DataSheet_1_A bidirectional causal relationship study between mental disorders and male and female infertility.docx

BackgroundThe relation between mental disorders (MDs) and infertility can be reciprocal. But exactly which MD affects infertility remains controversial. Our aim was to use Mendelian randomization (MR) to explore bidirectional causality between 15 MDs and male infertility and female infertility.MethodsThe data of MDs, male infertility, and female infertility were derived from published genome-wide association studies (GWAS). The inverse variance weighted method was considered to be the main analytical approach. Sensitivity analysis was performed using MR-Egger, Cochran’s Q, radial MR, and MR-PRESSO tests.ResultsOur results found that mood disorders (OR, 1.4497; 95% CI, 1.0093 – 2.0823; P = 0.0444) and attention deficit hyperactivity disorder (OR, 1.3921; 95% CI, 1.0943 – 1.7709; P = 0.0071) were positively correlated with male infertility, but obsessive-compulsive disorder (OR, 0.8208; 95% CI, 0.7146 – 0.9429; P = 0.0052) was negatively associated with male infertility. For females, anorexia nervosa (OR, 1.0898; 95% CI, 1.0070 – 1.1794; P = 0.0329), attention deficit hyperactivity disorder (OR, 1.1013; 95% CI, 1.0041 – 1.2079; P = 0.0406), and major depressive disorder (OR, 1.1423; 95% CI, 1.0213 – 1.2778; P = 0.0199) increased risk of infertility. In reverse relationship, female infertility increased the incidence of bipolar disorder (OR, 1.0009; 95% CI, 1.0001 – 1.0017; P = 0.0281).ConclusionWe demonstrated the association between five MDs and male or female infertility. Female infertility was also found to be associated with an increased risk of one MD. We look forward to better designed epidemiological studies to support our results.</p

DataSheet_1_Efficacy and toxicity of immune checkpoint inhibitors combination therapy for advanced renal cell carcinoma: a systematic review and network meta-analysis.docx

BackgroundAlthough immune checkpoint inhibitors (ICIs) show a significant overall survival advantage over standard advanced renal cell carcinoma (aRCC) therapies, tumor response to these agents remains poor. Some studies have shown that combination therapy including an ICI appears to be the best treatment; however, the overall benefit in terms of efficacy and toxicity still needs to be assessed. Thus, we performed a network meta-analysis to evaluate the differences in the efficacy of several combinations that include an ICI to provide a basis for clinical treatment selection.MethodsWe conducted a thorough search of PubMed, EMBASE, and the Cochrane Library for articles from January 2010 to June 2023. R 4.4.2 and STATA 16.0 were used to analyze data; hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CI) were used to assess the results.ResultsAn indirect comparison showed that nivolumab plus cabozantinib and pembrolizumab plus lenvatinib were the most effective treatments for progression-free survival (PFS), with no significant differences between the two interventions (HR, 1.31; 95% CI, 0.96–1.78; P=0.08); rank probability showed that pembrolizumab plus lenvatinib had a 57.1% chance of being the preferred treatment. In the absence of indirect comparisons between pembrolizumab plus axitinib, nivolumab plus ipilimumab, avelumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib, pembrolizumab plus axitinib (40.2%) was the best treatment option for overall survival (OS). Compared to pembrolizumab plus lenvatinib, nivolumab plus ipilimumab (OR, 0.07; 95% CI, 0.01–0.65; P=0.02) and pembrolizumab plus axitinib (OR, 0.05; 95% CI, 0.00–0.78; PConclusionPembrolizumab plus lenvatinib and pembrolizumab plus axitinib resulted in the highest PFS and OS rates, respectively. Pembrolizumab plus axitinib may be the best option when AEs are a concern.Systematic review registrationhttps://inplasy.com/, identifier INPLASY202410078.</p

DataSheet_1_Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modeling of cetagliptin in patients with type 2 diabetes mellitus.docx

