A Systematic Review and Meta-analysis of Renin-angiotensin System Inhibitors and Angiotensin Receptor Neprilysin Inhibitors in Preventing Recurrence After Atrial Fibrillation Ablation.

ABSTRACT: To systematically evaluate the efficacy and safety of renin-angiotensin system inhibitors (RASIs) and angiotensin receptor neprilysin inhibitors in preventing the recurrence of atrial fibrillation after atrial fibrillation ablation, we have written this meta-analysis. We systematically searched randomized controlled trials or cohort studies on RASIs and angiotensin receptor neprilysin inhibitor-sacubitril/valsartan (SV) in preventing the recurrence of atrial fibrillation. Two researchers independently screened the literature, extracted the data, and assessed the risk of bias in the included studies. Afterward, the meta-analysis was performed using RevMan 5.3 software. This meta-analysis results showed that the recurrence rate of atrial fibrillation after ablation in subjects using RASIs was lower than that in subjects not using them [relative risk = 0.85, 95% confidence interval (CI) (0.72-0.99), P = 0.03]; the recurrence rate in subjects using SV was lower than that in subjects using RASIs [RR= 0.50, 95% CI (0.37-0.68), P < 0.00001]. These results show that both the use of RASIs and SV can prevent the recurrence of after atrial fibrillation ablation, among which the use of SV is more effective.

Comparative assessment of efficacy and safety of approved oral therapies for overactive bladder: a systematic review and network meta-analysis.

bladder based on a systematic review and network meta-analysis approach. METHODS: Pubmed, Embase, Web of Science, and the Cochrane Register of Clinical Trials databases were systematically searched. The search time frame was from database creation to June 2, 2022. Randomized controlled double-blind trials of oral medication for overactive bladder were screened against the protocol's entry criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 software. RESULT: A total of 60 randomized controlled double-blind clinical trials were included involving 50,333 subjects. Solifenacin 10mg was the most effective in mean daily micturitions and incontinence episodes, solifenacin 5/10mg in mean daily urinary urgency episodes and nocturia episodes, fesoterodine 8mg in urgency incontinence episodes/d and oxybutynin 5mg in voided volume/micturition. In terms of safety, solifenacin 5mg, ER-tolterodine 4mg, mirabegron, vibegron and ER-oxybutynin 10mg all showed a better incidence of dry mouth, fesoterodine 4mg, ER-oxybutynin 10mg, tolterodine 2mg, and vibegron in the incidence of constipation. Compared to placebo, imidafenacin 0.1mg showed a significantly increased incidence in hypertension, solifenacin 10mg in urinary tract infection, fesoterodine 4/8mg and darifenacin 15mg in headache. CONCLUSION: Solifenacin showed better efficacy. For safety, most anticholinergic drugs were more likely to cause dry mouth and constipation, lower doses were better tolerated. The choice of drugs should be tailored to the patient's specific situation to find the best balance between efficacy and safety.

Efficacy and safety of single-dose antiviral drugs for influenza treatment: A systematic review and network meta-analysis.

