Pharmacokinetics, tissue distribution, and antitumor activity of a novel compound, NY-2, in non-small cell lung cancer

Introduction: ZLDI-8, which has a relatively strong antitumor activity, is an inhibitor of ADAM-17 and acts on the Notch signaling pathway. To further optimize its structure and improve its activity, a series of derivatives of ZLDI-8 was synthesized. NY-2 was the most effective derivative based on preliminary activity screening in vitro, with no obvious toxicity after administration in vivo.Method: The study aimed to determine the pharmacokinetics, tissue distribution, hepatotoxicity, nephrotoxicity, and antitumor activity of compound NY-2 on non-small cell lung cancer (NSCLC) in vitro and in vivo.Results: The in vivo pharmacokinetics parameters of NY-2 were better than those of ZLDI-8. The tissue distribution analysis showed that tail vein injection of 6 mg/kg of NY-2 in rats resulted in the highest concentration in the lung, so we hypothesized that NY-2 might be effective in the treatment of non-small cell lung cancer. In vitro assays showed that NY-2 significantly inhibited tumor colony formation, invasion, and migration and increased LDH activity and apoptosis in a concentration-dependent manner in non-small cell lung cancer cells. NY-2 also inhibited the formation of lung metastases without significant toxicity to major organs in nude mice.Conclusion: Compared with the parent compound, ZLDI-8, the activity and safety of NY-2 were higher. NY-2 acts on ADAM17 and simultaneously affects the downstream Notch1 and integrinβ1 signaling pathways resulting in antitumor activity. Thus, NY-2 could be a potential antitumor agent, inhibiting the organization and development of non-small cell lung cancer

Effect of thyroid hormone replacement treatment on cardiac diastolic function in adult patients with subclinical hypothyroidism: a meta-analysis

BackgroundAlthough subclinical hypothyroidism (SCH) is related to abnormalities in left ventricular diastolic function, the use of levothyroxine as a regular treatment remains debatable. This meta-analysis aimed to determine whether thyroid hormone replacement therapy affects cardiac diastolic function in patients with SCH as measured by echocardiography.MethodsThis meta-analysis included a search of the EMBASE, PubMed, Web of Science, and Cochrane Library databases from their inception to May 18, 2023, for studies analyzing cardiac morphology and functional changes in patients with SCH before and after thyroid hormone replacement. The outcome measures were cardiac morphology and diastolic and overall cardiac function, as assessed using ultrasound parameters (including ventricular wall thickness, chamber size, mitral wave flow, tissue Doppler, and speckle tracking). The quality of the studies was assessed using the Newcastle–Ottawa Scale. The standard mean differences (MDs) and 95% confidence intervals (CI) were calculated using fixed- or random-effects models.ResultsSeventeen studies met the inclusion criteria. A total of 568 patients participated and completed the follow-up. All studies specifically stated that serum thyrotropin levels returned to normal by the end of the study period. Compared with baseline levels, no significant morphological changes were observed in the heart. In terms of diastolic function, we discovered that the ratios of E-velocity to A-velocity (E/A) had greatly improved after thyroid hormone replacement therapy, whereas the ratios of the mitral inflow E wave to the tissue Doppler e’ wave (E/e’) had not. Global longitudinal strain (GLS) increased significantly after treatment with levothyroxine.ConclusionIn adult patients with SCH, thyroid hormone supplementation can partially but not completely improve parameters of diastolic function during the observation period. This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement, an updated guideline for reporting systematic reviews (11) and was registered with INPLASY (INPLASY202320083).Systematic review registrationhttps://inplasy.com/inplasy-2023-2-0083

Angiectatic nasal polyps with pleomorphism ‒ a diagnostic pitfall

Objective: To generalise the features of PANP in case of potential clinical and pathological pitfall of diagnosis. Methods: Thirteen patients diagnosed as PANP were retrospectively analyzed in the Pathology Department of Capital Medical University from August 2014 to December 2019. Immunohistochemical staining with CD34, CK, Vim, Calponin, Ki67, Bcl-2, and STAT-6 was performed with envision-two steps method. Results: PANP is a benign tumor presenting with gross variegated tan to gray soft fleshy tissue with foci of obvious hemorrhage and necrosis. The imaging shows internal heterogeneous hyperintensity with a peripheral hypointense rim while postcontrast images display a strong nodular and patchy enhancement. Vimentin (Vim) stain was consistently positive, while negative for CD34, STAT-6 and Bcl-2 (focal positive in two cases). Calponin and CK stain was positive in nine cases, respectively. Conclusion: PANP is a clinically rare tumor which may simulate malignancy lesion. Recognizing of characteristic features in these thirteen patients would be beneficial to avoid misdiagnosis and unnecessary aggressive treatment. Level of evidence: This work was Level 2 of evidence according to the Guide for Authors

