as the degree of leakage in CNV. In vitro, vascular endothelial growth factor A (VEGFA) stimulation promoted methyltransferases expression and suppressed Notum expression, consequently activating Wnt signaling, whereas exogenous 5-aza-dC reversed VEGFA-induced hyperpermeability, proliferation, migration, and tube formation in bEnd.3 cells via demethylation of Notum promoter. Conclusions: We observed that 5-aza-dC attenuates the growth of CNV by inhibiting the Wnt signaling pathway via promoter demethylation of the Wnt antagonist Notum. These findings provide a theoretical basis for methylation-based treatment with the Notum gene as a potential target for CNV treatment.

A microRNA sponge, LINC02193, promotes neutrophil activation by upregulating ICAM1 and is correlated with ANCA-associated vasculitis.

OBJECTIVE: To investigate the pathogenic role and underlying mechanisms of lncRNAs in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). METHODS：: RNA-sequencing (RNA-seq) was applied to screen the expression profile of lncRNAs in peripheral leukocytes from 5 AAV patients and 5 healthy controls (HC). Candidate lncRNAs were preliminarily verified in peripheral leukocytes from 46 AAV patients and 35 HC by qRT-PCR. Then, the identified LINC02193 was further validated in peripheral neutrophils from 67 AAV patients, 45 HC and 64 disease controls. Correlation between LINC02193 levels and disease activity was analyzed. Then, a loss-of-function study was conducted to investigate the role of LINC02193 in neutrophils activation. Furthermore, bioinformatics analysis, dual luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to explore the mechanism of LINC02193 regulating neutrophils activation. RESULTS: A total of 467 upregulated and 412 downregulated lncRNAs were identified in AAV patients. From top 5 upregulated lncRNAs, an elevation of LINC02193 was validated in a larger sample of AAV patients, and positively correlated with disease activity. Knockdown of LINC02193 inhibited ROS and NO production, NETs release and adhesion to endothelial cells of differentiated human promyelocytic leukaemia HL­60 cells (dHL-60), whereas overexpression of ICAM1 counteracted these effects. Mechanistic analysis demonstrated that LINC02193 acted as a miR-485-5p sponge to relieve the repressive effect of miR-485-5p on ICAM1, thus promoting ICAM1 expression. CONCLUSION: LINC02193, a novel lncRNA identified in AAV could function as competing endogenous RNAs (ceRNA) for miR-485-5p to promote ICAM1 expression and neutrophils activation, suggesting its potential as a therapeutic target of AAV.

Design, synthesis and biological evaluation of novel selective PI3Kδ inhibitors containing pyridopyrimidine scaffold.

Aim: In our study compounds with pyrido[3,2-d]pyrimidine and pyrido[3,4-d]pyrimidine were designed, synthesized and evaluated for their biological activity against hematologic tumors. Methods: The biological activity of compounds was evaluated by ADP-Glo Luminescence assay, MTT [3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide] assay, western blotting and flow cytometry, respectively. Results: Compounds A1, A5 and A7 containing pyrido[3,2-d]pyrimidine inhibited phosphoinositide 3-kinase-δ (PI3Kδ) at subnanomolar levels and had good δ-isoform selectivity. A1, A5 and A7 showed significant inhibitory effects against SU-DHL-6 cells and effectively inhibited Akt phosphorylation in a good concentration-dependent manner. A7 induced apoptosis and caused cell cycle arrest in SU-DHL-6 cells. Docking studies showed that A1, A5 and A7 bound tightly to PI3Kδ through key hydrogen bonding interactions. Conclusion: This study suggests that employing pyrido[3,2-d]pyrimidine can facilitate the design of novel potent and selective PI3Kδ inhibitors.

Physiological response and molecular mechanisms against UV-B radiation in Brachionus asplanchnoidis (Rotifera).