To conduct network meta-analysis (NMA) of clinical efficacy and safety of single-dose antiviral drugs, grouped by dosage, in treatment of influenza. Systematic retrievals were conducted in databases, including Pubmed, Embase, Web of Science, the Cochrane Register of Clinical Trials and from the website ClinicalTrials.gov, for clinical trials recorded between the interception of the databases and March 31, 2021. Randomized controlled trials (RCTs) of influenza treatment in which single-dose antiviral drugs were administered were selected according to preset inclusion and exclusion criteria by two researchers who screened the literature independently from each other. The quality of the included studies was assessed using the Cochrane bias risk assessment tool. Software such as Stata 16.0 and Review Manager 5.3 was adopted for statistical analysis. Pairwise meta-analysis and NMA were carried out under the random-effects model. For both binary and continuous variables, odds ratio (OR), mean difference (MD) and their 95% confidence intervals (CI) were used to rank treatment efficiencies and analyze the differences. A total of 12 RCTs involving 7296 participants were included in the analysis. According to the NMA results, peramivir 300 mg (MD = -17.68, 95% CI: [-34.05, -1.32]), peramivir 600 mg (MD = -16.15, 95% CI: [-29.35, -2.95]), baloxavir (MD = -14.67, 95% CI: [-26.75, -2.58]) and laninamivir 40 mg (MD = -12.42, 95% CI: [-22.53, -2.31]) remarkably outperformed laninamivir 20 mg in time to alleviation of symptoms (TTAS). However, no intervention statistically outperform others in antipyretic time, virus titer variations against the baseline 24 and 48 h after medication and adverse events (AEs). The efficacy rankings were: peramivir 300 mg (the surface under the cumulative ranking curve [SUCRA] = 80.3%) > peramivir 600 mg (SUCRA = 76.2%) > baloxavir (SUCRA = 68.4%) > laninamivir 40 mg (SUCRA = 55.0%) > laninamivir 20 mg (SUCRA = 16.6%) for TTAS; baloxavir (SUCRA = 76.3%) > peramivir 600 mg (SUCRA = 67.8%) > laninamivir 40 mg (SUCRA = 47.2%) > laninamivir 20 mg (SUCRA = 40.0%) for antipyretic time; baloxavir (SUCRA = 96.7%) > peramivir 300 mg (SUCRA = 64.5%) ≈ peramivir 600 mg (SUCRA = 63.2%), baloxavir (SUCRA = 93.2%) > peramivir 600 mg (SUCRA = 64.0%) ≈ peramivir 300 mg (SUCRA = 55.0%), for virus titer variations against the baseline 24 and 48 h after medication, respectively; and baloxavir (SUCRA = 83.4%) > peramivir 300 mg (SUCRA = 71.4%) > laninamivir 20 mg (SUCRA = 62.4%) > peramivir 600 mg (SUCRA = 56.2%) > laninamivir 40 mg (SUCRA = 36.8%) for adverse events. Among the single-dose anti-influenza virus drugs compared, peramivir is superior to baloxavir and laninamivir in TTAS, whereas baloxavir has the best efficacy in antipyretic time, virus titer variations against the baseline 24 and 48 h after medication and AEs. This study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO), with a registration number of CRD42021238220.

Sox7 negatively regulates prostate-specific membrane antigen (PSMA) expression through PSMA-enhancer.

BACKGROUND: PSMA expression in the prostate epithelium is controlled by a cis-element, PSMA enhancer (PSME). PSME contains multiple binding sites for Sox proteins, and in this study, we identified Sox7 protein as a negative regulator of PSMA expression through its interaction with PSME. METHODS: The statistical correlation between Sox7 and PSMA mRNA expression was evaluated using five prostate cancer studies from cBioportal. In vitro and in vivo interaction between Sox7 and PSME was evaluated by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and luciferase reporter assay. Synthetic oligonucleotides were generated to define the sites in PSME that interact with Sox7 protein. Sox7 mutants were generated to identify the region of this protein required to regulate PSMA expression. Sox7 was also stably expressed in LNCaP/C4-2 and 22Rv1 cells to validate the regulation of PSMA expression by Sox7 in vivo. RESULTS: Sox7 mRNA expression negatively correlated with PSMA/FOLH1 and PSMAL/FOLH1B mRNA expression in Broad/Cornell, TCGA and MSKCC studies, but not in two studies containing only metastatic prostate tumors. PC-3 cells mostly expressed the 48.5 KDa isoform 2 of Sox7, and the depletion of this isoform did not restore PSMA expression. Ectopic expression of canonical, wild-type Sox7 in C4-2 and 22Rv1 cells suppressed PSMA protein expression. ChIP assay revealed that canonical Sox7 protein preferentially interacts with PSME in vivo, and EMSA identified the SOX box sites #2 and #4 in PSME as required for its interaction. Sox7 was capable of directly binding to PSME and suppressed PSME-mediated transcription. The NLS regions of Sox7, but not its ß-catenin interacting motif, are essential for this suppressing activity. Furthermore, restoration of wild-type Sox7 expression but not Sox7-NLS mutant in Sox7-null prostate cancer cell lines suppressed PSMA expression. CONCLUSIONS: The inactivation of canonical Sox7 is responsible for the upregulated expression of PSMA in non-metastatic prostate cancer.

Curcumin-Loaded Lipid Cubic Liquid Crystalline Nanoparticles: Preparation, Optimization, Physicochemical Properties and Oral Absorption.

