The combination of methionine adenosyltransferase 2A inhibitor and methyltransferase like 3 inhibitor promotes apoptosis of non-small cell lung cancer cells and produces synergistic anti-tumor activity.

Methionine adenosyltransferase 2 A (MAT2A) mediates the synthesis of methyl donor S-Adenosylmethionine (SAM), providing raw materials for methylation reactions in cells. MAT2A inhibitors are currently used for the treatment of tumors with methylthioadenosine phosphorylase (MTAP) deficiency in clinical research. Methyltransferase like 3 (METTL3) catalyzes N6-methyladenosine (m6A) modification of mRNA in mammalian cells using SAM as the substrate which has been shown to affect the tumorigenesis of non-small cell lung cancer (NSCLC) from multiple perspectives. MAT2A-induced SAM depletion may have the potential to inhibit the methyl transfer function of METTL3. Therefore, in order to expand the applicability of inhibitors, improve anti-tumor effects and reduce toxicity, the combinational effect of MAT2A inhibitor AG-270 and METTL3 inhibitor STM2457 was evaluated in NSCLC. The results showed that this combination induced cell apoptosis rather than cell cycle arrest, which was non-tissue-specific and was independent of MTAP expression status, resulting in a significant synergistic anti-tumor effect. We further elucidated that the combination-induced enhanced apoptosis was associated with the decreased m6A level, leading to downregulation of PI3K/AKT protein, ultimately activating the apoptosis-related proteins. Unexpectedly, although combination therapy resulted in metabolic recombination, no significant change in methionine metabolic metabolites was found. More importantly, the combination also exerted synergistic effects in vivo. In summary, the combination of MAT2A inhibitor and METTL3 inhibitor showed synergistic effects both in vivo and in vitro, which laid a theoretical foundation for expanding the clinical application research of the two types of drugs.

Profilin1 Regulates Trophoblast Invasion and Macrophage Differentiation.

Unexplained recurrent spontaneous abortion (URSA) has been associated with the dysfunction of trophoblasts and decidual macrophages. Current evidence suggests that profilin1 (PFN1) plays an important role in many biological processes. However, little is known about whether PFN1 is related to URSA. Herein, the location of PFN1 was detected by immunohistochemistry, and the level of PFN1 was detected by quantitative real-time PCR, Western blot analysis, and immunohistochemistry. The proliferation of trophoblasts was detected by CCK8 and 5-ethynyl-2'-deoxyuridine assays, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays were used to detect apoptosis of trophoblasts. The migration and invasion ability of trophoblasts was assessed by using the wound-healing test and transwell test. Polarization of macrophages was detected in macrophages cultured in trophoblast conditioned medium. PFN1 expression was observed in cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts and was decreased in the villous tissue of patients with URSA. The migration and invasion ability and cell viability of trophoblastic cell lines that underwent PFN1 knockdown significantly decreased, and apoptosis increased. Opposite findings were observed after the overexpression of PFN1 in trophoblastic cells. In addition, PFN1 could regulate trophoblast function through phosphatidylinositol 3-kinase/AKT signal transduction rather than mitogen-activated protein kinase signaling pathways. Finally, knockdown of PFN1 in trophoblasts promoted tumor necrosis factor-α secretion to induce macrophage polarization to M1 phenotype, mediated by the NF-κB signaling pathway. These findings indicate that PFN1 has a broad therapeutic potential for patients with URSA.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

BACKGROUND: Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. METHODS: GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. RESULTS: Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. CONCLUSIONS: GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

Pepsin-mediated inflammation in laryngopharyngeal reflux via the ROS/NLRP3/IL-1ß signaling pathway.