Ultraviolet B (UV-B, 280-320 nm) radiation is a major environmental stressor for aquatic organisms on Earth's surface. Its effects on biological systems are well known, but the mechanisms by which organisms respond and adapt to UV-B radiation are still being explored. In this study, we investigated the effects of UV-B radiation on the monogonont rotifer Brachionus asplanchnoidis, focusing on physiological parameters, antioxidant systems, DNA damage, and DNA repair-related molecular mechanism. Our results showed that the LD50 was at 28.53 kJ/m2, indicating strong tolerance to UV-B. However, UV-B radiation caused adverse effects on growth and reproduction, with shortened reproductive period and longevity, decreased fecundity and hatchability, and inhibition of population growth. Biochemical analyses revealed severe oxidative damage and lipid peroxidation, with increased ROS and MDA levels. Activities of antioxidant enzymes were highly induced at low doses but decreased at high doses. DNA damage also occurred in UV-B-exposed rotifers. Furthermore, selected DNA repair-related genes were up-regulated in a dose-dependent manner. These findings provide a comprehensive understanding of the effects of UV-B radiation on rotifers and highlight the importance of considering both ecological and molecular responses in assessing the impact of UV-B radiation on aquatic organisms.

Plant Polyphenols Attenuate DSS-induced Ulcerative Colitis in Mice via Antioxidation, Anti-inflammation and Microbiota Regulation.

The pathogenesis of ulcerative colitis (UC) is associated with inflammation, oxidative stress, and gut microbiota imbalance. Although most researchers have demonstrated the antioxidant bioactivity of the phenolic compounds in plants, their UC-curing ability and underlying mechanisms still need to be further and adequately explored. Herein, we studied the antioxidation-structure relationship of several common polyphenols in plants including gallic acid, proanthocyanidin, ellagic acid, and tannic acid. Furthermore, the in vivo effects of the plant polyphenols on C57BL/6 mice with dextran-sulfate-sodium-induced UC were evaluated and the action mechanisms were explored. Moreover, the interplay of several mechanisms was determined. The higher the number of phenolic hydroxyl groups, the stronger the antioxidant activity. All polyphenols markedly ameliorated the symptoms and pathological progression of UC in mice. Furthermore, inflammatory cytokine levels were decreased and the intestinal barrier was repaired. The process was regulated by the antioxidant-signaling pathway of nuclear-erythroid 2-related factor 2. Moreover, the diversity of the intestinal microbiota, Firmicutes-to-Bacteroides ratio, and relative abundance of beneficial bacteria were increased. An interplay was observed between microbiota regulation and oxidative stress, immunity, and inflammatory response. Furthermore, intestinal barrier repair was found to be correlated with inflammatory responses. Our study results can form a basis for comprehensively developing plant-polyphenol-related medicinal products.

Perioperative active warming strategies in children: a protocol for a multicentre, prospective, randomized controlled trial.

Introduction: Inadvertent perioperative hypothermia (IPH) refers to a core body temperature lower than 36.0 °C, which can contribute to many adverse events. The special physiological characteristics in children further increase the incidence of IPH. Therefore, it is very important to perform effective perioperative warming measures for children. Traditional passive warming measures with additional layers have limited thermal insulation effects. Active warming measures might be the better choice, and most measures have achieved good effects in adults. This study combines a variety of active warming measures to propose perioperative active warming strategies and aims to verify the feasibility and thermal insulation effects of perioperative active warming strategies in children. Methods: This study is a multicentre, prospective, randomized controlled trial. From August 2022 to July 2024, 400 paediatric patients undergoing elective surgery will be recruited in four centres and randomly divided into the active warming strategies group and control group at a ratio of 1:1. The primary outcome is the perioperative cumulative hypothermia effect value (Σ ΔTi × Δti, i = 1…, n). Multiple complications covering the anaesthesia recovery period and postoperative hospitalization will be considered as secondary outcomes to comprehensively analyse the prognosis. Trial registration: ClinicalTrials.gov identifier: ChiCTR2200062168. Registered on July 26th, 2022. Registered with the name of "Perioperative Active Warming Strategies in Children: A multicenter, prospective, randomized controlled trial". URL:http://www.chictr.org.cn/showproj.aspx?proj=172778.

Discovery of potent and selective PI3Kδ inhibitors bearing amino acid fragments.

The selective inhibition of PI3Kδ is a potential therapeutic strategy for the treatment of hematologic malignancies. Herein, we report a series of compounds bearing amino acid fragments as potent and selective PI3Kδ inhibitors. Among them, compound A10 exhibited sub-nanomolar PI3Kδ potency. In cellular assays, A10 achieved strong antiproliferation against SU-DHL-6 cells, and caused cell cycle arrest, and induced apoptosis in SU-DHL-6 cells. The docking study showed that A10 tightly bound to PI3Kδ protein with a planar-shaped conformation. Collectively, compound A10 represented a promising potent and selective PI3Kδ inhibitor bearing amino acid fragement albeit with moderate selectivity over PI3Kγ but superior selectivity against PI3Kα and ß. This study suggested that using the amino acid fragments instead of the pyrrolidine ring is new strategy for design of potent PI3Kδ inhibitors.