In order to improve the oral absorption of curcumin, curcumin-loaded lipid cubic liquid crystalline nanoparticles were prepared and evaluated in vitro and in vivo. The hot and high-pressure homogenization method was used to prepare the nanoparticles. The formulation and process were optimized by uniform design with drug loading and entrapment efficiency as index, and physicochemical properties were also investigated. Spherical nanoparticles were observed under transmission electron microscope (TEM), with average particle size of 176.1 nm, zeta potential of -25.19 mV, average drug loading of (1.5 ± 0.2)% and entrapment efficiency of (95 ± 1.8)%. The in vitro release of curcumin from the nanoparticle formulation showed a sustained property, while the pharmacokinetics results after oral administration of curcumin loaded lipid cubic liquid crystalline nanoparticles in rat showed that the oral absorption of curcumin fitted one-compartment model and relative bioavailability was 395.56% when compared to crude curcumin. It can be concluded from these results that the lipid cubic liquid crystalline nanoparticles, as carriers, can markedly improve the oral absorption of curcumin.

Targeting lipid peroxidation-associated ferroptosis suppresses lung carcinoma progression by regulating cell cycle arrest.

Lung carcinoma is a frequently encountered cancerous growth that affects the respiratory tract and has a high occurrence rate globally. In light of the ongoing worldwide health emergency, the significance of efficient therapeutic agents and strategies is of utmost importance. A meticulous control of the cell cycle is crucial for comprehending the pathophysiology and molecular causes of lung cancer, as well as for the formulation of efficacious therapeutic medicines. The mechanism by which cells synchronize cell cycle with cell survival and death is still not fully understood. In this study, we demonstrate that the halting of the cell cycle has a strong inhibitory impact on ferroptosis, a specific type of controlled cell death triggered by excessive lipid peroxidation at the membranes of cells. Ferroptosis is halted through the mechanism of cell cycle arrest, which involves the deposition of intracellular lipids mediated by diacylglycerol acyltransferase (DGAT). Excessive amounts of polyunsaturated fatty acids (PUFAs) are stored as triacylglycerols (TAGs) within inactive cells. As a result, inhibiting DGAT causes a rearrangement of PUFAs from TAGs to phospholipids and makes arrested cells more susceptible to ferroptosis. We demonstrate that certain lung cancer cells that are resistant to antimitotic drugs and have a slow-cycling behavior exhibit an increase in lipid droplets. Furthermore, we find that the growth of tumors resistant to 5-fluorouracil, lorlatinib, and docetaxel can be effectively suppressed by a combination treatment involving the use of ferroptosis inducers and DGAT inhibitors, which induces ferroptosis. Collectively, these findings demonstrate the involvement of cell cycle arrest in conferring resistance to ferroptosis and propose a potential therapeutic approach for addressing the challenge of slow-cycling malignancies that exhibit resistance to ferroptosis.

MiR-92b regulates the cell growth, cisplatin chemosensitivity of A549 non small cell lung cancer cell line and target PTEN.

MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance of human cancer. Fewer studies were explored the roles of miR-92b on human lung cancer cell growth and resistance to cisplatin (CDDP). In this paper, we utilized real-time PCR to verify miR-92b was significantly up-regulated in non-small cell lung cancer (NSCLC) tissues compared to matched adjacent normal tissues. In vitro assay demonstrated that knock-down of miR-92b inhabits cell growth and sensitized the A549/CDDP cells to CDDP. Furthermore, we found miR-92b could directly target PTEN, a unique tumor suppressor gene, which was downregulated in lung cancer tissues compared to the matched adjacent normal tissues. These data indicate that the miR-92b play an oncogene roles by regulates cell growth, cisplatin chemosensitivity phenotype, and could serve as a novel potential maker for NSCLC therapy.

Clinical research progress of novel biologics for the treatment of lupus nephritis.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is one of the most common manifestations of severe organ damage in SLE, and also an important cause of disability and death. Its pathogenesis is associated with immune abnormalities such as immune cells, cytokines, and immune complex deposition. Traditional immunosuppressive therapy has been unable to meet the treatment needs of patients while bringing them toxic effects. In recent years, targeted therapies have emerged, and several novel biologics have gradually entered people's sight. This review will briefly introduce the pathogenesis of LN and the mechanism of biological targets, and summarize and analyze the clinical trials of new biologics for treating LN. Although not all biologics show positive results in clinical trials, the experience learned from these trials can help researchers adjust and plan future trial programs to seek better treatment methods.

Efficacy and safety of vibegron compared with mirabegron for overactive bladder: A systematic review and network meta-analysis.