BACKGROUND: Laryngopharyngeal reflux (LPR) is one of the most common disorders in otorhinolaryngology, affecting up to 10% of outpatients visiting otolaryngology departments. In addition, 50% of hoarseness cases are related to LPR. Pepsin reflux-induced aseptic inflammation is a major trigger of LPR; however, the underlying mechanisms are unclear. The nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome has become an important bridge between stimulation and sterile inflammation and is activated by intracellular reactive oxygen species (ROS) in response to danger signals, leading to an inflammatory cascade. In this study, we aimed to determine whether pepsin causes LPR-associated inflammatory injury via mediating inflammasome activation and explore the potential mechanism. METHODS: We evaluated NLRP3 inflammasome expression and ROS in the laryngeal mucosa using immunofluorescence and immunohistochemistry. Laryngeal epithelial cells were exposed to pepsin and analyzed using flow cytometry, western blotting, and real-time quantitative PCR to determine ROS, NLRP3, and pro-inflammatorycytokine levels. RESULTS: Pepsin expression was positively correlated with ROS as well as caspase-1 and IL-1ß levels in laryngeal tissues. Intracellular ROS levels were elevated by increased pepsin concentrations, which were attenuated by apocynin (APO)-a ROS inhibitor-in vitro. Furthermore, pepsin significantly induced the mRNA and protein expression of thioredoxin-interacting protein, NLRP3, caspase-1, and IL-1ß in a dose-dependent manner. APO and the NLRP3 inhibitor, MCC950, inhibited NLRP3 inflammasome formation and suppressed laryngeal epithelial cell damage. CONCLUSION: Our findings verified that pepsin could regulate the NLRP3/IL-1ß signaling pathway through ROS activation and further induce inflammatory injury in LPR. Targeting the ROS/NLRP3 inflammasome signaling pathway may help treat patients with LPR disease.

Observation of Diverse Asymmetric Structures in High-Dimensional Einstein-Podolsky-Rosen Steering.

Einstein-Podolsky-Rosen (EPR) steering, a distinctive quantum correlation, reveals a unique and inherent asymmetry. This research delves into the multifaceted asymmetry of EPR steering within high-dimensional quantum systems, exploring both theoretical frameworks and experimental validations. We introduce the concept of genuine high-dimensional one-way steering, wherein a high Schmidt number of bipartite quantum states is demonstrable in one steering direction but not reciprocally. Additionally, we explore two criteria to certify the lower and upper bounds of the Schmidt number within a one-sided device-independent context. These criteria serve as tools for identifying potential asymmetric dimensionality of EPR steering in both directions. By preparing two-qutrit mixed states with high fidelity, we experimentally observe asymmetric structures of EPR steering in the C^{3}⊗C^{3} Hilbert space. Our Letter offers new perspectives to understand the asymmetric EPR steering beyond qubits and has potential applications in asymmetric high-dimensional quantum information tasks.

Long-Term Sodium Deficiency Reduces Sodium Excretion but Impairs Renal Function and Increases Stone Formation in Hyperoxaluric Calcium Oxalate Rats.

Excessive sodium intake is associated with nephrolithiasis, but the impact of sodium-deficient (SD) diets is unknown. Hence, we investigated the effects of short- and long-term SD diets on the expression of renal aquaporins and sodium transporters, and thus calcium oxalate (CaOx) crystal formation in hyperoxaluria rats. In a short-term sodium balance study, six male rats received drinking water and six received 0.75% ethylene glycol (EG) to induce hyperoxaluria. After a 30-day period of feeding on normal chow, both groups were treated with a normal-sodium diet for 5 days, followed by a sodium-free diet for the next 5 days. In a long-term SD study (42 days), four groups, induced with EG or not, were treated with normal-sodium water and sodium-free drinking water, alternately. Short-term sodium restriction in EG rats reversed the daily positive sodium balance, but progressively caused a negative cumulative water balance. In the long-term study, the abundant levels of of Na/H exchanger, thiazide-sensitive Na-Cl cotransporter, Na-K-ATPase, and aquaporins-1 from SD + EG rats were markedly reduced, corresponding to a decrease in Uosm, as compared to SD rats. Increased urine calcium, AP(CaOx)index, and renal CaOx deposition were also noted in SD + EG rats. Although the SD treatment reduced sodium excretion, it also increased urinary calcium and impaired renal function, ultimately causing the formation of more CaOx crystals.

Pterostilbene ameliorates oxidative damage and ferroptosis in human ovarian granulosa cells by regulating the Nrf2/HO-1 pathway.