Which Is the Most Appropriate PI3K Inhibitor for Breast Cancer Patients with or without PIK3CA Status Mutant? A Systematic Review and Network Meta-Analysis

Objective. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is a promising treatment target for patients with breast cancer (BC). Our study aimed to evaluate the most effective and safe PI3K inhibitor for patients with BC, especially in PIK3CA mutation. Methods. Electronics databases were systematically searched from their inception to June 2020 for published randomized controlled trials (RCTs) comparing PI3K inhibitor therapy versus non-PI3K inhibitor therapy in patients with BC that mentioned or reported data of PIK3CA-mutated patient subgroups. Eligible RCTs had to report at least one of the following clinical outcomes: objective response rate (ORR), progression-free survival (PFS), or adverse events (AE). Results. Nine eligible RCTs involving 3872 BC patients and four PI3K inhibitor therapy arms (i.e., alpelisib, buparlisib, pictilisib, and taselisib) were included. In evaluating ORR, beneficial significant results of PI3K inhibitors could be found in the PIK3CA mutated group (1.952, 1.012 to 3.766); analogous results could also be found in 6m-PFS (1.519, 1.144 to 2.018) and PFS from HR data (-0.346, -0.525 to -0.168). From pairwise and network meta-analyses, buparlisib showed the most favorable ORR, as it was significantly different from fulvestrant in the PIK3CA-mutated patient group (2.80, 1.56 to 5.03). Alpelisib ranked first in the assessment of 6m-PFS and was significantly different from fulvestrant in the PIK3CA-mutated group (2.33, 1.45 to 3.44). The above PI3K inhibitors had good safety with few serious AEs. PROSPERO registration CRD42020193932. Conclusion. The PI3K inhibitors alpelisib and buparlisib appear to have superior efficacy and safety therapeutic choices for patients with BC, especially in PIK3CA-mutated patients

Study on the mechanism and response law of fracture movement on the super-high position hard-thick strata

Abstract In this paper, a thick plate structural mechanical model was established for the hard-thick rock strata in the Ordos region, which was characterized by the occurrence of high-energy strong earthquakes caused by the fracture of hard-thick rock strata. Subsequently, based on Vlasov's theory, the evolution process of hard-thick rock strata was analyzed. And the paper validated the analysis results using high-energy mine earthquake and surface subsidence data. The following conclusions were drawn: (1) The hard-thick strata in the cretaceous system will not be broken during the advancing and mining process of the test panel of the Shilawusu coal mine. (2) When the test panel is mined to a distance of two panel widths, no fracture occurred in the lower part of the hard-thick strata, because no separated space was formed. (3) When the test panel was advanced to about 856 m, the hard-thick strata have fractured in a vertical direction. (4) No high-energy mine earthquake event has occurred during mining at test panel, and the amount of surface subsidence is approximately 200 mm. (5) In the mining at test panel, two high-energy mining earthquakes occurred at 837 m, 1153 m away from the initial position of the panel, respectively, and the maximum amount of surface subsidence increased to 1397 mm, which accords with the results of the first and periodic breaks calculated by theory. The research results of this paper are of guiding significance for the study of the breaking law of hard-thick strata under similar engineering geological conditions and disaster pre-control

Safety and immunogenicity of a quadrivalent influenza vaccine in adults aged 60 years or above: a phase III randomized controlled clinical study

To control seasonal influenza epidemics in elders, a quadrivalent, inactivated, split-virion influenza vaccine (IIV4) comprising A and B lineages is produced for young individuals and adults aged ≥60 years. In this phase III, randomized, double-blind, active-controlled trial, we compared safety and immunogenicity of IIV4 with a licensed quadrivalent inactivated vaccine (IIV4-HL) produced by Hualan Biological Engineering during the 2019 influenza season. Participants were randomly assigned to receive IIV4 (n = 959) or IIV4-HL (n = 959). Compared to IIV4-HL, geometric mean titers (GMT) of hemagglutination inhibition (HAI) titers and seroconversion rate (SCR) of IIV4 demonstrated better antibody responses in A lineages (H1N1 and H3N2) (P  .01) in both age groups. After immunization, IIV4 provided a satisfactory SCR and seroprotection rate (SPR) in elders. No discernible variation in immunogenicity was observed between the two age cohorts. In both age groups, IIV4 and IIV4-HL recipients experienced similar levels of solicited and unsolicited adverse events (AEs), and the incidence of AEs was low in both vaccine groups. Most AEs were of mild-to-moderate severity and no grade 3 AEs in IIV4 group, but AEs in adults aged 60–65 were little higher than in adults over 65 years in IIV4 and IIV4-HL groups (IIV4: 14.66% vs. 10.36%; IIV4-HL:14.67% vs. 11.43%). Totally, IIV4 was generally well tolerated and induced high antibody titers against all four influenza strains in elderly, making it a compelling alternative for the elderly aged ≥60 years. Trial registration: Clinical Trials.gov: 2015L00649-2