OBJECTIVES: The aim of this study was to indirectly compare the efficacy and safety of mirabegron and vibegron in patients with overactive bladder. METHODS: A systematic search was performed on Pubmed, Web of Science, Embase, and the Cochrane Central Register of Controlled Trials databases to identify studies from the date of database inception to January 1, 2022. All randomized controlled trials comparing mirabegron or vibegron with tolterodine, imidafenacin, or placebo were eligible. One reviewer extracted data, and a second reviewer checked. Included trials were assessed for similarity, and networks were developed using Stata 16.0 software. Mean differences for continuous variables and odds ratios for dichotomous variables together with their 95% confidence intervals (CIs) were used to rank treatments and compare the differences, respectively. RESULTS: A total of 11 randomized controlled trials and 10 806 patients were included. For each outcome, results for all licensed treatment doses were included. Both vibegron and mirabegron were more efficacious than placebo at reducing the frequency of micturition, incontinence, urgency, urgency incontinence, and nocturia. Vibegron was more efficacious than mirabegron in reducing mean voided volume/micturition (95% CI [5.15, 14.98]). Safety outcomes for vibegron and mirabegron were similar to those in the placebo group, except for mirabegron, which had a higher risk of nasopharyngitis and cardiovascular adverse events than placebo. CONCLUSIONS: Both drugs seem to be comparable and well tolerated, particularly as direct comparisons are not available. However, vibegron may be more effective than mirabegron in reducing mean voided volume.

Rapid health technology assessment of the novel endonuclease inhibitor baloxavir for the treatment of influenza.

Through a Rapid Health Technology Assessment (RHTA), we evaluated the efficacy, safety and cost-effectiveness of baloxavir in the treatment of influenza, providing the necessary scientific information and evidence-based basis for healthcare professionals and health insurance decision-makers in making rational selections. Through systematic searches of Pubmed, Embase, Web of Science, The Cochrane Register of Clinical Trials database and the official website of Health Technology Assessment (HTA) agencies, we collected systematic reviews (SR)/Meta-analysis, cost-effectiveness evaluations and HTA reports of baloxavir for influenza, with a search time frame of date of database establishment to July 31, 2022. We then performed data extraction, literature screening and quality evaluation on the literature that met our selection criteria, after which the results of the studies were pooled and qualitatively described for analysis. 10 studies were included, including 6 SR/Meta-analysis, three economics studies, and 1 HTA report. In terms of efficacy, baloxavir had an advantage over oseltamivir for all three types of influenza patients (otherwise healthy patients, high-risk patients, and patients are not separated into groups with and without underlying health conditions) concerning change in virus titer from baseline at 24 and 48 h; about otherwise healthy patients and high-risk patients, baloxavir had an advantage over peramivir; pertaining to high-risk patients, baloxavir had an advantage over laninamivir; the above differences between groups were all statistically significant. In terms of safety, in otherwise healthy patients and patients are not separated into groups with and without underlying health conditions, baloxavir significantly reduced the incidence of DRAEs and nausea compared with oseltamivir, as well as significantly reduced the incidence of DRAEs compared with laninamivir; in patients are not separated into groups with and without underlying health conditions, baloxavir significantly reduced the incidence of AEs and diarrhoea compared with oseltamivir; the differences between the above groups were all statistically significant. Economically, in Japanese adult influenza patients and high-risk populations, the Quality-Adjusted Life Years (QALY) of baloxavir slightly triumphed over that of laninamivir (Δ = 0.000112 and 0.00209 QALY per 1 patient, respectively); moreover, the incremental cost-effectiveness ratio (ICER: 2,231,260 and 68,855 yen/QALY, respectively) was below the willingness-to-pay (WTP) threshold (5,000,000 yen/QALY); in Chinese adult influenza patients without underlying diseases and adult high-risk influenza patients, baloxavir had a higher QALY compared with oseltamivir (Δ = 0.000246 and 0.000186 respectively), however, their ICER (12,230 and 64,956 RMB/QALY) was above the local WTP threshold (10,000 RMB/QALY) and thus did not provide a cost-effectiveness advantage. Baloxavir had a favorable efficacy and safety profile compared to neuraminidase inhibitors (NAIs), and the currently available evidence suggested that it had an economic advantage only in Japan.

Advances in Studies of Chiglitazar Sodium, a Novel PPAR Pan-Agonist, for the Treatment of Type 2 Diabetes Mellitus.