Hypoxia-induced miR-9 expression promotes ovarian cancer progression via activating PI3K/AKT/mTOR/GSK3ß signaling pathway.

Ovarian cancer (OC) is one of the most prevalent malignant tumors affecting women's life and health. Since OC has a poor prognosis due to extensive metastasis, there is a need to explore a new mechanism of OC metastasis. microRNAs (miRs) are single-stranded, non-coding RNAs. miR-9 has been reported to promote cancer and may provide a new strategy for OC diagnosis. The purpose of this study was to examine the function and underlying mechanism of miR-9 in OC. RT-qPCR was used to assess miR-9 expression levels. Transwell assays were used to determine the number of migrating and invading OC cells. The protein expression levels of the PI3K/AKT/mTOR/GSK3ß signaling pathway were examined using western blotting. The results informed that, when compared to normal ovarian tissues, miR-9 was remarkably expressed in OC tissues, and hypoxia might lead to overexpression of miR-9-5p while inhibiting miR-9 notably suppressed the migrating and invading cell numbers in OC cells. In vivo, miR-9-5p knockdown inhibited tumor growth in a subcutaneous nude mice model of SKOV3 cells. Our findings suggest that miR-9 could be an underlying oncogene in OC, opening up new avenues for OC diagnosis and treatment of OC by targeting miR-9.

Generating Hypergraph-Based High-Order Representations of Whole-Slide Histopathological Images for Survival Prediction.

Patient survival prediction based on gigapixel whole-slide histopathological images (WSIs) has become increasingly prevalent in recent years. A key challenge of this task is achieving an informative survival-specific global representation from those WSIs with highly complicated data correlation. This article proposes a multi-hypergraph based learning framework, called "HGSurvNet," to tackle this challenge. HGSurvNet achieves an effective high-order global representation of WSIs via multilateral correlation modeling in multiple spaces and a general hypergraph convolution network. It has the ability to alleviate over-fitting issues caused by the lack of training data by using a new convolution structure called hypergraph max-mask convolution. Extensive validation experiments were conducted on three widely-used carcinoma datasets: Lung Squamous Cell Carcinoma (LUSC), Glioblastoma Multiforme (GBM), and National Lung Screening Trial (NLST). Quantitative analysis demonstrated that the proposed method consistently outperforms state-of-the-art methods, coupled with the Bayesian Concordance Readjust loss. We also demonstrate the individual effectiveness of each module of the proposed framework and its application potential for pathology diagnosis and reporting empowered by its interpretability potential.

Advances in the synthesis of three typical tetraterpenoids including ß-carotene, lycopene and astaxanthin.

Carotenoids are natural pigments that widely exist in nature. Due to their excellent antioxidant, anticancer and anti-inflammatory properties, carotenoids are commonly used in food, medicine, cosmetic and other fields. At present, natural carotenoids are mainly extracted from plants, algae and microorganisms. With the rapid development of metabolic engineering and molecular biology as well as the continuous in-depth study of carotenoids synthesis pathways, industrial microorganisms have showed promising applications in the synthesis of carotenoids. In this review, we introduced the properties of several carotenoids and their biosynthetic metabolism process. Then, the microorganisms synthesizing carotenoids through the natural and non-natural pathways and the extraction methods of carotenoids were summarized and compared. Meanwhile, the influence of substrates on the carotenoids production was also listed. The methods and strategies for achieving high carotenoid production are categorized to help with future research.

Follicular fluid lipidomic profiling reveals potential biomarkers of polycystic ovary syndrome: A pilot study.