The survival of ovarian granulosa cells is of great significance to the physiological maintenance of the ovary. Oxidative damage to the ovarian granulosa cells can lead to various diseases related to ovarian dysfunction. Pterostilbene exerts many pharmacological effects, such as anti-inflammatory and cardiovascular protective effects. Moreover, pterostilbene was shown to have antioxidant properties. This study aimed to investigate the effect and underlying mechanism of pterostilbene on oxidative damage in ovarian granulosa cells. Ovarian granulosa cell (OGC) lines COV434 and KGN were exposed to H2O2 to establish an oxidative damage model. After treatment with different concentrations of H2O2 or pterostilbene, the cell viability, mitochondrial membrane potential, oxidative stress, and iron levels were detected, and the expression of ferroptosis-related and Nrf2/HO-1 signaling pathway-related proteins were evaluated. Pterostilbene treatment could effectively improve cell viability, reduce oxidative stress, and inhibit ferroptosis stimulated by H2O2. More importantly, pterostilbene could up-regulate Nrf2 transcription by stimulating histone acetylation, and inhibition of Nrf2 signaling could reverse the therapeutic effect of pterostilbene. In conclusion, this research shows that pterostilbene protects human OGCs from oxidative stress and ferroptosis through the Nrf2/HO-1 pathway.

The Mayo adhesive probability score predicts postoperative fever and intraoperative hemorrhage in mini-percutaneous nephrolithotomy.

PURPOSE: Contemporary predictive tools for miniaturized percutaneous nephrolithotomy (mPCNL) mainly focus on stone clearance but not perioperative complications, especially infection and hemorrhage. This study aimed to evaluate whether the Mayo adhesive probability (MAP) score, an index of the perinephric fat characteristics, can predict postoperative fever and intraoperative hemorrhage in mPCNL. METHODS: This is a retrospective study recruiting 159 mPCNL patients from July 2018 to January 2022. MAP scores were recorded using preoperative computed tomography. Postoperative complications included postoperative fever and intraoperative bleeding, defined as hemoglobin drop. RESULTS: Over half patients had the MAP score ≧ 3. Men, elderly, chronic kidney disease, and diabetes were associated with a higher MAP score. The patients with a higher MAP score were more likely to have postoperative fever after mPCNL. On multivariate analysis, preoperative positive urine culture (OR 2.68) and a higher MAP score (OR 2.28) were both significantly associated with postoperative fever. ROC curves analysis of the combination of these two factors on predicting postoperative fever showed AUC values were 0.731 (0.652-0.810). Moreover, a higher MAP score (OR 2.30) and longer operative time (OR 2.16) were significantly associated with higher hemoglobin drop on multivariate analysis. CONCLUSION: A high MAP score was associated with postoperative fever and intraoperative hemorrhage in patients undergoing mPCNL. The MAP score can be a novel and easy predictive tool to help endourologists improve the awareness of mPCNL safety.

Nephrolithiasis is associated with the severity of coronary artery calcification, but not with coronary artery stenosis.

PURPOSE: Emerging data have indicated that nephrolithiasis is possibly associated with subclinical coronary artery disease (CAD). Considering that a significant proportion of obstructive CAD in non-elderly individuals occurs in those without detectable calcium score (CACS), this study aimed to investigate whether nephrolithiasis is still associated with CAD as assessed by coronary computed tomography (CT)-derived luminal stenosis [using Gensini score (GS)]. METHODS: A total of 1170 asymptomatic adults without known CAD who underwent health examinations were recruited. Nephrolithiasis was assessed using abdominal ultrasonography (US). Individuals with a self-reported stone history, but no evidence of nephrolithiasis were excluded. The CACS and GS were measured using 256-slice coronary CT. RESULTS: Nearly half of these patients had a CACS > 0 (48.1%), and a higher prevalence of nephrolithiasis was observed than in those who had zero CACS (13.1% vs. 9.7%). However, no significant intergroup difference in GS was detected. A greater proportion of stone formers than non-stone formers had a higher risk category, whereas no significant difference was noted in Gensini category. Multiple linear regression analyses showed that the CACS independently predicted the presence of nephrolithiasis after adjustment. Importantly, we found that stone formers had a nearly threefold higher risk than non-stone formers of developing severe coronary calcification (CAC > 400). CONCLUSIONS: Nephrolithiasis was significantly associated with coronary artery calcification presence and severity, but not coronary luminal stenosis in patients without known CAD. Accordingly, the relationship between stone disease and CAD remains controversial, and additional studies are imperative to validate these findings.

Prevalence of polycystic ovary syndrome under NIH criteria among the tenth-grade Chinese schoolgirls in Guangzhou area: a cross-sectional epidemiological survey.