Chiglitazar sodium is a new peroxisome proliferator-activated receptor (PPAR) pan-agonist with independent intellectual property rights in China. It can treat type 2 diabetes mellitus and regulate metabolism by modestly activating PPARα, PPARγ, and PPARδ to improve insulin sensitivity, regulate blood glucose, and promote fatty acid oxidation and utilization. Chiglitazar sodium has a significant insulin-sensitizing effect and is advantageous in reducing fasting and postprandial blood glucose levels, particularly at the 48 mg dose in patients with concomitant high triglycerides in terms of blood glucose and triglyceride level control.

Efficacy and safety of novel biologics in the treatment of lupus nephritis based on registered clinical trials: a systematic review and network meta-analysis.

To compare the clinical effectiveness and safety of novel biologics for the treatment of lupus nephritis based on a reticulated meta-analysis approach. Registered clinical trials in 4 major databases (PubMed, Embase, Web of Science, The Cochrane Register of Clinical Trials) and ClinicalTrials.gov were systematically searched with a search time frame of build to June 2022. And we screened registered randomized controlled clinical trials of biologics for the treatment of lupus nephritis according to the protocol's nadir criteria. Trials were evaluated for quality using the Cochrane Risk of Bias Assessment Tool, and data were statistically analyzed using Stata 16.0 and Review Manager 5.3 software to compare and rank differences in effectiveness and safety between the biologics. A total of 10 registered randomized controlled clinical trials involving 2148 subjects were included in this study. The interventions were ranked from best to worst in terms of the primary outcome indicator of effectiveness, renal complete remission: belimumab > anifrolumab (900 + 300) mg > obinutuzumab > ocrelizumab 400 mg > abatacept 30/10 mg/kg > belimumab + rituximab > abatacept 10/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > ocrelizumab 1000 mg > rituximab > anifrolumab 300 mg, belimumab was superior to placebo [OR = 1.75, 95% CI (1.13, 2.70)] and anifrolumab 300 mg [OR = 3.27, 95% CI (1.05, 10.14)], anifrolumab (900 + 300) mg was superior to anifrolumab 300 mg [OR = 3.56, 95% CI (1.30, 9.76)], and all were statistically significant. The ranking of each intervention in terms of overall renal remission for secondary outcome indicators from best to worst was: obinutuzumab > belimumab + rituximab > anifrolumab (900 + 300) mg > ocrelizumab 1000 mg > ocrelizumab 400 mg > belimumab > rituximab 1000 mg > abatacept 30/10 mg/kg > abatacept (30/10 + 10/10) mg/kg > placeo > abatacept 10/10 mg/kg > anifrolumab 300 mg, obinutuzumab was superior to placebo [OR = 2.27, 95% CI (1.11, 4.67)] and belimumab was also superior to placebo [OR = 1.56, 95% CI (1.07, 2.27)], and all were statistically significant. In terms of safety, with a focus on serious adverse events and serious infections, the results were: Serious adverse events at 1 year of monitoring occurred better with ocrelizumab 1000 mg than ocrelizumab 400 mg [OR = 0.51, 95% CI (0.29, 0.89)] and were statistically different; serious adverse events at 2 years of monitoring infection adverse events occurred better with obinutuzumab than with abatacept (30/10 + 10/10) mg/kg [OR = 0.24, 95% CI (0.07, 0.81)] and were statistically different. The safety of the new biologics in combination with conventional standard therapies is generally good, but it is belimumab and obinutuzumab that are most effective in achieving complete and overall remission in the kidney. This study protocol has been registered with PROSPERO, with a registration number of CRD42021262498.

[Preparation and physiochemical properties of curcumin-loaded lipid cubic liquid crystalline nanoparticles].

OBJECTIVE: To prepare curcumin-loaded lipid cubic liquid crystalline nanoparticles and evaluate its physiochemical properties. METHODS: The nanoparticles were prepared using hot and high-pressure homogenization. The prescription and preparation process were optimized by uniform design with drug loading and entrapment efficiency as indexes. RESULTS: The nanoparticles were spherical under transmission electron microscope (TEM) with average particle size of 176.1 nm, zeta potential of -25.19 mV, average drug loading of (1.5 +/- 0.2)% and entrapment efficiency of (95 +/- 1.8)%. The release equation: In (1-Q) = -0.0251t-0.0075. The cumulative release percentage was 60% at 36 h in vitro. CONCLUSION: The obtained curcumin-loaded lipid cubic liquid crystalline nanoparticles shows high entrapment efficiency and good sustain release property.