AimsTo evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cetagliptin (CAS number:2243737-33-7) in Chinese patients with type 2 diabetes mellitus (T2DM). A population PK/PD model was developed to quantify the PK and PD characteristics of cetagliptin in patients.Materials and methods32 Chinese adults with T2DM were enrolled in this study. The subjects were randomly assigned to receive either cetagliptin (50 mg or 100 mg), placebo, or sitagliptin (100 mg) once daily for 14 days. Blood samples were collected for PK and PD analysis. Effects on glucose, insulin, C-peptide, and glucagon were evaluated following an oral glucose tolerance test (OGTT) (day15). Effects on HbA1c and glycated albumin (GA), and safety assessments were also conducted. Meanwhile, a population PK/PD model was developed by a sequential two-step analysis approach using Phoenix.ResultsFollowing multiple oral doses, cetagliptin was rapidly absorbed and the mean half-life were 34.9-41.9 h. Steady-state conditions were achieved after 1 week of daily dosing and the accumulation was modest. The intensity and duration of DPP-4 inhibition induced by 50 mg cetagliptin were comparable with those induced by sitagliptin, and 100 mg cetagliptin showed a much longer sustained DPP-4 inhibition (≥80%) than sitagliptin. Compared with placebo group, plasma active GLP-1 AUEC0-24h increased by 2.20- and 3.36-fold in the 50 mg and 100 mg cetagliptin groups. A decrease of plasma glucose and increase of insulin and C-peptide were observed following OGTT in cetagliptin groups. Meanwhile, a tendency of reduced GA was observed, whereas no decreasing trend was observed in HbA1c. All adverse events related to cetagliptin and sitagliptin were assessed as mild. A population PK/PD model was successfully established. The two-compartment model and Sigmoid-Emax model could fit the observed data well. Total bilirubin (TBIL) was a covariate of volume of peripheral compartment distribution (V2), and V2 increased with the increase of TBIL.ConclusionsCetagliptin was well tolerated, inhibited plasma DPP-4 activity, increased plasma active GLP-1 levels, and exhibited a certain trend of glucose-lowering effect in patients with T2DM. The established population PK/PD model adequately described the PK and PD characteristics of cetagliptin.</p

Rakicidin J and K, two cytotoxic and antibacterial cyclic depsipeptides from the marine bacterium <i>Micromonospora chalcea</i>

Rakicidin J (1) and rakicidin K (2), two new cyclic depsipeptides, were isolated from culture broth of Micromonospora chalcea FIM-R150103. Their structures were elucidated by extensive analysis of NMR, HR-ESI-MS, and electronic circular dichroism (ECD) data. The two compounds showed strong cytotoxic activity against human colon carcinoma HCT-8 and human pancreatic cancer PANC-1 cells under normoxic and hypoxic conditions in the range of IC50 values from 0.024 to 0.79 μg/mL. Moreover, compounds 1 and 2 also showed moderate antibacterial activity against ten Gram-positive bacterial strains with MIC values ranging from 4 to more than 32 μg/mL. Structure–activity relationship of these two compounds with a close analogue, rakicidin B1, is also discussed.</p

Enhancing the Osteogenic Capability of Core–Shell Bilayered Bioceramic Microspheres with Adjustable Biodegradation

This study describes the fabrication and biological evaluation of core–shell bilayered bioceramic microspheres with adjustable compositional distribution via a coaxial bilayer capillary system. Beyond the homogeneous hybrid composites, varying the diameter of capillary nozzles and the composition of the bioceramic slurries makes it easy to create bilayered β-tricalcium phosphate (CaP)/β-calcium silicate (CaSi) microspheres with controllable compositional distribution in the core or shell layer. Primary investigations in vitro revealed that biodegradation could be adjusted by compositional distribution or shell thickness and that poorly soluble CaP located on the shell layer of CaP or CaSi@CaP microspheres was particularly beneficial for mesenchymal stem cell adhesion and growth in the early stage, but the ion release from the CaP@CaSi exhibited a potent stimulating effect on alkaline phosphatase expression of the cells at longer times. When the bilayered microspheres (CaSi@CaP, CaP@CaSi) and the monolayered microspheres (CaP, CaSi) were implanted into the critical-sized femoral bone defect in rabbit models, significant differences in osteogenic capacity over time were measured at 6–18 weeks post implantation. The CaP microspheres showed the lowest biodegradation rate and slow new bone regeneration, whereas the CaSi@CaP showed a fast degradation of the CaSi core through the porous CaP shell so that a significant osteogenic response was observed at 12–18 weeks. The CaP@CaSi microspheres possessed excellent surface bioactivity and osteogenic activity, whereas the CaSi microspheres group exhibited a poor bone augmentation in the later stage due to extreme biodegradation. These findings demonstrated that the bioactive response in such core–shell-structured bioceramic systems could be adjusted by compositional distribution, and this strategy can be used to fabricate a variety of bioceramic microspheres with adjustable biodegradation rates and enhanced biological response for bone regeneration applications in medicine

The inconsistant results of specimens genotyping with the partial gene of RdRp or VP1 of NoV.

<p>Note: ‘--’means the specimen was not successfully genotyped.</p

The Maximum Likelihood (ML) phylogenetic tree was constructed with partial nucleotide sequences of ORF1(326 bp) using the primers of JV12/JV13.

<p>▴ represented reference strains including New Orleans 2009 (GQ845367), Kenepuru NZ327 (EF187497), Terneuzen70 (EF126964), Hunter 2004 (DQ078814), Apeldoorn2008 (HQ009513), Niigata12008 (AB541310), Henry 2001(EU310927), US 1995/96 (AY741811), Farmington Hill 2002 (AY502023), Shellharbour (EF684915), Nijimegen115 (EF126966),Camberwell 1994 (AF145896), Lordsdale 1993 (X86557), Hawaii (U07611), Saitama U1 (AB039775), Goulburn Vally G5175 (DQ379714), Melksham (X81879), Toronto (U02030),Hokkaido (AB212306), DesertShield (U04469), Norwalk (M87661), Southampton (L07418), Chiba407 (AB042808),VA97207 (AY038599).</p

The Maximum Likelihood (ML) phylogenetic tree was constructed with partial nucleotide sequences of ORF2(265 bp).