BACKGROUND: Polycystic ovary syndrome (PCOS) is currently considered to have a peri-adolescence onset and continuously influence the reproductive and metabolic health of the patients, while the diagnostic criteria among adolescent population haven't been universally unified till now. This survey seeks to preliminarily evaluate the prevalence of PCOS in the tenth grade schoolgirls in Guangzhou area under NIH criteria and analyze the clinical features of adolescents with PCOS. METHODS: The cross-sectional epidemiological survey was carried out among the tenth grade schoolgirls in Guangzhou area by the method of cluster sampling. The contents of this survey included the questionnaire, physical exams and serum measurements. Until now, totally 1294 girls underwent this survey and 1095 serum samples were restored. 235 non-hirsute (mFG < 6), postmenarcheally 2-year girls were randomly selected as the control group, among which the cut-off value of biochemical hyperandrogenemia was set accordingly. The prevalence of PCOS among this population was preliminarily evaluated according to the NIH criteria. RESULTS: Along with the increase of gynecological age, the menstruations of girls was becoming more regular and the incidence of oligomenorrhea or amenorrhea was declining. Even among those who were less than 2 years after menarche, those whose menstrual cycle were longer than 90 days accounted for lower than 5%. The 95th percentile of mFG score was 6 among the girls who were < 2 years after menarche, and 5 among the girls who were > 2 years after menarche. Among the 235 healthy girls, the 95th percentile values of Testosterone (T), Free androgen index (FAI) and Androstenedione (A2) were 2.28 nmol/mL, 4.37, and 5.20 nmol/mL respectively. Based on the NIH criteria, the prevalence of PCOS in this survey was 3.86%. The prevalence of adolescent PCOS tend to slightly increase with age and gynecological age, but the difference was not statistically significant. The prevalence of PCOS among obese girls was markedly higher than that in lean girls. CONCLUSION: Based on the NIH criteria, the prevalence of PCOS among the tenth grade schoolgirls in Guangzhou area was 3.86%. The diagnosis of hyperandrogenism among adolescents should also be based on both clinical and biochemical parameters.

Gross hematuria as the presentation of ureteral paraganglioma: a case report and literature review.

BACKGROUND: Paraganglioma of genitourinary tract is uncommon, and origin from ureter is even rarer. We aim to present a case of paraganglioma from ureter in a 48-year-old female patient, who presented with gross hematuria. CASE PRESENTATION: We present a 48-year-old female who complained of gross hematuria for one week. A left ureteral tumor was found by image study. However, hypertension was unexpectedly recorded during diagnostic ureteroscopy survey. Due to persisted gross hematuria and bladder tamponade, she underwent left nephroureterectomy with bladder cuff resection. Blood pressure surged again when the tumor was surgically approached. Ureteral paraganglioma was confirmed according to pathological report. After the surgery, the patient recovered well, and no more gross hematuria was noted. She is now under regular follow-up at our outpatient clinic. CONCLUSION: Ureteral paraganglioma should be kept in mind not only when blood pressure fluctuates during operation, but also before we manipulate the ureteral tumor when gross hematuria is the only sign. Whenever the presumption of paraganglioma is raised, laboratory evaluation and anatomical or even functional imaging should be considered. The concomitant anesthesia consultation before the surgery should not be deferred, either.

Hypoxia-induced polarization of M2 macrophages and C-C motif chemokine ligand 5 secretion promotes the migration and invasion of trophoblasts†.

In the early stage of pregnancy, hypoxia in the placenta is of great significance to the migration and invasion of trophoblasts. In addition, changes to the polarity and activity of macrophages can affect embryo implantation, trophoblast migration and invasion, and vascular remodeling by affecting cytokine secretion. However, the mechanism of the effects of hypoxic conditions in the placenta on trophoblasts remains unknown. We used gene knockdown on macrophages, and drug treatment on trophoblasts, and cultured them under hypoxic and normoxic conditions. The cells were then subjected to wound-healing assays, Transwell cell invasion experiments, quantitative real-time reverse transcription Polymerase Chain Reaction (PCR), western blotting, and immunofluorescence. The polarization of macrophages in each group, the migration and invasion ability of trophoblasts, and changes to the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were detected. Hypoxic conditions induce M2 polarization of macrophages. The conditioned medium from macrophages under hypoxic conditions increased the migration and invasion of trophoblasts and enhanced the levels of phosphorylated (p)-PI3K and p-AKT in trophoblasts. After C-C motif chemokine ligand 5 knockdown in macrophages, the ability of conditioned medium from macrophages cultured under hypoxic conditions to promote the migration and invasion of trophoblasts was weakened significantly. The use of PI3K/AKT signaling pathway agonists could reverse the attenuation effect caused by C-C motif chemokine ligand 5 knockdown.