Urinary metabolomics study of vancomycin-associated nephrotoxicity based on ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

Drug-induced nephrotoxicity is widespread and seriously affects human health. Vancomycin is a classical glycopeptide antibiotic. Vancomycin is widely used for severe infections caused by Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus but its obvious nephrotoxicity affects the safety of its clinical application. However, the etiology of vancomycin induced kidney injury is not well understood. This study aimed to explore the potential mechanism of vancomycin-induced nephrotoxicity in rats. Vancomycin (400 mgkg-1) was used to establish kidney injury models in rats. A metabonomic approach was employed using ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) to delineate metabolic alterations. As a result, 15, 22, and 37 biomarkers were identified in urine samples from the treatment group compared to the control model on D2, D4, and D7, respectively. Changes in the levels of these metabolites indicated that amino acid metabolism and energy metabolism were disturbed in rats with vancomycin-associated nephrotoxicity. This study revealed the kidney effect of vancomycin, which may provide novel and promising research approaches to vancomycin-induced renal toxicity.

Hofmeister effects on activity and stability of alkaline phosphatase.

We have studied the effects on alkaline phosphatase of adding high concentrations (normally 1.0 M) of simple salts. It is necessary to allow for significant effects of salts on the extinction coefficient of the reaction product, and on the apparent pH of the buffer. Both activity and stability of the enzyme correlate well with the Hofmeister series in terms of the salt's kosmotropic/chaotropic properties, which are assessed by the Jones-Dole viscosity B coefficients (B(+) for cations and B(-) for anions). The catalytic activity or V(max)/K(m) of the enzyme showed a bell-shaped relationship with the (B(-)-B(+)) values of the salts present, being optimal with salts (such as NaCl, KCl, and KNO(3)) where the anion and cation have similar kosmotropic/chaotropic properties. This effect is believed to be enzyme-specific and relates to the impact of both cations and anions on the enzyme's surface pH, active site, and catalytic mechanism. Anions play a more predominant role than cations in affecting enzyme stability. The rate of irreversible thermal inactivation is strongly reduced by addition of kosmotropic anions like SO(4)(2-) (half-life increased from 8 to 580 min at 60 degrees C). This effect is general and the mechanism probably involves the ability of the ions to affect the water solvation layer around the enzyme molecule and to interact with both the surface and internal structure of the enzyme.

Construction and properties of the antibacterial epitaxial transition layer on a zirconia ceramic surface.

Secondary caries is one of the main causes of dental zirconia restoration failure in the clinic. Therefore, it is urgent to improve the antibacterial performance of zirconia ceramics to reduce the occurrence of secondary caries. In this study, a quaternary ammonium compound antibacterial polymer was innovatively synthesized by solution polymerization with a quaternary ammonium salt monomer as the antibacterial component. The antibacterial epitaxial transition layer was successfully prepared on the surface of zirconia ceramics by the hydroxyl group on HEMA reacting with the siloxane group in the KH570 hydrolysate, which makes the antibacterial polymer indirectly chemically combine with the silicate epitaxial transition layer. The antibacterial epitaxial transition layer exhibited excellent mechanical properties, satisfactory biocompatibility and significant antibacterial effects, and the maximum antibacterial rate is 99%. The antibacterial epitaxial transition layer plays an important role in preventing secondary caries and improving the success rate of clinical zirconia ceramic restorations.

Leflunomide Suppresses the Growth of LKB1-Inactivated Tumors in the Immune-Competent Host and Attenuates Distant Cancer Metastasis.