<p>▴ represented reference strains including Shellharbour (EF684915), Asia 2003 (DQ369797), Henry 2001(EU310927), Farmington Hill 2002 (AY502023), Kenepuru/NZ327 (EF187497), Hunter 2004 (DQ078814), New Orleans 2009 (GQ845367), Apeldoorn2008 (HQ009513), US 1995/96 (AY741811), Osaka 2007 (AB541319), Camberwell 1994 (AF145896), Lordsdale 1993 (X86557), VA97207 (AY038599), Amsterdam (AF195848), Leeds(AJ277608), Toronto (U02030), Hillingdon (AJ277607), Melksham (X81879), Erfurt (AF427118), Hawaii (U07611), Wortley (AJ277618), Saitama U1 (AB039775), Seacroft (AJ277620), DesertShield(U04469), Winchester(AJ277609), Boxer (AF538679), Chiba407(AB042808), Norwalk (M87661), Southampton (L07418), Hesse/BS5 (AF093797), Musgrove(AJ277614), Goulburn Vally G5175 (DQ379714).</p

Effects of CYP3A4*1G and CYP3A5*3 polymorphisms on pharmacokinetics of tylerdipine hydrochloride in healthy Chinese subjects

<p></p><p>The aim of this analysis was to explore the influence of CYP3A4*1G and CYP3A5*3 polymorphisms on the pharmacokinetics of tylerdipine in healthy Chinese subjects.</p><p>A total of 64 and 63 healthy Chinese subjects were included and identified as the genotypes of CYP3A4*1G and CYP3A5*3, respectively. Plasma samples were collected for up to 120 h post-dose to characterize the pharmacokinetic profile following single oral dose of the drug (5, 15, 20, 25 and 30 mg). Plasma levels were measured by a high-performance liquid chromatography-mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated using non-compartmental method. The maximum concentration (<i>C</i>_max) and the area under the curve (AUC_0–24 h) were all corrected by the dose given.</p><p>In the wild-type group, the mean dose-corrected AUC_0–24 h was 1.35-fold larger than in CYP3A4*1G carriers (<i>p</i> = .018). Among the three CYP3A5 genotypes, there showed significantly difference (<i>p</i> = .008) in the <i>t</i>_1/2, but no significant difference was observed for the AUC_0–24 h and <i>C</i>_max. In subjects with the CYP3A5*3/*3 genotype, the mean <i>t</i>_1/2 was 1.35-fold higher than in CYP3A5*1/*1 group (<i>p</i> = .007). And the <i>t</i>_1/2 in CYP3A5*3 carriers also was 1.32-fold higher than in the wild-type group (<i>p</i> = .004).</p><p>CYP3A4*1G and CYP3A5*3 polymorphisms may influence tylerdipine pharmacokinetic in healthy Chinese subjects.</p><p></p> <p>The aim of this analysis was to explore the influence of CYP3A4*1G and CYP3A5*3 polymorphisms on the pharmacokinetics of tylerdipine in healthy Chinese subjects.</p> <p>A total of 64 and 63 healthy Chinese subjects were included and identified as the genotypes of CYP3A4*1G and CYP3A5*3, respectively. Plasma samples were collected for up to 120 h post-dose to characterize the pharmacokinetic profile following single oral dose of the drug (5, 15, 20, 25 and 30 mg). Plasma levels were measured by a high-performance liquid chromatography-mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated using non-compartmental method. The maximum concentration (<i>C</i>_max) and the area under the curve (AUC_0–24 h) were all corrected by the dose given.</p> <p>In the wild-type group, the mean dose-corrected AUC_0–24 h was 1.35-fold larger than in CYP3A4*1G carriers (<i>p</i> = .018). Among the three CYP3A5 genotypes, there showed significantly difference (<i>p</i> = .008) in the <i>t</i>_1/2, but no significant difference was observed for the AUC_0–24 h and <i>C</i>_max. In subjects with the CYP3A5*3/*3 genotype, the mean <i>t</i>_1/2 was 1.35-fold higher than in CYP3A5*1/*1 group (<i>p</i> = .007). And the <i>t</i>_1/2 in CYP3A5*3 carriers also was 1.32-fold higher than in the wild-type group (<i>p</i> = .004).</p> <p>CYP3A4*1G and CYP3A5*3 polymorphisms may influence tylerdipine pharmacokinetic in healthy Chinese subjects.</p