Risk of hepatocellular carcinoma in antiviral treatment-naïve chronic hepatitis B patients treated with entecavir or tenofovir disoproxil fumarate: a network meta-analysis.

BACKGROUND: Long-term antiviral treatments are associated with a significantly lower hepatocellular carcinoma (HCC) incidence in chronic hepatitis B (CHB) patients by reducing HBV DNA concentrations. However, it is still controversial whether antiviral strategies affect HCC development in antiviral treatment-naïve CHB patients. This study aimed to estimate the incidence of HCC in antiviral treatment-naïve CHB patients who were treated with Entecavir (ETV) and Tenofovir Disoproxil Fumarate (TDF) and compare the efficacy of two treatment regimens in HCC reduction. METHODS: The PubMed, Embase, China National Knowledge Infrastructure, and Wanfang databases were systematically searched until June 24, 2021. The pooled incidence and 95% confidence interval of HCC were calculated by the Freeman-Tukey double arcsine transformation method. The efficacies of ETV and TDF treatments in HCC reduction were compared through a network meta-analysis. RESULTS: A total of 27 studies were identified as eligible for this systematic review. The incidence densities in the ETV and TDF treatment groups were 2.78 (95% CI: 2.21-3.40) and 2.59 (95% CI: 1.51-3.96) per 100 persons-year among patients with preexisting cirrhosis and 0.49 (95% CI: 0.32-0.68) and 0.30 (95% CI: 0.06-0.70) per 100 persons-year among patients without preexisting cirrhosis. As the proportion of CHB patients with preexisting cirrhosis increased, the incidence density of HCC also increased gradually. Compared with other Nucleos(t)ide analogs (NAs) treatments, ETV and TDF treatments significantly lowered the risk of HCC, with hazard ratios (HRs) of 0.60 (95% CI: 0.40-0.90) and 0.56 (95% CI: 0.35-0.89), respectively. However, there was no difference in the incidence density of HCC between ETV and TDF treatments (HR = 0.92, 95% CI: 0.71-1.20) regardless of preexisting cirrhosis. CONCLUSION: ETV and TDF treatments were associated with significantly lower risks of HCC than other NAs treatments. However, no difference was observed between ETV and TDF treatments in the risk of HCC development regardless of preexisting cirrhosis among treatment-naïve CHB patients.

Discovery of MTR-106 as a highly potent G-quadruplex stabilizer for treating BRCA-deficient cancers.

G-quadruplexes (G4s) are DNA or RNA structures formed by guanine-rich repeating sequences. Recently, G4s have become a highly attractive therapeutic target for BRCA-deficient cancers. Here, we show that a substituted quinolone amide compound, MTR-106, stabilizes DNA G-quadruplexes in vitro. MTR-106 displayed significant antiproliferative activity in homologous recombination repair (HR)-deficient and PARP inhibitor (PARPi)-resistant cancer cells. Moreover, MTR-106 increased DNA damage and promoted cell cycle arrest and apoptosis to inhibit cell growth. Importantly, its oral and i.v. administration significantly impaired tumor growth in BRCA-deficient xenograft mouse models. However, MTR-106 showed modest activity against talazoparib-resistant xenograft models. In rats, the drug rapidly distributes to tissues within 5 min, and its average concentrations were 12-fold higher in the tissues than in the plasma. Overall, we identified MTR-106 as a novel G-quadruplex stabilizer with high tissue distribution, and it may serve as a potential anticancer agent.

miR-34a attenuates myocardial fibrosis in diabetic cardiomyopathy mice via targeting Pin-1.