Liver kinase B1 (LKB1)-inactivated tumors are vulnerable to the disruption of pyrimidine metabolism, and leflunomide emerges as a therapeutic candidate because its active metabolite, A77-1726, inhibits dihydroorotate dehydrogenase, which is essential for de novo pyrimidine biosynthesis. However, it is unclear whether leflunomide inhibits LKB1-inactivated tumors in vivo, and whether its inhibitory effect on the immune system will promote tumor growth. Here, we carried out a comprehensive analysis of leflunomide treatment in various LKB1-inactivated murine xenografts, patient-derived xenografts, and genetically engineered mouse models. We also generated a mouse tumor-derived cancer cell line, WRJ388, that could metastasize to the lung within a month after subcutaneous implantation in all animals. This model was used to assess the ability of leflunomide to control distant metastasis. Leflunomide treatment shrank a HeLa xenograft and attenuated the growth of an H460 xenograft, a patient-derived xenograft, and lung adenocarcinoma in the immune-competent genetically engineered mouse models. Interestingly, leflunomide suppressed tumor growth through at least three different mechanisms. It caused apoptosis in HeLa cells, induced G1 cell-cycle arrest in H460 cells, and promoted S-phase cell-cycle arrest in WRJ388 cells. Finally, leflunomide treatment prevented lung metastasis in 78% of the animals in our novel lung cancer metastasis model. In combination, these results demonstrated that leflunomide utilizes different pathways to suppress the growth of LKB1-inactivated tumors, and it also prevents cancer metastasis at distant sites. Therefore, leflunomide should be evaluated as a therapeutic agent for tumors with LKB1 inactivation.

Effect of chronic intermittent hypoxia on biological behavior and hypoxia-associated gene expression in lung cancer cells.

Hypoxia plays an important role in the development of solid tumors and is associated with their therapeutic resistance. There exist three major forms of hypoxia: acute, chronic, and intermittent hypoxia. Previous studies have shown that cancer cells could behave in the form of adaptation to hypoxia in tumor growth, which could result in their biological changes and determine their responses to the therapies. To investigate the tumor cells' adaptation to hypoxia, we recreated two models using two lung cancer cell lines in the presence of intermittent hypoxia, which is characterized by changes in oxygen pressure within the disorganized vascular network. We investigated biological behaviors such as cell cycle, proliferation, radiation sensitivity, apoptosis and migration, hypoxia signal pathway in the lung cancer cells treated with chronic intermittent hypoxia, as well as the role of hypoxia inducible factor 1 there, hypoxia-inducible genes analyzed by real-time RT-PCR chip in H446 cells treated with the model. The results indicated the changes of some hypoxia target gene expressions of those induced by hypoxia, some of which were confirmed by real-time RT-PCR. The cells mediated by irradiation induced resistance to radiation and apoptosis and increased metastasis in lung cancer cells. It was found that such changes were related to hypoxia inducible factor 1, alpha subunit (HIF-1α).

Investigating the shear bond strength of five resin-based luting agents to zirconia ceramics.

The present study investigated the bond strength and aging resistance performance of five resin-based luting agents to zirconia. A total of 100 large blocks (10.0 mm × 10.0 mm × 2.5 mm) and 100 small blocks (4.0 mm × 4.0 mm × 2.5 mm) of zirconia were airborne-particle abraded and randomly divided into five groups: (RelyX Ultimate [RUl]; Panavia F [PF]; Clearfil SA Luting [SAC]; Multilink Speed [MS]; and RelyX Unicem [RUn]). The small blocks were bonded to the large blocks using the resin-based luting agents. Shear bond strengths (SBS) and failure mode were determined before and after 5,000 thermocycles. After being stored in water for 24 h, the SBS were MS > PF > RUl > SAC > RUn (P < 0.05). After 5,000 thermocycles, the SBS were MS > SAC ≈ RUl > PF ≈ RUn (P < 0.05); the SBS of the PF, MS, and RUn groups were lower than that before 5,000 thermocycles (P < 0.01). Adhesive failure, cohesive failure, or mixed failure occurred in the specimens. In general, Clearfil SA Luting, a self-adhesive resin-based luting agent containing 10-methacryloxy decyl diphosphate, had good initial and durable SBS to zirconia and was a better adhesive.

Construction of a silicate-based epitaxial transition film on a zirconia ceramic surface to improve the bonding quality of zirconia restorations.

The effect of a silicate-based epitaxial transition film on zirconia produced by a silicate solution during zirconia-resin bonding was investigated. The airborne-particle abraded zirconia was placed in different concentrations of silicate solutions and heated at 50 °C. The silicate transition film was characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), energy-dispersive X-ray spectroscopy (EDX), contact angle measurement and profilometry. The silicate-based epitaxial transition film was successfully constructed on the surface of zirconia, and the surface morphology and composition of zirconia changed. After coupling with KH570 hydrolysate, the shear bond strength (SBS) of zirconia-resin after either 24 h water storage or 5000 thermal cycles can be significantly improved by a silicate-based epitaxial transition film on the surface of zirconia, and all the samples had no cytotoxicity. This may provide a new strategy for improving the bonding quality of zirconia restorations.