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder associated with multiple metabolic conditions including obesity, insulin resistance, and dyslipidemia. PCOS is the most common cause of anovulatory infertility; however, the molecular diversity of the ovarian follicle microenvironment is not fully understood. This study aimed to investigate the follicular fluid (FF) lipidomic profiles in different phenotypes of PCOS and to explore novel lipid biomarkers. Methods: A total of 25 women with PCOS and 12 women without PCOS who underwent in vitro fertilization and embryo transfer were recruited, and their FF samples were collected for the lipidomic study. Liquid chromatography-tandem mass spectrometry was used to compare the differential abundance of FF lipids between patients with different PCOS phenotypes and controls. Subsequently, correlations between specific lipid concentrations in FF and high-quality embryo rate (HQER) were analyzed to further evaluate the potential interferences of lipid levels with oocyte quality in PCOS. Candidate biomarkers were then compared via receiver operating characteristic (ROC) curve analysis. Results: In total, 19 lipids were identified in ovarian FF. Of these, the concentrations of ceramide (Cer) and free fatty acids (FFA) in FF were significantly increased, whereas those of lysophosphatidylglycerol (LPG) were reduced in women with PCOS compared to controls, especially in obese and insulin-resistant groups. In addition, six subclasses of ceramide, FFA, and LPG were correlated with oocyte quality. Twenty-three lipid subclasses were identified as potential biomarkers of PCOS, and ROC analysis indicated the prognostic value of Cer,36:1;2, FFA C14:1, and LPG,18:0 on HQER in patients with PCOS. Conclusions: Our study showed the unique lipidomic profiles in FF from women with PCOS. Moreover, it provided metabolic signatures as well as candidate biomarkers that help to better understand the pathogenesis of PCOS.

High current flux electrochemical sensor based on nickel-iron bimetal pyrolytic carbon material of paper waste pulp for clenbuterol detection.

As a ß-stimulant, clenbuterol (CLB) is abused to varying degrees by athletes worldwide. It is also used in the meat and dairy industries. CLB inadvertently enters the human body through the food chain, endangering human health. Therefore, a rapid and convenient method for detecting CLB is needed. In this study, nanocarbon-supported NiFe2O4 electrode materials (NiFe2O4-NPCs) were synthesized, and an electrochemical sensor (NiFe2O4-NPCs/GCE) for CLB detection was fabricated. NiFe2O4-NPCs have good electrical conductivity, electrocatalytic activity, and high electrical flux, owing to their large specific surface area and the anti-spinel structure of NiFe2O4. The fabricated sensor is an effective detector of CLB. The sensor exhibits linear ranges of 10-7-10-5 M and 7 × 10-11-10-7 M and a limit of detection (LOD) of 3.03 × 10-12 M (S/N = 3). The sensor also exhibits good sensitivities of 3.264 µA µM-1 cm-2 and 0.751 µA µM-1 cm-2 (S/N = 3). Additionally, NiFe2O4-NPCs/GCE successfully detected CLB in real samples of human urine. Thus, this study highlights the potential of the NiFe2O4-NPCs/GCE sensor for the detection of CLB in biological samples.

Follicular free fatty acid metabolic signatures and their effects on oocyte competence in non-obese PCOS patients.

In Brief: Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility in women. This study identified changes in free fatty acids profiles in the follicular fluid that may lead to better diagnosis and management of infertility in PCOS women. Abstract: Polycystic ovary syndrome (PCOS) is a heterogeneous disease characterized by various endocrine/metabolic disorders and impaired reproductive potential. Alterations in oocyte competence are considered potentially causative factors for infertility in PCOS women and analyzing the composition of follicular fluid in these patients may help to identify which changes have the potential to alter oocyte quality. In this study, free fatty acid metabolic signatures in follicular fluid were performed to identify changes that may impact oocyte competence in non-obese PCOS women. Sixty-four non-obese women (32 with PCOS and 32 age- and BMI-matched controls) undergoing in vitro fertilization were recruited. Embryo quality was morphologically assessed. Free fatty acid metabolic profiling in follicular fluid was performed using gas/liquid chromatography-mass spectrometry. Principal component analysis and orthogonal partial least squares-discriminant analysis models were further constructed. Nine free fatty acids and 24 eicosanoids were identified and several eicosanoids synthesized by the cyclooxygenase pathway were significantly elevated in PCOS patients compared to controls. The combination of PGE2, PGF2α, PGJ2, and TXB2 had an area under the curve of 0.867 (0.775-0.960) for PCOS discrimination. Furthermore, follicular fluid levels of PGE2 and PGJ2 were negatively correlated with high-quality embryo rate in PCOS patients (P < 0.05). Metabolomic analysis revealed that follicular fluid lipidomic profiles undergo changes in non-obese PCOS women, which suggests that identifying changes in important metabolic signatures may give us a better understanding of the pathogenesis of PCOS. Furthermore, elevated PGE2 and PGJ2 concentrations may contribute to impaired oocyte competence in non-obese PCOS patients.