Diabetic cardiomyopathy (DCM) is characterized by myocardial hypertrophy and fibrosis. This study aimed to investigate the effects of microRNA (miR)-34a on myocardial fibrosis in DCM and its potential mechanism of targeting Pin-1 signaling. Vimentin and Pin-1 proteins in mouse cardiac tissues were detected by immunohistochemical staining. Locked nucleic acid in situ hybridization was used to measure miR-34a expression in cardiac tissues. Primary mouse cardiac fibroblasts (CFs) were transfected with a mimics control/miR-34a mimics or Pin-1 plasmid and cultured in high-glucose (HG) Dulbecco's modified Eagle's medium. The miR-34a levels were measured by quantitative polymerase chain reaction. The apoptosis and viability of transfected cells were detected by the terminal deoxynucleotidyl transferase dUTP nick end labeling and Cell Counting Kit-8 assays respectively. A cell migration experiment and dual-luciferase reporter assay were also performed. The body weight and fasting blood glucose of DCM mice were significantly higher than those in the control (CTL) group. In addition, DCM mice had decreased serum insulin levels and impaired cardiac function. The number of CFs in the DCM group was higher than in the CTL group and Pin-1 expression was upregulated. The expression level of miR-34a in the cardiac tissue of mice in the DCM group was obviously downregulated compared with the CTL group. The HG stimulation of CFs for 48 h significantly downregulated the expression level of miR-34a and was associated with increased Type I collagen expression, cell viability, and migration and decreased apoptosis. However, these effects could be reversed by overexpressing miR-34a in HG-induced CFs. Furthermore, we found that Pin-1 was a direct target of miR-34a. Our results suggest that miR-34a can attenuate myocardial fibrosis in DCM by reducing Type I collagen production, cell viability, and migration and increasing the apoptosis of CFs by targeting Pin-1 signaling.

Identification of 2-substituted pyrrolo[1,2-b]pyridazine derivatives as new PARP-1 inhibitors.

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC50s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.

Lucidumones B-H, racemic meroterpenoids that inhibit tumor cell migration from Ganoderma lucidum.

Seven new meroterpenoids, lucidumones B-H (1 and 3-8), along with one known meroterpenoid (2), were isolated from the fruiting bodies of Ganoderma lucidum. The structures of the new compounds were assigned by spectroscopic and computational methods. All the isolated compounds were tested for their inhibition on human cancer cell migration. It was found that compounds (-)-1, (+)-2, (-)-4, (+)-6, and (+)-8 could significantly inhibit cell migration in KYSE30 cell line. Further examination disclosed that cell migration inhibition of (+)-6 and (+)-8 might be related with downregulation of N-cadherin.

Obstetricians' perspectives on trial of labor after cesarean (TOLAC) under the two-child policy in China: a cross-sectional study.

BACKGROUND: As the birth policy has been adjusted from one-child-one-couple to universal two-child-one-couple in China, there is an increasing number of women undergoing a second pregnancy after a previous cesarean section (CS). Undertaking an elective repeat CS (ERCS) has been taken for granted and has thus become a major contributor to the increasing CS rate in China. Promoting trial of labor after CS (TOLAC) can reduce the CS rate without compromising delivery outcomes. This study aimed to investigate Chinese obstetricians' perspectives regarding TOLAC, and the factors associated with their decision-making regarding recommending TOLAC to pregnant women with a history of CS under the two-child policy. METHODS: A cross-sectional survey was carried out between May and July 2018. Binary logistic regression was used to determine the factors associated with the obstetricians' intention to recommend TOLAC to pregnant women with a history of CS. The independent variables included sociodemographic factors and perceptions regarding TOLAC (selection criteria for TOLAC, basis underlying the selection criteria for TOLAC, and perceived challenges regarding promoting TOLAC). RESULTS: A total of 426 obstetricians were surveyed, with a response rate of ≥83%. The results showed that 31.0% of the obstetricians had no intention to recommend TOLAC to pregnant women with a history of CS. Their decisions were associated with the perceived lack of confidence regarding undergoing TOLAC among pregnant women with a history of CS and their families (odds ratio [OR] = 2.31; 95% CI: 1.38-1.38); obstetricians' uncertainty about the safety of TOLAC for pregnant women with a history of CS (OR = 0.49; 95% CI: 0.27-0.96), and worries about medical lawsuits due to adverse delivery outcomes (OR = 0.14; 95% CI: 0.07-0.31). The main reported challenges regarding performing TOLAC were lack of clear guidelines for predicting or avoiding the risks associated with TOLAC (83.4%), obstetricians' uncertainty about the safety of TOLAC for women with a history of CS (81.2%), pregnant women's unwillingness to accept the risks associated with TOLAC (81.0%) or demand for ERCS (80.7%), and the perceived lack of confidence (77.5%) or understanding (69.7%) regarding undergoing TOLAC among pregnant women and their families. CONCLUSION: A proportion of Chinese obstetricians did not intend to recommend TOLAC to pregnant women with a history of CS. This phenomenon was closely associated with obstetricians' concerns about TOLAC safety and perceived attitudes of the pregnant women and their families regarding TOLAC. Effective measures are needed to help obstetricians predict and reduce the risks associated with TOLAC, clearly specify the indications for TOLAC, improve labor management, and popularize TOLAC in China. Additionally, public health education on TOLAC is necessary to improve the understanding of TOLAC among pregnant women with a history of CS and their families, and to improve their interactions with their obstetricians regarding shared decision making.

Acute and subacute inhalation toxicity assessment of WS-23 in Sprague-Dawley rats.

2-isopropyl-N,2,3-trimethylbutyramide (WS-23) is a well-known artificial synthesis cooling agent widely used in foods, medicines, and tobaccos. As a commonly cooling agent in e-cigarette liquids, WS-23 has led to concerns about the inhalation toxicity with the prosperous of e-cigarettes in recent years. Thus, the aim of this study is to assess the acute and subacute inhalation toxicity of WS-23 in Sprague-Dawley (SD) rats according to the Organization for Economic Cooperation and Development (OECD) guidelines. In the acute toxicity study, there was no mortality and behavioral signs of toxicity at the limit test dose level (340.0 mg/m3 ) in the exposure period and the following 14-day observation period. In the subacute inhalation toxicity study, there was no significant difference observed in the body weights, feed consumption, and relative organ weights. Haematological, serum biochemical, urine, and bronchoalveolar lavage fluid (BALF) analysis revealed the non-adverse effects after 28-day repeated WS-23 inhalation (342.85 mg/m3 ), accompanied by slight changes in few parameters which returned to normal during the 28-day recovery period. The histopathologic examination also did not show any differences in vital organs. In conclusion, the maximum tolerated dose for WS-23 acute inhalation is not less than 340.0 mg/m3 , and the No Observed Adverse Effect Level (NOAEL) of WS-23 subacute inhalation was determined to be over 342.85 mg/m3 .

A Classification and Prediction Hybrid Model Construction with the IQPSO-SVM Algorithm for Atrial Fibrillation Arrhythmia.

Atrial fibrillation (AF) is the most common cardiovascular disease (CVD), and most existing algorithms are usually designed for the diagnosis (i.e., feature classification) or prediction of AF. Artificial intelligence (AI) algorithms integrate the diagnosis of AF electrocardiogram (ECG) and predict the possibility that AF will occur in the future. In this paper, we utilized the MIT-BIH AF Database (AFDB), which is composed of data from normal people and patients with AF and onset characteristics, and the AFPDB database (i.e., PAF Prediction Challenge Database), which consists of data from patients with Paroxysmal AF (PAF; the records contain the ECG preceding an episode of PAF), and subjects who do not have documented AF. We extracted the respective characteristics of the databases and used them in modeling diagnosis and prediction. In the aspect of model construction, we regarded diagnosis and prediction as two classification problems, adopted the traditional support vector machine (SVM) algorithm, and combined them. The improved quantum particle swarm optimization support vector machine (IQPSO-SVM) algorithm was used to speed the training time. During the verification process, the clinical FZU-FPH database created by Fuzhou University and Fujian Provincial Hospital was used for hybrid model testing. The data were obtained from the Holter monitor of the hospital and encrypted. We proposed an algorithm for transforming the PDF ECG waveform images of hospital examination reports into digital data. For the diagnosis model and prediction model trained using the training set of the AFDB and AFPDB databases, the sensitivity, specificity, and accuracy measures were 99.2% and 99.2%, 99.2% and 93.3%, and 91.7% and 92.5% for the test set of the AFDB and AFPDB databases, respectively. Moreover, the sensitivity, specificity, and accuracy were 94.2%, 79.7%, and 87.0%, respectively, when tested using the FZU-FPH database with 138 samples of the ECG composed of two labels. The composite classification and prediction model using a new water-fall ensemble method had a total accuracy of approximately 91% for the test set of the FZU-FPH database with 80 samples with 120 segments of ECG with three labels.